Gut microbiota

{{short description|Community of microorganisms in the gut}} {{redirect|Enteric bacteria}} {{distinguish|Gut Microbes}} {{Use American English|date=March 2025}} {{Use dmy dates|date=March 2025}} {{cs1 config|name-list-style=vanc|display-authors=3}}

[[File:E. coli Bacteria (7316101966).jpg|thumb|right|''Escherichia coli'', one of the many species of bacteria present in the human gut]] '''Gut microbiota''', '''gut microbiome''', or '''gut flora''' are the microorganisms, including bacteria, archaea, fungi, and viruses, that live in the digestive tracts of animals.<ref name="Moszak">{{Cite journal |last1=Moszak |first1=M |last2=Szulińska |first2=M |last3=Bogdański |first3=P |date=15 April 2020 |title=You Are What You Eat – The Relationship between Diet, Microbiota, and Metabolic Disorders-A Review. |journal=Nutrients |volume=12 |issue=4 |page=1096 |doi=10.3390/nu12041096 |pmc=7230850 |pmid=32326604 |doi-access=free }}</ref><ref name="Engel"/> The gastrointestinal metagenome is the aggregate of all the genomes of the gut microbiota.<ref name="Segata">{{Cite journal |last1=Segata |first1=N |last2=Boernigen |first2=D |last3=Tickle |first3=TL |last4=Morgan |first4=XC |last5=Garrett |first5=WS |last6=Huttenhower |first6=C |date=14 May 2013 |title=Computational meta'omics for microbial community studies. |journal=Molecular Systems Biology |volume=9 |article-number=666 |doi=10.1038/msb.2013.22 |pmc=4039370 |pmid=23670539 |doi-access=free}}</ref><ref name="Saxena2016">{{Cite book |last1=Saxena |first1=R. |title=Medical and Health Genomics |last2=Sharma |first2=V.K |publisher=Elsevier Science |year=2016 |isbn=978-0-12-799922-7 |editor-first1=D. |editor-last1=Kumar |page=117 |chapter=A Metagenomic Insight Into the Human Microbiome: Its Implications in Health and Disease |doi=10.1016/B978-0-12-420196-5.00009-5 |editor-last2=S. Antonarakis |chapter-url=https://books.google.com/books?id=3ylOBQAAQBAJ&pg=PA117}}</ref> The gut is the main location of the human microbiome.<ref name="Prescotts" /> The gut microbiota has broad impacts, including effects on colonization, resistance to pathogens, maintaining the intestinal epithelium, metabolizing dietary and pharmaceutical compounds, controlling immune function, and even behavior through the gut–brain axis.<ref name="Saxena2016" /> Imbalances in the gut microbiota (dysbiosis) have been associated with numerous diseases, including inflammatory bowel disease, certain cancers, and even neurological disorders, prompting increased efforts to develop microbiome-targeted therapies.<ref>El Boukhari R, Matin M, Bouissane L, Ławiński M, Lushchak O, Singla RK, Mickael ME, Mayneris-Perxachs J, Grafakou ME, Xu S, Liu B, Guan J, Półtorak A, Szpicer A, Wierzbicka A, Tzvetkov NT, Banach M, Horbańczuk JO, Jóźwik A, Cascella M, Shen B, Pirgozliev VR, Wang D, Litvinova O, Adamska O, Kamińska A, Łapiński M, Stolarczyk A, Berindan-Neagoe I, Milella L, Yeung AWK, Suravajhala P, Bishayee A, Lordan R, Iantovics LB, Lagoa R, Michalczuk M, Stoyanov J, Kinghorn AD, Jalil B, Weckwerth W, Goh BH, Li MY, Chaubey G, Russo GL, Frazzini S, Rossi L, Battino M, Jia W, Su Q, Ma X, Rollinger JM, Rittmann SKR, Sheridan H, Walsh JJ, Lizard G, Karpiński TM, Silva AS, Piwowarski J, Xie L, Fan TP, Giampieri F, El Midaoui A, Wong KH, Gan RY, Fatimi A, Atanasov AG. [https://pmc.ncbi.nlm.nih.gov/articles/PMC12130569/ Enhancing human gut health: Global innovations in dysbiosis management]. Imeta. 2025 Apr 13;4(3):e70028. [https://onlinelibrary.wiley.com/doi/10.1002/imt2.70028 doi: 10.1002/imt2.70028].PMCID: PMC12130569.</ref>

The microbial composition of the gut microbiota varies across regions of the digestive tract. The colon contains the highest microbial density of any human-associated microbial community studied so far, representing between 300 and 1000 different species.<ref name="Guarner and Malagelada 2003b" /> Bacteria are the largest and to date, best studied component and 99% of gut bacteria come from about 30 or 40 species.<ref name="Beaugerie L and Petit JC">{{Cite journal |last1=Beaugerie |first1=Laurent |last2=Petit |first2=Jean-Claude |year=2004 |title=Antibiotic-associated diarrhoea |journal=Best Practice & Research Clinical Gastroenterology |volume=18 |issue=2 |pages=337–352 |doi=10.1016/j.bpg.2003.10.002 |pmid=15123074}}</ref> About 55% of the dry mass of feces is bacteria.<ref name="Stephen and Cummings">{{Cite journal |last1=Stephen |first1=A. M. |last2=Cummings |first2=J. H. |year=1980 |title=The Microbial Contribution to Human Faecal Mass |journal=Journal of Medical Microbiology |volume=13 |issue=1 |pages=45–56 |doi=10.1099/00222615-13-1-45 |pmid=7359576 |doi-access=free}}</ref> Over 99% of the bacteria in the gut are anaerobes, but in the cecum, aerobic bacteria reach high densities.<ref name="Prescotts" /> It is estimated that the human gut microbiota has around a hundred times as many genes as there are in the human genome.

==Overview== thumb|300px|Composition and distribution of gut microbiota in human body In humans, the gut microbiota has the highest numbers and species of bacteria compared to other areas of the body.<ref name="Quigley2013rev">{{Cite journal |last1=Quigley |first1=E. M |year=2013 |title=Gut bacteria in health and disease |journal=Gastroenterology & Hepatology |volume=9 |issue=9 |pages=560–569 |pmc=3983973 |pmid=24729765}}</ref> The approximate number of bacteria composing the gut microbiota is about 1013–1014 (10 to 100 trillion).<ref>{{Cite journal |last1=Turnbaugh |first1=Peter J. |last2=Ley |first2=Ruth E. |last3=Hamady |first3=Micah |last4=Fraser-Liggett |first4=Claire M. |last5=Knight |first5=Rob |last6=Gordon |first6=Jeffrey I. |date=October 2007 |title=The Human Microbiome Project |url=|journal=Nature |volume=449 |issue=7164 |pages=804–810 |doi=10.1038/nature06244 |pmid=17943116 |pmc=3709439 |bibcode=2007Natur.449..804T }}</ref> In humans, the gut flora is established at birth and gradually transitions towards a state resembling that of adults by the age of two,<ref>{{Cite journal |last1=Ma |first1=Guangyu |last2=Shi |first2=Yuguo |last3=Meng |first3=Lulu |last4=Fan |first4=Haolong |last5=Tang |first5=Xiaomei |last6=Luo |first6=Huijuan |last7=Wang |first7=Dongju |last8=Zhou |first8=Juan |last9=Xiao |first9=Xiaomin |date=2023 |title=Factors affecting the early establishment of neonatal intestinal flora and its intervention measures |journal=Frontiers in Cellular and Infection Microbiology |volume=13 |article-number=1295111 |doi=10.3389/fcimb.2023.1295111 |doi-access=free |pmid=38106467 |pmc=10722192 }}</ref> coinciding with the development and maturation of the intestinal epithelium and intestinal mucosal barrier. This barrier is essential for supporting a symbiotic relationship with the gut flora while providing protection against pathogenic organisms.<ref name="Sommer2013rev">{{Cite journal |last1=Sommer |first1=Felix |last2=Bäckhed |first2=Fredrik |year=2013 |title=The gut microbiota – masters of host development and physiology |journal=Nature Reviews Microbiology |volume=11 |issue=4 |pages=227–238 |doi=10.1038/nrmicro2974 |pmid=23435359 }}</ref><ref name="Faderl2015rev">{{Cite journal |last1=Faderl |first1=Martin |last2=Noti |first2=Mario |last3=Corazza |first3=Nadia |last4=Mueller |first4=Christoph |year=2015 |title=Keeping bugs in check: The mucus layer as a critical component in maintaining intestinal homeostasis |journal=IUBMB Life |volume=67 |issue=4 |pages=275–285 |doi=10.1002/iub.1374 |pmid=25914114 |doi-access=free}}</ref>

The relationship between some gut microbiota and humans is not merely commensal (a non-harmful coexistence), but rather a mutualistic relationship.<ref name="Prescotts" />{{rp|700}} Some human gut microorganisms benefit the host by fermenting dietary fiber into short-chain fatty acids (SCFAs), such as acetic acid and butyric acid, which are then absorbed by the host.<ref name=Quigley2013rev/><ref name=Clarke2014rev/> Intestinal bacteria also play a role in synthesizing certain B vitamins and vitamin K as well as metabolizing bile acids, sterols, and xenobiotics.<ref name="Prescotts">{{cite book |last1=Sherwood |first1=Linda |last2=Willey |first2=Joanne |last3=Woolverton |first3=Christopher J. |title=Prescott's Microbiology |date=2013 |publisher=McGraw-Hill Education |isbn=978-0-07-340240-6 |pages=713–721 }}</ref><ref name="Clarke2014rev">{{Cite journal |last1=Clarke |first1=Gerard |last2=Stilling |first2=Roman M |last3=Kennedy |first3=Paul J |last4=Stanton |first4=Catherine |last5=Cryan |first5=John F |last6=Dinan |first6=Timothy G |year=2014 |title=Minireview: Gut Microbiota: The Neglected Endocrine Organ |journal=Molecular Endocrinology |volume=28 |issue=8 |pages=1221–1238 |doi=10.1210/me.2014-1108 |pmc=5414803 |pmid=24892638}}</ref> The systemic importance of the SCFAs and other compounds they produce are like hormones and the gut flora itself appears to function like an endocrine organ.<ref name=Clarke2014rev/> Dysregulation of the gut flora has been correlated with a host of inflammatory and autoimmune conditions.<ref name=Quigley2013rev/><ref name="Shen2016rev">{{Cite journal |last1=Shen |first1=Sj |last2=Wong |first2=Connie HY |year=2016 |title=Bugging inflammation: Role of the gut microbiota |journal=Clinical & Translational Immunology |volume=5 |issue=4 |pages=e72 |doi=10.1038/cti.2016.12 |pmc=4855262 |pmid=27195115}}</ref>

The composition of human gut microbiota changes over time, when the diet changes, and as overall health changes.<ref name=Quigley2013rev/><ref name=Shen2016rev/> A systematic review from 2016 examined the preclinical and small human trials that have been conducted with certain commercially available strains of probiotic bacteria and identified those that had the most potential to be useful for certain central nervous system disorders.<ref name="CNS SystRev 2016" /> It should also be highlighted that the Mediterranean diet, rich in vegetables and fibers, stimulates the activity and growth of beneficial bacteria for the brain.<ref name="Microbiome summary">{{cite journal |last1=Salvadori |first1=M |title=Update on the gut microbiome in health and diseases |journal=World J Methodol |date=20 March 2024 |volume=14 |issue=1 |doi=10.5662/wjm.v14.i1.89196 |doi-access=free |pmid=38577200 |pmc=10989414 }}</ref>

== Classifications == The microbial composition of the gut microbiota varies across the digestive tract. In the stomach and small intestine, relatively few species of bacteria are generally present.<ref name="Guarner and Malagelada 2003b">{{Cite journal |last1=Guarner |first1=F |last2=Malagelada |first2=J |year=2003 |title=Gut flora in health and disease |journal=The Lancet |volume=361 |issue=9356 |pages=512–519 |doi=10.1016/S0140-6736(03)12489-0 |pmid=12583961 }}</ref><ref name="Sears">{{Cite journal |last1=Sears |first1=Cynthia L. |year=2005 |title=A dynamic partnership: Celebrating our gut flora |journal=Anaerobe |volume=11 |issue=5 |pages=247–251 |doi=10.1016/j.anaerobe.2005.05.001 |pmid=16701579}}</ref> Fungi, protists, archaea, and viruses are also present in the gut flora, but less is known about their activities.<ref name="Lozupone2012">{{Cite journal |last1=Lozupone |first1=Catherine A. |last2=Stombaugh |first2=Jesse I. |last3=Gordon |first3=Jeffrey I. |last4=Jansson |first4=Janet K. |last5=Knight |first5=Rob |year=2012 |title=Diversity, stability and resilience of the human gut microbiota |journal=Nature |volume=489 |issue=7415 |pages=220–230 |bibcode=2012Natur.489..220L |doi=10.1038/nature11550 |pmc=3577372 |pmid=22972295}}</ref>

[[File:Candida albicans.jpg|thumb|''Candida albicans'', a yeast found in the gut]]

Many species in the gut have not been studied outside of their hosts because they cannot be cultured.<ref name=Sears/><ref name="Beaugerie L and Petit JC" /><ref name="Shanahan">{{Cite journal |last1=Shanahan |first1=Fergus |year=2002 |title=The host–microbe interface within the gut |journal=Best Practice & Research Clinical Gastroenterology |volume=16 |issue=6 |pages=915–931 |doi=10.1053/bega.2002.0342 |pmid=12473298}}</ref> While there are a small number of core microbial species shared by most individuals, populations of microbes can vary widely.<ref name="Tap">{{Cite journal |last1=Tap |first1=Julien |last2=Mondot |first2=Stanislas |last3=Levenez |first3=Florence |last4=Pelletier |first4=Eric |last5=Caron |first5=Christophe |last6=Furet |first6=Jean-Pierre |last7=Ugarte |first7=Edgardo |last8=Muñoz-Tamayo |first8=Rafael |last9=Paslier |first9=Denis L. E. |last10=Nalin |first10=Renaud |last11=Dore |first11=Joel |last12=Leclerc |first12=Marion |year=2009 |title=Towards the human intestinal microbiota phylogenetic core |journal=Environmental Microbiology |volume=11 |issue=10 |pages=2574–2584 |doi=10.1111/j.1462-2920.2009.01982.x |pmid=19601958|bibcode=2009EnvMi..11.2574T |doi-access=free }}</ref> Within an individual, their microbial populations stay fairly constant over time, with some alterations occurring due to changes in lifestyle, diet and age.<ref name="Guarner and Malagelada 2003b" /><ref name=OHara06/> The Human Microbiome Project has set out to better describe the microbiota of the human gut and other body locations.{{citation needed|date=March 2023}}

The four dominant bacterial phyla in the human gut are Bacillota (Firmicutes), Bacteroidota, Actinomycetota, and Pseudomonadota.<ref name="pmid24388028">{{Cite journal |last1=Khanna |first1=Sahil |last2=Tosh |first2=Pritish K |year=2014 |title=A Clinician's Primer on the Role of the Microbiome in Human Health and Disease |journal=Mayo Clinic Proceedings |volume=89 |issue=1 |pages=107–114 |doi=10.1016/j.mayocp.2013.10.011 |pmid=24388028 |doi-access=}}</ref> Most bacteria belong to the genera ''Bacteroides'', ''Clostridium'', ''Faecalibacterium'',<ref name="Guarner and Malagelada 2003b" /><ref name="Beaugerie L and Petit JC" /> ''Eubacterium'', ''Ruminococcus'', ''Peptococcus'', ''Peptostreptococcus'', and ''Bifidobacterium''.<ref name="Guarner and Malagelada 2003b" /><ref name="Beaugerie L and Petit JC" /> Other genera, such as ''Escherichia'' and ''Lactobacillus'', are present to a lesser extent.<ref name="Guarner and Malagelada 2003b" /> Species from the genus ''Bacteroides'' alone constitute about 30% of all bacteria in the gut, suggesting that this genus is especially important in the functioning of the host.<ref name=Sears/>

Fungal genera that have been detected in the gut include ''Candida'', ''Saccharomyces'', ''Aspergillus'', ''Penicillium'', ''Rhodotorula'', ''Trametes'', ''Pleospora'', ''Sclerotinia'', ''Bullera'', and ''Galactomyces'', among others.<ref name="mycobiome">{{Cite journal |last1=Cui |first1=Lijia |last2=Morris |first2=Alison |last3=Ghedin |first3=Elodie |year=2013 |title=The human mycobiome in health and disease |journal=Genome Medicine |volume=5 |issue=7 |page=63 |doi=10.1186/gm467 |pmc=3978422 |pmid=23899327 |doi-access=free }}</ref><ref name="SIFO">{{Cite journal |last1=Erdogan |first1=Askin |last2=Rao |first2=Satish S. C |year=2015 |title=Small Intestinal Fungal Overgrowth |journal=Current Gastroenterology Reports |volume=17 |issue=4 |page=16 |doi=10.1007/s11894-015-0436-2 |pmid=25786900 }}</ref> ''Rhodotorula'' is most frequently found in individuals with inflammatory bowel disease while ''Candida'' is most frequently found in individuals with hepatitis B cirrhosis and chronic hepatitis B.<ref name="mycobiome" />

Archaea constitute another large class of gut flora which are important in the metabolism of the bacterial products of fermentation.

Industrialization is associated with changes in the microbiota and the reduction of diversity could drive certain species to extinction; in 2018, researchers proposed a biobank repository of human microbiota.<ref>{{Cite journal |last1=Bello |first1=Maria G. Dominguez |last2=Knight |first2=Rob |last3=Gilbert |first3=Jack A. |last4=Blaser |first4=Martin J. |date=4 October 2018 |title=Preserving microbial diversity |journal=Science |volume=362 |issue=6410 |pages=33–34 |bibcode=2018Sci...362...33B |doi=10.1126/science.aau8816 |pmid=30287652 }}</ref>

=== Enterotype ===

An enterotype is a classification of living organisms based on its bacteriological ecosystem in the human gut microbiome not dictated by age, gender, body weight, or national divisions.<ref name="Nature">{{Cite journal |last1=Arumugam |first1=Manimozhiyan |last2=Raes |first2=Jeroen |last3=Pelletier |first3=Eric |last4=Le Paslier |first4=Denis |last5=Yamada |first5=Takuji |last6=Mende |first6=Daniel R. |last7=Fernandes |first7=Gabriel R. |last8=Tap |first8=Julien |last9=Bruls |first9=Thomas |last10=Batto |first10=Jean-Michel |last11=Bertalan |first11=Marcelo |last12=Borruel |first12=Natalia |last13=Casellas |first13=Francesc |last14=Fernandez |first14=Leyden |last15=Gautier |first15=Laurent |year=2011 |title=Enterotypes of the human gut microbiome |journal=Nature |volume=473 |issue=7346 |pages=174–180 |bibcode=2011Natur.473..174. |doi=10.1038/nature09944 |pmc=3728647 |pmid=21508958 |last16=Hansen |first16=Torben |last17=Hattori |first17=Masahira |last18=Hayashi |first18=Tetsuya |last19=Kleerebezem |first19=Michiel |last20=Kurokawa |first20=Ken |last21=Leclerc |first21=Marion |last22=Levenez |first22=Florence |last23=Manichanh |first23=Chaysavanh |last24=Nielsen |first24=H. Bjørn |last25=Nielsen |first25=Trine |last26=Pons |first26=Nicolas |last27=Poulain |first27=Julie |last28=Qin |first28=Junjie |last29=Sicheritz-Ponten |first29=Thomas |last30=Tims |first30=Sebastian}}</ref> There are indications that long-term diet influences enterotype.<ref name="Wu et al">{{Cite journal |last1=Wu |first1=G. D. |last2=Chen |first2=J. |last3=Hoffmann |first3=C. |last4=Bittinger |first4=K. |last5=Chen |first5=Y.-Y. |last6=Keilbaugh |first6=S. A. |last7=Bewtra |first7=M. |last8=Knights |first8=D. |last9=Walters |first9=W. A. |last10=Knight |first10=R. |last11=Sinha |first11=R. |last12=Gilroy |first12=E. |last13=Gupta |first13=K. |last14=Baldassano |first14=R. |last15=Nessel |first15=L. |year=2011 |title=Linking Long-Term Dietary Patterns with Gut Microbial Enterotypes |journal=Science |volume=334 |issue=6052 |pages=105–108 |bibcode=2011Sci...334..105W |doi=10.1126/science.1208344 |pmc=3368382 |pmid=21885731 |last16=Li |first16=H. |last17=Bushman |first17=F. D. |last18=Lewis |first18=J. D.}}</ref> Three human enterotypes have been proposed,<ref name="Nature" /><ref>{{Cite news |last1=Zimmer |first1=Carl |date=April 20, 2011 |title=Bacteria Divide People Into 3 Types, Scientists Say |work=The New York Times |url=https://www.nytimes.com/2011/04/21/science/21gut.html |access-date=April 21, 2011 |quote=a group of scientists now report just three distinct ecosystems in the guts of people they have studied.}}</ref> but their value has been questioned.<ref name="2014cellhostandmicrobentero">{{Cite journal |last1=Knights |first1=Dan |last2=Ward |first2=Tonya |last3=McKinlay |first3=Christopher |last4=Miller |first4=Hannah |last5=Gonzalez |first5=Antonio |last6=McDonald |first6=Daniel |last7=Knight |first7=Rob |date=8 October 2014 |title=Rethinking "Enterotypes" |journal=Cell Host & Microbe |volume=16 |issue=4 |pages=433–437 |doi=10.1016/j.chom.2014.09.013 |pmc=5558460 |pmid=25299329}}</ref>

== Composition == {{See also|Human microbiome#Gastrointestinal tract}} [[File:Microbiome.jpg|thumb|left|upright=1.6|Diagram of human gastrointestinal tract microbiota depicted in various regions]]

===Bacteria===

==== Stomach ==== Due to the high acidity of the stomach, most microorganisms cannot survive there. The main bacteria of the '''gastric microbiota''' belong to five major phyla: Firmicutes, Bacteroidetes, Actinobacteria, Fusobacteriota, and Proteobacteria. The dominant genera are ''Prevotella'', ''Streptococcus'', ''Veillonella'', ''Rothia'', and ''Haemophilus''.<ref name="Nardone">{{cite journal |last1=Nardone |first1=G |last2=Compare |first2=D |title=The human gastric microbiota: Is it time to rethink the pathogenesis of stomach diseases? |journal=United European Gastroenterology Journal |date=June 2015 |volume=3 |issue=3 |pages=255–60 |doi=10.1177/2050640614566846 |pmid=26137299|pmc=4480535 }}</ref> The interaction between the pre-existing gastric microbiota with the introduction of ''H. pylori'' may influence disease progression.<ref name="Nardone"/> When there is a presence of ''H. pylori'' it becomes the dominant species of the microbiota.<ref name="Yao">{{cite journal |last1=Yao |first1=X |last2=Smolka |first2=AJ |title=Gastric Parietal Cell Physiology and Helicobacter pylori-Induced Disease. |journal=Gastroenterology |date=June 2019 |volume=156 |issue=8 |pages=2158–2173 |doi=10.1053/j.gastro.2019.02.036 |pmid=30831083|pmc=6715393 }}</ref>

==== Intestines ==== {| class="wikitable" style = "float: right; margin-left:15px; text-align:center" | colspan="2" |'''Bacteria commonly found in the human colon'''<ref name="TxtbookBacteriology">{{Cite web |first1=Kenneth |last1=Todar |year=2012 |title=The Normal Bacterial Flora of Humans |url=http://www.textbookofbacteriology.net/normalflora_3.html |access-date=June 25, 2016 |website=Todar's Online Textbook of Bacteriology}}</ref> |- !Bacterium ! Incidence (%) |- |''Bacteroides fragilis'' | style="text-align:right;"| 100 |- |''Bacteroides melaninogenicus'' | style="text-align:right;"| 100 |- |''Bacteroides oralis'' | style="text-align:right;"| 100 |- |''Enterococcus faecalis'' | style="text-align:right;"| 100 |- |''Escherichia coli'' | style="text-align:right;"| 100 |- |''Enterobacter sp.'' | style="text-align:right;"| 40–80 |- |''Klebsiella sp.'' | style="text-align:right;"| 40–80 |- |''Bifidobacterium bifidum'' | style="text-align:right;"| 30–70 |- |''Staphylococcus aureus'' | style="text-align:right;"| 30–50 |- |''Lactobacillus'' | style="text-align:right;"| 20–60 |- |''Clostridium perfringens'' | style="text-align:right;"| 25–35 |- |''Proteus mirabilis'' | style="text-align:right;"| 5–55 |- |''Clostridium tetani'' | style="text-align:right;"| 1–35 |- |''Clostridium septicum'' | style="text-align:right;"| 5–25 |- |''Pseudomonas aeruginosa'' | style="text-align:right;"| 3–11 |- |''Salmonella enterica'' | style="text-align:right;"| 3–7 |- |''Faecalibacterium prausnitzii'' | style="text-align:right;"| ?common |- |''Peptostreptococcus sp.'' | style="text-align:right;"| ?common |- |''Peptococcus sp.'' | style="text-align:right;"| ?common |}

The small intestine contains a trace amount of microorganisms due to the proximity and influence of the stomach. Gram-positive cocci and rod-shaped bacteria are the predominant microorganisms found in the small intestine.<ref name="Prescotts" /> However, in the distal portion of the small intestine alkaline conditions support gram-negative bacteria of the ''Enterobacteriaceae''.<ref name="Prescotts" /> The bacterial flora of the small intestine aid in a wide range of intestinal functions. The bacterial flora provide regulatory signals that enable the development and utility of the gut. Overgrowth of bacteria in the small intestine can lead to intestinal failure.<ref name="quigley2006">{{Cite journal |last1=Quigley |first1=Eamonn M.M |last2=Quera |first2=Rodrigo |year=2006 |title=Small Intestinal Bacterial Overgrowth: Roles of Antibiotics, Prebiotics, and Probiotics |journal=Gastroenterology |volume=130 |issue=2 |pages=S78–90 |doi=10.1053/j.gastro.2005.11.046 |pmid=16473077 |doi-access=free }}</ref> In addition the large intestine contains the largest bacterial ecosystem in the human body.<ref name="Prescotts" /> About 99% of the large intestine and feces flora are made up of obligate anaerobes such as ''Bacteroides'' and ''Bifidobacterium.''<ref>{{Cite book |last1=Adams |first1=M. R. |title=Food Microbiology |last2=Moss |first2=M. O. |year=2007 |isbn=978-0-85404-284-5 |doi=10.1039/9781847557940 |edition=3rd|publisher=RSC Publishing|p=175}}</ref> Factors that disrupt the microorganism population of the large intestine include antibiotics, stress, and parasites.<ref name="Prescotts" />

Bacteria make up most of the flora in the colon<ref name="University of Glasgow">{{Cite web|date=2004|title=The normal gut flora|url=http://www.gla.ac.uk/departments/humannutrition/students/resources/meden/Infection.pdf|access-date=2023-01-02|archive-url=https://web.archive.org/web/20040526195616/http://www.gla.ac.uk/departments/humannutrition/students/resources/meden/Infection.pdf |archive-date=2004-05-26| type= slideshow| via= University of Glasgow }}</ref> and account for 60% of fecal nitrogen.<ref name="Guarner and Malagelada 2003b" /> This fact makes feces an ideal source of gut flora for any tests and experiments by extracting the nucleic acid from fecal specimens, and bacterial 16S rRNA gene sequences are generated with bacterial primers. This form of testing is also often preferable to more invasive techniques, such as biopsies.

Five phyla dominate the intestinal microbiota: Bacteroidota, Bacillota (Firmicutes), Actinomycetota, Pseudomonadota, and Verrucomicrobiota{{snd}}with Bacteroidota and Bacillota constituting 90% of the composition.<ref name="pmid26963713">{{Cite journal |vauthors=Braune A, Blaut M |year=2016 |title=Bacterial species involved in the conversion of dietary flavonoids in the human gut |journal=Gut Microbes |volume=7 |issue=3 |pages=216–234 |doi=10.1080/19490976.2016.1158395 |pmc=4939924 |pmid=26963713}}</ref> Somewhere between 300<ref name="Guarner and Malagelada 2003b" /> and 1000 different species live in the gut,<ref name="Sears" /> with most estimates at about 500.<ref name="Steinhoff">{{Cite journal |last1=Steinhoff |first1=U |year=2005 |title=Who controls the crowd? New findings and old questions about the intestinal microflora |journal=Immunology Letters |volume=99 |issue=1 |pages=12–16 |doi=10.1016/j.imlet.2004.12.013 |pmid=15894105}}</ref><ref name="gibson" /> However, it is probable that 99% of the bacteria come from about 30 or 40 species,{{citation needed|date=May 2026}} with ''Faecalibacterium prausnitzii'' (phylum firmicutes) being the most common species in healthy adults.<ref name="Beaugerie L and Petit JC" /><ref>{{Cite journal |last1=Miquel |first1=S |last2=Martín |first2=R |last3=Rossi |first3=O |last4=Bermúdez-Humarán |first4=LG |last5=Chatel |first5=JM |last6=Sokol |first6=H |last7=Thomas |first7=M |last8=Wells |first8=JM |last9=Langella |first9=P |year=2013 |title=Faecalibacterium prausnitzii and human intestinal health |journal=Current Opinion in Microbiology |volume=16 |issue=3 |pages=255–261 |doi=10.1016/j.mib.2013.06.003 |pmid=23831042}}</ref>

Research suggests that the relationship between gut flora and humans is not merely commensal (a non-harmful coexistence), but rather is a mutualistic, symbiotic relationship.<ref name="Sears" /> Though people can survive with no gut flora,<ref name="Steinhoff" /> the microorganisms perform a host of useful functions, such as fermenting unused energy substrates, training the immune system via end products of metabolism like propionate and acetate, preventing growth of harmful species, regulating the development of the gut, producing vitamins for the host (such as biotin and vitamin K), and producing hormones to direct the host to store fats.<ref name="Prescotts" /> Extensive modification and imbalances of the gut microbiota and its microbiome or gene collection are associated with obesity.<ref>{{Cite journal |last1=Ley |first1=Ruth E |year=2010 |title=Obesity and the human microbiome |journal=Current Opinion in Gastroenterology |volume=26 |issue=1 |pages=5–11 |doi=10.1097/MOG.0b013e328333d751 |pmid=19901833 }}</ref> However, in certain conditions, some species are thought to be capable of causing disease by causing infection or increasing cancer risk for the host.<ref name="Guarner and Malagelada 2003b" /><ref name="University of Glasgow" />

===Fungi=== {{Further|Mycobiome}} Fungi also make up a part of the gut flora, but less is known about their activities.<ref name="Nash et al 2017">{{Cite journal |last1=Nash |first1=Andrea K |last2=Auchtung |first2=Thomas A |last3=Wong |first3=Matthew C |last4=Smith |first4=Daniel P |last5=Gesell |first5=Jonathan R |last6=Ross |first6=Matthew C |last7=Stewart |first7=Christopher J |last8=Metcalf |first8=Ginger A |last9=Muzny |first9=Donna M |last10=Gibbs |first10=Richard A |last11=Ajami |first11=Nadim J |last12=Petrosino |first12=Joseph F |year=2017 |title=The gut mycobiome of the Human Microbiome Project healthy cohort |journal=Microbiome |volume=5 |issue=1 |page=153 |doi=10.1186/s40168-017-0373-4 |pmc=5702186 |pmid=29178920 |doi-access=free }}</ref>

Due to the prevalence of fungi in the natural environment, determining which genera and species are permanent members of the gut mycobiome is difficult.<ref>{{cite journal |last1=Hallen-Adams |first1=Heather E. |last2=Suhr |first2=Mallory J. |title=Fungi in the healthy human gastrointestinal tract |journal=Virulence |date=3 April 2017 |volume=8 |issue=3 |pages=352–358 |doi=10.1080/21505594.2016.1247140 |pmc=5411236 |pmid=27736307 }}</ref><ref name="Quadram" /> Research is underway as to whether ''Penicillium'' is a permanent or transient member of the gut flora, obtained from dietary sources such as cheese, though several species in the genus are known to survive at temperatures around 37 °C, about the same as the core body temperature.<ref name=Quadram /> ''Saccharomyces cerevisiae'', brewer's yeast, is known to reach the intestines after being ingested and can be responsible for the condition auto-brewery syndrome in cases where it is overabundant,<ref name="Quadram">{{Cite web |title=What fungi live in the gut? Meet the gut mycobiome |url=https://quadram.ac.uk/blogs/what-fungi-live-in-the-gut-meet-the-gut-mycobiome/ |access-date=2024-07-25 |website=Quadram Institute |language=en-GB}}</ref><ref>{{Cite web |last=Klein |first=Alice |date=20 October 2019 |title=Man's body brews its own beer after yeast take over his gut microbiome |url=https://www.newscientist.com/article/2220432-mans-body-brews-its-own-beer-after-yeast-take-over-his-gut-microbiome/ |access-date=2024-07-25 |website=New Scientist |language=en-US}}</ref><ref>{{Citation |last1=Painter |first1=Kelly |title=Auto-Brewery Syndrome |date=2024 |work=StatPearls |url=https://www.ncbi.nlm.nih.gov/books/NBK513346/ |access-date=2024-07-25 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30020718 |last2=Cordell |first2=Barbara J. |last3=Sticco |first3=Kristin L.}}</ref> while ''Candida albicans'' is likely a permanent member, and is believed to be acquired at birth through vertical transmission.<ref>{{cite journal |last1=Browne |first1=Hilary P |last2=Shao |first2=Yan |last3=Lawley |first3=Trevor D |title=Mother–infant transmission of human microbiota |journal=Current Opinion in Microbiology |date=October 2022 |volume=69 |article-number=102173 |doi=10.1016/j.mib.2022.102173 |pmid=35785616 |doi-access=free }}</ref>{{Medical citation needed|date=July 2024}}

===Viruses=== {{Further|Virome}} The human virome includes all viruses associated with the human body, ranging from viruses that infect native cells to bacteriophages that infect bacteria in the microbiome. Among these, bacteriophages are by far the most numerous.<ref name="ScarpelliniIaniro2015">{{Cite journal |last1=Scarpellini |first1=Emidio |last2=Ianiro |first2=Gianluca |last3=Attili |first3=Fabia |last4=Bassanelli |first4=Chiara |last5=De Santis |first5=Adriano |last6=Gasbarrini |first6=Antonio |year=2015 |title=The human gut microbiota and virome: Potential therapeutic implications |journal=Digestive and Liver Disease |volume=47 |issue=12 |pages=1007–1012 |doi=10.1016/j.dld.2015.07.008 |pmc=7185617 |pmid=26257129 |doi-access=free}}</ref>

==Variation== === Age ===

There are common patterns of microbiome composition evolution during life.<ref name="Gerritsen et al 2012">{{Cite journal |last1=Gerritsen |first1=Jacoline |last2=Smidt |first2=Hauke |last3=Rijkers |first3=Ger |last4=de Vos |first4=Willem |date=27 May 2011 |title=Intestinal microbiota in human health and disease: the impact of probiotics |journal=Genes & Nutrition |volume=6 |issue=3 |pages=209–240 |doi=10.1007/s12263-011-0229-7 |pmc=3145058 |pmid=21617937}}</ref> In general, the diversity of microbiota composition of fecal samples is significantly higher in adults than in children, although interpersonal differences are higher in children than in adults.<ref name="Tanya Yatsunenko 2012" /> Much of the maturation of microbiota into an adult-like configuration happens during the first three years of life.<ref name="Tanya Yatsunenko 2012">{{Cite journal |last1=Yatsunenko |first1=T. |last2=Rey |first2=F. E. |last3=Manary |first3=M. J. |last4=Trehan |first4=I. |last5=Dominguez-Bello |first5=M. G. |last6=Contreras |first6=M. |last7=Magris |first7=M. |last8=Hidalgo |first8=G. |last9=Baldassano |first9=R. N. |last10=Anokhin |first10=A. P. |last11=Heath |first11=A. C. |last12=Warner |first12=B. |last13=Reeder |first13=J. |last14=Kuczynski |first14=J. |last15=Caporaso |first15=J. G. |year=2012 |title=Human gut microbiome viewed across age and geography |journal=Nature |volume=486 |issue=7402 |pages=222–227 |bibcode=2012Natur.486..222Y |doi=10.1038/nature11053 |pmc=3376388 |pmid=22699611 |last16=Lozupone |first16=C. A. |last17=Lauber |first17=C. |last18=Clemente |first18=J. C. |last19=Knights |first19=D. |last20=Knight |first20=R. |last21=Gordon |first21=J. I.}}</ref>

As the microbiome composition changes, so does the composition of bacterial proteins produced in the gut. In adult microbiomes, a high prevalence of enzymes involved in fermentation, methanogenesis and the metabolism of arginine, glutamate, aspartate and lysine have been found. In contrast, in infant microbiomes the dominant enzymes are involved in cysteine metabolism and fermentation pathways.<ref name="Tanya Yatsunenko 2012" />

=== Geography ===

Gut microbiome composition depends on the geographic origin of populations. Variations in a trade-off of ''Prevotella'', the representation of the urease gene, and the representation of genes encoding glutamate synthase/degradation or other enzymes involved in amino acids degradation or vitamin biosynthesis show significant differences between populations from the US, Malawi, or Amerindian origin.<ref name="Tanya Yatsunenko 2012" />

The US population has a high representation of enzymes encoding the degradation of glutamine and enzymes involved in vitamin and lipoic acid biosynthesis; whereas Malawi and Amerindian populations have a high representation of enzymes encoding glutamate synthase and they also have an overrepresentation of α-amylase in their microbiomes. As the US population has a diet richer in fats than Amerindian or Malawian populations which have a corn-rich diet, the diet is probably the main determinant of the gut bacterial composition.<ref name="Tanya Yatsunenko 2012" />

Further studies have indicated a large difference in the composition of microbiota between European and rural African children. The fecal bacteria of children from Florence were compared to that of children from the small rural village of Boulpon in Burkina Faso. The diet of a typical child living in this village is largely lacking in fats and animal proteins and rich in polysaccharides and plant proteins. The fecal bacteria of European children were dominated by ''Firmicutes'' and showed a marked reduction in biodiversity, while the fecal bacteria of the Boulpon children was dominated by ''Bacteroidetes''. The increased biodiversity and different composition of the gut microbiome in African populations may aid in the digestion of normally indigestible plant polysaccharides and also may result in a reduced incidence of non-infectious colonic diseases.<ref name="Carlotta De Filippo 2010">{{Cite journal |last1=De Filippo |first1=C |last2=Cavalieri |first2=D |last3=Di Paola |first3=M |last4=Ramazzotti |first4=M |last5=Poullet |first5=J. B |last6=Massart |first6=S |last7=Collini |first7=S |last8=Pieraccini |first8=G |last9=Lionetti |first9=P |year=2010 |title=Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa |journal=Proceedings of the National Academy of Sciences |volume=107 |issue=33 |pages=14691–14696 |bibcode=2010PNAS..10714691D |doi=10.1073/pnas.1005963107 |pmc=2930426 |pmid=20679230 |doi-access=free}}</ref> Studies of hunter-gatherer populations have further demonstrated the impact of subsistence strategy on gut microbiome composition. Research on the Hadza, a hunter-gatherer community in Tanzania, found significantly greater microbial diversity compared to Italian controls, with enrichment in taxa such as ''Treponema'', ''Prevotella'', and unclassified ''Bacteroidetes'' associated with the fermentation of fibrous plant foods.<ref>{{cite journal |last1=Schnorr |first1=Stephanie L. |last2=Candela |first2=Marco |last3=Rampelli |first3=Simone |last4=Centanni |first4=Manuela |last5=Consolandi |first5=Clarissa |last6=Basaglia |first6=Giulia |last7=Turroni |first7=Silvia |last8=Biagi |first8=Elena |last9=Peano |first9=Clelia |last10=Crittenden |first10=Alyssa N. |last11=Henry |first11=Amanda G. |last12=Brigidi |first12=Patrizia |last13=Marlowe |first13=Frank W. |last14=Rampelli |first14=Simone |display-authors=3 |title=Gut microbiome of the Hadza hunter-gatherers |journal=Nature Communications |date=2014 |volume=5 |page=3654 |doi=10.1038/ncomms4654 |pmid=24736369 |pmc=3996546 |bibcode=2014NatCo...5.3654S}}</ref> Similarly, analysis of the gut microbiome of Yanomami Amerindians in Venezuela, a community with no prior documented contact with Western populations, revealed the highest level of bacterial diversity recorded in a human group. This suggests that industrialization and Western diets are associated with a progressive loss of ancestral microbial diversity.<ref>{{cite journal |last1=Clemente |first1=Jose C. |last2=Pehrsson |first2=Erica C. |last3=Blaser |first3=Martin J. |last4=Sandhu |first4=Kuldip |last5=Gao |first5=Zhan |last6=Wang |first6=Bing |last7=Magris |first7=Magda |last8=Hidalgo |first8=Glida |last9=Contreras |first9=Monica |last10=Noya-Alarcón |first10=Óscar |display-authors=3 |title=The microbiome of uncontacted Amerindians |journal=Science Advances |date=2015 |volume=1 |issue=3 |article-number=e1500183 |doi=10.1126/sciadv.1500183 |pmid=26229982 |pmc=4517851 |bibcode=2015SciA....1E0183C}}</ref>

On a smaller scale, it has been shown that sharing numerous common environmental exposures in a family is a strong determinant of individual microbiome composition. This effect has no genetic influence and it is consistently observed in culturally different populations.<ref name="Tanya Yatsunenko 2012" />

==== Malnourishment ==== Malnourished children have less mature and less diverse gut microbiota than healthy children, and changes in the microbiome associated with nutrient scarcity can in turn be a pathophysiological cause of malnutrition.<ref name="Jonkers">{{Cite journal |last1=Jonkers |first1=Daisy M.A.E. |year=2016 |title=Microbial perturbations and modulation in conditions associated with malnutrition and malabsorption |journal=Best Practice & Research Clinical Gastroenterology |volume=30 |issue=2 |pages=161–172 |doi=10.1016/j.bpg.2016.02.006 |pmid=27086883}}</ref><ref name="Million">{{cite journal |last1=Million |first1=Matthieu |last2=Diallo |first2=Aldiouma |last3=Raoult |first3=Didier |title=Gut microbiota and malnutrition |journal=Microbial Pathogenesis |date=May 2017 |volume=106 |pages=127–138 |doi=10.1016/j.micpath.2016.02.003 |pmid=26853753 |url=https://hal.archives-ouvertes.fr/hal-01573801/file/Million2017.pdf }}</ref> Malnourished children also typically have more potentially pathogenic gut flora, and more yeast in their mouths and throats.<ref name="Rytter">{{Cite journal |last1=Rytter |first1=Maren Johanne Heilskov |last2=Kolte |first2=Lilian |last3=Briend |first3=André |last4=Friis |first4=Henrik |last5=Christensen |first5=Vibeke Brix |year=2014 |title=The Immune System in Children with Malnutrition – A Systematic Review |journal=PLOS ONE |volume=9 |issue=8 |article-number=e105017 |bibcode=2014PLoSO...9j5017R |doi=10.1371/journal.pone.0105017 |pmc=4143239 |pmid=25153531 |doi-access=free}}</ref> Altering diet may lead to changes in gut microbiota composition and diversity.<ref name="Alcocketal2014"/>

===Race and ethnicity=== Researchers with the American Gut Project and Human Microbiome Project found that twelve microbe families varied in abundance based on the race or ethnicity of the individual. The strength of these associations is limited by the small sample size: the American Gut Project collected data from 1,375 individuals, 90% of whom were white.<ref name="Renson" /> The Healthy Life in an Urban Setting (HELIUS) study in Amsterdam found that those of Dutch ancestry had the highest level of gut microbiota diversity, while those of South Asian and Surinamese descent had the lowest diversity. The study results suggested that individuals of the same race or ethnicity have more similar microbiomes than individuals of different racial backgrounds.<ref name="Renson" />

===Socioeconomic status=== As of 2020, at least two studies have demonstrated a link between an individual's socioeconomic status (SES) and their gut microbiota. A study in Chicago found that individuals in higher SES neighborhoods had greater microbiota diversity. People from higher SES neighborhoods also had more abundant ''Bacteroides'' bacteria. Similarly, a study of twins in the United Kingdom found that higher SES was also linked with a greater gut diversity.<ref name="Renson">{{Cite journal |last1=Renson |first1=Audrey |last2=Herd |first2=Pamela |last3=Dowd |first3=Jennifer B. |author-link3=Jennifer Dowd |year=2020 |title=Sick Individuals and Sick (Microbial) Populations: Challenges in Epidemiology and the Microbiome |journal=Annual Review of Public Health |volume=41 |pages=63–80 |doi=10.1146/annurev-publhealth-040119-094423 |pmid=31635533 |pmc=9713946 |doi-access=free}}</ref>

===Antibiotic use=== As of 2023, a study suggests that antibiotics, especially those used in the treatment of broad-spectrum bacterial infections, have negative effects on the gut microbiota.<ref name="doi.org">Colella, M., Charitos, I. A., Ballini, A., Cafiero, C., Topi, S., Palmirotta, R., & Santacroce, L. (2023). Microbiota revolution: How gut microbes regulate our lives. World journal of gastroenterology, 29(28), 4368–4383. https://doi.org/10.3748/wjg.v29.i28.4368</ref> The study also states that there are many experts on intestinal health concerned that antibody usage has reduced the diversity of the gut microbiota, many of the strains are lost, and if there is a re-emergence of the bacteria, it is gradual and long-term.<ref name="doi.org"/>

== Functions == When the study of gut flora began in 1995,<ref>{{Cite journal |last1=Gibson |first1=G. R. |last2=Roberfroid |first2=M. B. |year=1995 |title=Dietary modulation of the human colonic microbiota: Introducing the concept of prebiotics |journal=The Journal of Nutrition |volume=125 |issue=6 |pages=1401–1412 |doi=10.1093/jn/125.6.1401 |pmid=7782892}}</ref> it was thought to have three key roles: direct defense against pathogens, fortification of host defense by its role in developing and maintaining the intestinal epithelium and inducing antibody production there, and metabolizing otherwise indigestible compounds in food. Subsequent work discovered its role in training the developing immune system, and yet further work focused on its role in the gut–brain axis.<ref name="2014Wangrev">{{Cite journal |last1=Wang |first1=Yan |last2=Kasper |first2=Lloyd H |year=2014 |title=The role of microbiome in central nervous system disorders |journal=Brain, Behavior, and Immunity |volume=38 |pages=1–12 |doi=10.1016/j.bbi.2013.12.015 |pmc=4062078 |pmid=24370461}}</ref> The gut microbiota not only influences intestinal health but also plays a role in systemic immune regulation, including interactions with the pulmonary immune environment through what is known as the 'gut–lung axis'.<ref>Huang, L., Wen, Y., Li, Z., Li, H., Fan, B., Zeng, X., & Zhang, L. (2025). The gut microbiota modulates airway inflammation in allergic asthma through the gut–lung axis related immune modulation: A review. Biomolecules and Biomedicine, 25(4), 171–185. doi:10.17305/bjbms.2024.11280</ref>

=== Direct inhibition of pathogens === The gut flora community plays a direct role in defending against pathogens by fully colonising the space, making use of all available nutrients, and by secreting compounds known as cytokines that kill or inhibit unwelcome organisms that would compete for nutrients with it.<ref name="Yoon2014rev">{{Cite journal |last1=Yoon |first1=My Young |last2=Lee |first2=Keehoon |last3=Yoon |first3=Sang Sun |year=2014 |title=Protective role of gut commensal microbes against intestinal infections |journal=Journal of Microbiology |volume=52 |issue=12 |pages=983–989 |doi=10.1007/s12275-014-4655-2 |pmid=25467115 }}</ref> Different strains of gut bacteria cause the production of different cytokines. Cytokines are chemical compounds produced by our immune system for initiating the inflammatory response against infections. Disruption of the gut flora allows competing organisms like ''Clostridioides difficile'' to become established that otherwise are kept in abeyance.<ref name=Yoon2014rev/>

===Development of enteric protection and immune system=== [[File:Transvesicular transport by microfold cells.png|thumbnail|right|Microfold cells transfer antigens (Ag) from the lumen of the gut to gut-associated lymphoid tissue (GALT) via transcytosis and present them to different innate and adaptive immune cells.]] Gut flora in infants becomes similar to an adult within one to two years of birth.<ref name=Sommer2013rev/> As the gut flora establishes, the lining of the intestines – the intestinal epithelium and the intestinal mucosal barrier that it secretes – develop a symbiosis with microorganisms.<ref name=Sommer2013rev/> Specifically, goblet cells that produce the mucosa proliferate, and the mucosa layer thickens, providing an outside mucosal layer in which favorable microorganisms can anchor and feed, and an inner layer that these organisms cannot penetrate.<ref name=Sommer2013rev/><ref name=Faderl2015rev/> Additionally, the development of gut-associated lymphoid tissue (GALT), which forms part of the intestinal epithelium and which detects and reacts to pathogens, develops during the time that the gut flora becomes established.<ref name=Sommer2013rev/> The GALT that develops is tolerant to gut flora species, but not to other microorganisms.<ref name=Sommer2013rev/> GALT also normally becomes tolerant to food the infant consumes, and the gut flora metabolites (molecules formed from metabolism) produced from food.<ref name=Sommer2013rev/>

The human immune system creates cytokines that can drive the immune system to produce inflammation in order to protect itself, and that can tamp down the immune response to maintain homeostasis and allow healing after insult or injury.<ref name=Sommer2013rev/> Different bacterial species that appear in gut flora have been shown to be able to drive the immune system to create cytokines selectively; for example ''Bacteroides fragilis'' and some ''Clostridia'' species appear to drive an anti-inflammatory response, while some segmented filamentous bacteria drive the production of inflammatory cytokines.<ref name=Sommer2013rev/><ref>{{Cite journal |last1=Reinoso Webb |first1=Cynthia |last2=Koboziev |first2=Iurii |last3=Furr |first3=Kathryn L |last4=Grisham |first4=Matthew B |year=2016 |title=Protective and pro-inflammatory roles of intestinal bacteria |journal=Pathophysiology |volume=23 |issue=2 |pages=67–80 |doi=10.1016/j.pathophys.2016.02.002 |pmc=4867289 |pmid=26947707}}</ref> Gut flora can also regulate the production of antibodies by the immune system.<ref name=Sommer2013rev/><ref>{{Cite journal |last1=Mantis |first1=N J |last2=Rol |first2=N |last3=Corthésy |first3=B |year=2011 |title=Secretory IgA's complex roles in immunity and mucosal homeostasis in the gut |journal=Mucosal Immunology |volume=4 |issue=6 |pages=603–611 |doi=10.1038/mi.2011.41 |pmc=3774538 |pmid=21975936}}</ref> One function of this regulation is to cause B cells to class switch to IgA. In most cases B cells need activation from T helper cells to induce class switching; however, in another pathway, gut flora cause NF-kB signaling by intestinal epithelial cells which results in further signaling molecules being secreted.<ref name="Peterson">{{Cite journal |last1=Peterson |first1=Lance W |last2=Artis |first2=David |year=2014 |title=Intestinal epithelial cells: Regulators of barrier function and immune homeostasis |journal=Nature Reviews Immunology |volume=14 |issue=3 |pages=141–153 |doi=10.1038/nri3608 |pmid=24566914 }}</ref> These signaling molecules interact with B cells to induce class switching to IgA.<ref name=Peterson/> IgA is an important type of antibody that is used in mucosal environments like the gut. It has been shown that IgA can help diversify the gut community and helps in getting rid of bacteria that cause inflammatory responses.<ref name="Honda">{{Cite journal |last1=Honda |first1=Kenya |last2=Littman |first2=Dan R |year=2016 |title=The microbiota in adaptive immune homeostasis and disease |journal=Nature |volume=535 |issue=7610 |pages=75–84 |bibcode=2016Natur.535...75H |doi=10.1038/nature18848 |pmid=27383982 }}</ref> Ultimately, IgA maintains a healthy environment between the host and gut bacteria.<ref name=Honda/> These cytokines and antibodies can have effects outside the gut, in the lungs and other tissues.<ref name=Sommer2013rev/>

A 2022 review indicated that various mechanisms are under preliminary research to assess how gut microbes may modulate vaccine immunogenicity, including effects on antigen presentation and cytokine profiles.<ref>{{Cite journal |last1=Lynn |first1=David J. |last2=Benson |first2=Saoirse C. |last3=Lynn |first3=Miriam A. |last4=Pulendran |first4=Bali |date=January 2022 |title=Modulation of immune responses to vaccination by the microbiota: implications and potential mechanisms|pmc=8127454|pmid=34002068|journal=Nature Reviews Immunology |language=en |volume=22 |issue=1 |pages=33–46 |doi=10.1038/s41577-021-00554-7 |issn=1474-1741}}</ref>

=== Metabolism === {{Tryptophan metabolism by human microbiota|align=right}} Without gut flora, the human body would be unable to utilize some of the undigested carbohydrates it consumes, because some types of gut flora have enzymes that human cells lack for breaking down certain polysaccharides.<ref name=Clarke2014rev/> Rodents raised in a sterile environment and lacking in gut flora need to eat 30% more calories just to remain the same weight as their normal counterparts.<ref name=Clarke2014rev/> Carbohydrates that humans cannot digest without bacterial help include certain starches, fiber, oligosaccharides, and sugars that the body failed to digest and absorb like lactose in the case of lactose intolerance and sugar alcohols, mucus produced by the gut, and proteins.<ref name=Quigley2013rev/><ref name=Clarke2014rev/>

Bacteria turn carbohydrates they ferment into short-chain fatty acids by a form of fermentation called saccharolytic fermentation.<ref name=gibson/> Products include acetic acid, propionic acid and butyric acid.<ref name="Beaugerie L and Petit JC" /><ref name=gibson/> These materials can be used by host cells, providing a major source of energy and nutrients.<ref name=gibson/> Gases (which are involved in signaling<ref>{{cite journal |last1=Hopper |first1=Christopher P. |last2=De La Cruz |first2=Ladie Kimberly |last3=Lyles |first3=Kristin V. |last4=Wareham |first4=Lauren K. |last5=Gilbert |first5=Jack A. |last6=Eichenbaum |first6=Zehava |last7=Magierowski |first7=Marcin |last8=Poole |first8=Robert K. |last9=Wollborn |first9=Jakob |last10=Wang |first10=Binghe |title=Role of Carbon Monoxide in Host–Gut Microbiome Communication |journal=Chemical Reviews |date=23 December 2020 |volume=120 |issue=24 |pages=13273–13311 |doi=10.1021/acs.chemrev.0c00586 |pmid=33089988 }}</ref> and may cause flatulence) and organic acids, such as lactic acid, are also produced by fermentation.<ref name="Beaugerie L and Petit JC" /> Acetic acid is used by muscle, propionic acid facilitates liver production of ATP, and butyric acid provides energy to gut cells.<ref name=gibson/>

Gut flora also synthesize vitamins like biotin and folate, and facilitate absorption of dietary minerals, including magnesium, calcium, and iron.<ref name="Guarner and Malagelada 2003b" /><ref name="OHara06">{{Cite journal |last1=O'Hara |first1=Ann M |last2=Shanahan |first2=Fergus |year=2006 |title=The gut flora as a forgotten organ |journal=EMBO Reports |volume=7 |issue=7 |pages=688–693 |doi=10.1038/sj.embor.7400731 |pmc=1500832 |pmid=16819463}}</ref> ''Methanobrevibacter smithii'' is unique because it is not a species of bacteria, but rather a member of domain ''Archaea'', and is the most abundant methane-producing archaeal species in the human gastrointestinal microbiota.<ref>{{Cite journal |last1=Rajilić-Stojanović |first1=Mirjana |last2=De Vos |first2=Willem M |year=2014 |title=The first 1000 cultured species of the human gastrointestinal microbiota |journal=FEMS Microbiology Reviews |volume=38 |issue=5 |pages=996–1047 |doi=10.1111/1574-6976.12075 |pmc=4262072 |pmid=24861948}}</ref>

Gut microbiota also serve as a source of vitamins K and B12, which are not produced by the body or produced in little amount.<ref>{{cite journal |last1=Hill |first1=M J |title=Intestinal flora and endogenous vitamin synthesis |journal=European Journal of Cancer Prevention |date=March 1997 |volume=6 |pages=S43–S45 |doi=10.1097/00008469-199703001-00009 |pmid=9167138 }}</ref><ref>{{Cite web |date=2013-09-17 |title=The Microbiome |url=https://now.tufts.edu/articles/microbiome |access-date=2020-12-09 |website=Tufts Now |language=en}}</ref>

==== Cellulose degradation ==== Bacteria that degrade cellulose (such as ''Ruminococcus'') are prevalent among great apes, ancient human societies, hunter-gatherer communities, and even modern rural populations. However, they are rare in industrialized societies. Human-associated strains have acquired genes that can degrade specific plant fibers such as maize, rice, and wheat. Bacterial strains found in primates can also degrade chitin, a polymer abundant in insects, which are part of the diet of many nonhuman primates. The decline of these bacteria in the human gut were likely influenced by the shift toward western lifestyles.<ref>{{cite journal |last1=Moraïs |first1=Sarah |last2=Winkler |first2=Sarah |last3=Zorea |first3=Alvah |last4=Levin |first4=Liron |last5=Nagies |first5=Falk S. P. |last6=Kapust |first6=Nils |last7=Lamed |first7=Eva |last8=Artan-Furman |first8=Avital |last9=Bolam |first9=David N. |last10=Yadav |first10=Madhav P. |last11=Bayer |first11=Edward A. |last12=Martin |first12=William F. |last13=Mizrahi |first13=Itzhak |title=Cryptic diversity of cellulose-degrading gut bacteria in industrialized humans |journal=Science |date=15 March 2024 |volume=383 |issue=6688 |article-number=eadj9223 |doi=10.1126/science.adj9223 |pmid=38484069 |pmc=7615765 |bibcode=2024Sci...383j9223M }}</ref>

==== Pharmacomicrobiomics ==== The human metagenome (i.e., the genetic composition of an individual and all microorganisms that reside on or within the individual's body) varies considerably between individuals.<ref name="Pharmacomicrobiomics">{{Cite journal |vauthors=ElRakaiby M, Dutilh BE, Rizkallah MR, Boleij A, Cole JN, Aziz RK |date=July 2014 |title=Pharmacomicrobiomics: the impact of human microbiome variations on systems pharmacology and personalized therapeutics |journal=Omics |volume=18 |issue=7 |pages=402–414 |doi=10.1089/omi.2014.0018 |pmc=4086029 |pmid=24785449}}</ref><ref name="Human microbiome">{{cite journal | vauthors = Cho I, Blaser MJ | title = The human microbiome: at the interface of health and disease | journal = Nature Reviews. Genetics | volume = 13 | issue = 4 | pages = 260–270 | date = March 2012 | pmid = 22411464 | doi = 10.1038/nrg3182 | quote=The composition of the microbiome varies by anatomical site (Figure 1). The primary determinant of community composition is anatomical location: interpersonal variation is substantial23,24 and is higher than the temporal variability seen at most sites in a single individual25.| pmc = 3418802 }}</ref> Since the total number of microbial cells in the human body (over 100 trillion) greatly outnumbers ''Homo sapiens'' cells (tens of trillions),{{#tag:ref|There is substantial variation in microbiome composition and microbial concentrations by anatomical site.<ref name="Pharmacomicrobiomics" /><ref name="Human microbiome" /> Fluid from the human colon – which contains the highest concentration of microbes of any anatomical site – contains approximately one trillion (10^12) bacterial cells/ml.<ref name="Pharmacomicrobiomics" />|group="note"}}<ref name="Pharmacomicrobiomics" /><ref name="Gut feeling">{{Cite journal |vauthors=Hutter T, Gimbert C, Bouchard F, Lapointe FJ |year=2015 |title=Being human is a gut feeling |journal=Microbiome |volume=3 |article-number=9 |doi=10.1186/s40168-015-0076-7 |pmc=4359430 |pmid=25774294|doi-access=free }}</ref> there is considerable potential for interactions between drugs and an individual's microbiome, including: drugs altering the composition of the human microbiome, drug metabolism by microbial enzymes modifying the drug's pharmacokinetic profile, and microbial drug metabolism affecting a drug's clinical efficacy and toxicity profile.<ref name="Pharmacomicrobiomics" /><ref name="Human microbiome" /><ref name="Microbial amphetamine metabolism - E. coli">{{cite journal |last1=Kumar |first1=Kundan |last2=Dhoke |first2=Gaurao V. |last3=Sharma |first3=Ashok K. |last4=Jaiswal |first4=Shubham K. |last5=Sharma |first5=Vineet K. |title=Mechanistic elucidation of amphetamine metabolism by tyramine oxidase from human gut microbiota using molecular dynamics simulations |journal=Journal of Cellular Biochemistry |date=July 2019 |volume=120 |issue=7 |pages=11206–11215 |doi=10.1002/jcb.28396 |pmid=30701587 }}</ref>

Apart from carbohydrates, gut microbiota can also metabolize other xenobiotics such as drugs, phytochemicals, and food toxicants. More than 30 drugs have been shown to be metabolized by gut microbiota.<ref>{{Cite journal |last1=Sousa |first1=Tiago |last2=Paterson |first2=Ronnie |last3=Moore |first3=Vanessa |last4=Carlsson |first4=Anders |last5=Abrahamsson |first5=Bertil |last6=Basit |first6=Abdul W |year=2008 |title=The gastrointestinal microbiota as a site for the biotransformation of drugs |journal=International Journal of Pharmaceutics |volume=363 |issue=1–2 |pages=1–25 |doi=10.1016/j.ijpharm.2008.07.009 |pmid=18682282}}</ref> The microbial metabolism of drugs can sometimes inactivate the drug.<ref>{{Cite journal |last1=Haiser |first1=H. J |last2=Gootenberg |first2=D. B |last3=Chatman |first3=K |last4=Sirasani |first4=G |last5=Balskus |first5=E. P |last6=Turnbaugh |first6=P. J |year=2013 |title=Predicting and Manipulating Cardiac Drug Inactivation by the Human Gut Bacterium Eggerthella lenta |journal=Science |volume=341 |issue=6143 |pages=295–298 |bibcode=2013Sci...341..295H |doi=10.1126/science.1235872 |pmc=3736355 |pmid=23869020}}</ref>

===== Contribution to drug metabolism ===== The gut microbiota is an enriched community that contains diverse genes with huge biochemical capabilities to modify drugs, especially those taken by mouth.<ref name=":8">{{cite journal |last1=Koppel |first1=Nitzan |last2=Maini Rekdal |first2=Vayu |last3=Balskus |first3=Emily P. |title=Chemical transformation of xenobiotics by the human gut microbiota |journal=Science |date=23 June 2017 |volume=356 |issue=6344 |article-number=eaag2770 |doi=10.1126/science.aag2770 |pmid=28642381 |pmc=5534341 }}</ref> Gut microbiota can affect drug metabolism via direct and indirect mechanisms.<ref name="Spanogiannopoulos 273–287">{{cite journal |last1=Spanogiannopoulos |first1=Peter |last2=Bess |first2=Elizabeth N. |last3=Carmody |first3=Rachel N. |last4=Turnbaugh |first4=Peter J. |title=The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism |journal=Nature Reviews Microbiology |date=May 2016 |volume=14 |issue=5 |pages=273–287 |doi=10.1038/nrmicro.2016.17 |pmid=26972811 |pmc=5243131 }}</ref> The direct mechanism is mediated by the microbial enzymes that can modify the chemical structure of the administered drugs.<ref name="Maini Rekdal">{{cite journal |last1=Maini Rekdal |first1=Vayu |last2=Bess |first2=Elizabeth N. |last3=Bisanz |first3=Jordan E. |last4=Turnbaugh |first4=Peter J. |last5=Balskus |first5=Emily P. |title=Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism |journal=Science |date=14 June 2019 |volume=364 |issue=6445 |article-number=eaau6323 |doi=10.1126/science.aau6323 |pmid=31196984 |pmc=7745125 }}</ref> Conversely, the indirect pathway is mediated by the microbial metabolites which affect the expression of host metabolizing enzymes such as cytochrome P450.<ref name="Dempsey 481–490">{{cite journal |last1=Dempsey |first1=Joseph L. |last2=Cui |first2=Julia Yue |title=Microbiome Is a Functional Modifier of P450 Drug Metabolism |journal=Current Pharmacology Reports |date=December 2019 |volume=5 |issue=6 |pages=481–490 |doi=10.1007/s40495-019-00200-w |pmid=33312848 |pmc=7731899 }}</ref><ref name="Spanogiannopoulos 273–287" /> The effects of the gut microbiota on the pharmacokinetics and bioavailability of the drug have been investigated a few decades ago.<ref>{{Cite journal |last1=Boerner |first1=Udo |last2=Abbott |first2=Seth |last3=Roe |first3=Robert L. |date=January 1975 |title=The Metabolism of Morphine and Heroin in Man |url=|journal=Drug Metabolism Reviews |volume=4 |issue=1 |pages=39–73 |doi=10.3109/03602537508993748 |pmid=1204496 }}</ref><ref name="Dobkin 325–327">{{cite journal |last1=Dobkin |first1=Jay F. |last2=Saha |first2=Jnan R. |last3=Butler |first3=Vincent P. |last4=Neu |first4=Harold C. |last5=Lindenbaum |first5=John |title=Digoxin-Inactivating Bacteria: Identification in Human Gut Flora |journal=Science |date=15 April 1983 |volume=220 |issue=4594 |pages=325–327 |doi=10.1126/science.6836275 |pmid=6836275 }}</ref><ref>{{cite journal |last1=Sahota |first1=S. S. |last2=Bramley |first2=P. M. |last3=Menzies |first3=I. S. |title=The Fermentation of Lactulose by Colonic Bacteria |journal=Microbiology |date=February 1982 |volume=128 |issue=2 |pages=319–325 |doi=10.1099/00221287-128-2-319 |pmid=6804597 |doi-access=free }}</ref> These effects can be varied; it could activate the inactive drugs such as lovastatin,<ref name="Yoo 1508–1513">{{cite journal |last1=Yoo |first1=Dae-Hyoung |last2=Kim |first2=In Sook |last3=Van Le |first3=Thi Kim |last4=Jung |first4=Il-Hoon |last5=Yoo |first5=Hye Hyun |last6=Kim |first6=Dong-Hyun |title=Gut Microbiota-Mediated Drug Interactions between Lovastatin and Antibiotics |journal=Drug Metabolism and Disposition |date=September 2014 |volume=42 |issue=9 |pages=1508–1513 |doi=10.1124/dmd.114.058354 |pmid=24947972 }}</ref> inactivate the active drug such as digoxin<ref>{{Cite journal |last1=Haiser |first1=Henry J. |last2=Gootenberg |first2=David B. |last3=Chatman |first3=Kelly |last4=Sirasani |first4=Gopal |last5=Balskus |first5=Emily P. |last6=Turnbaugh |first6=Peter J. |date=19 July 2013 |title=Predicting and Manipulating Cardiac Drug Inactivation by the Human Gut Bacterium ''Eggerthella lenta'' |journal=Science |volume=341 |issue=6143 |pages=295–298 |doi=10.1126/science.1235872 |pmid=23869020 |pmc=3736355 |bibcode=2013Sci...341..295H }}</ref> or induce drug toxicity as in irinotecan.<ref>{{cite journal |last1=Parvez |first1=Md Masud |last2=Basit |first2=Abdul |last3=Jariwala |first3=Parth B. |last4=Gáborik |first4=Zsuzsanna |last5=Kis |first5=Emese |last6=Heyward |first6=Scott |last7=Redinbo |first7=Matthew R. |last8=Prasad |first8=Bhagwat |title=Quantitative Investigation of Irinotecan Metabolism, Transport, and Gut Microbiome Activation |journal=Drug Metabolism and Disposition |date=August 2021 |volume=49 |issue=8 |pages=683–693 |doi=10.1124/dmd.121.000476 |pmid=34074730 |pmc=8407663 }}</ref> Since then, the impacts of the gut microbiota on the pharmacokinetics of many drugs were heavily studied.<ref name=":9" /><ref name=":8" />

The human gut microbiota plays a crucial role in modulating the effect of the administered drugs on the human. Directly, gut microbiota can synthesize and release a series of enzymes with the capability to metabolize drugs such as microbial biotransformation of L-dopa by decarboxylase and dehydroxylase enzymes.<ref name="Maini Rekdal" /> On the contrary, gut microbiota may also alter the metabolism of the drugs by modulating the host drug metabolism. This mechanism can be mediated by microbial metabolites or by modifying host metabolites which in turn change the expression of host metabolizing enzymes.<ref name="Dempsey 481–490" />

A large number of studies have demonstrated the metabolism of over 50 drugs by the gut microbiota.<ref name=":9">{{cite journal |last1=Sousa |first1=Tiago |last2=Paterson |first2=Ronnie |last3=Moore |first3=Vanessa |last4=Carlsson |first4=Anders |last5=Abrahamsson |first5=Bertil |last6=Basit |first6=Abdul W. |title=The gastrointestinal microbiota as a site for the biotransformation of drugs |journal=International Journal of Pharmaceutics |date=November 2008 |volume=363 |issue=1–2 |pages=1–25 |doi=10.1016/j.ijpharm.2008.07.009 |pmid=18682282 }}</ref><ref name="Spanogiannopoulos 273–287" /> For example, lovastatin (a cholesterol-lowering agent) which is a lactone prodrug is partially activated by the human gut microbiota forming active acid hydroxylated metabolites.<ref name="Yoo 1508–1513" /> Conversely, digoxin (a drug used to treat Congestive Heart Failure) is inactivated by a member of the gut microbiota (i.e. ''Eggerthella'' ''lanta'').<ref name=":0">{{cite journal |last1=Koppel |first1=Nitzan |last2=Bisanz |first2=Jordan E |last3=Pandelia |first3=Maria-Eirini |last4=Turnbaugh |first4=Peter J |last5=Balskus |first5=Emily P |title=Discovery and characterization of a prevalent human gut bacterial enzyme sufficient for the inactivation of a family of plant toxins |journal=eLife |date=15 May 2018 |volume=7 |article-number=e33953 |doi=10.7554/eLife.33953 |pmid=29761785 |pmc=5953540 |doi-access=free }}</ref> ''Eggerthella'' ''lanta'' has a cytochrome-encoding operon up-regulated by digoxin and associated with digoxin-inactivation.<ref name=":0" /> Gut microbiota can also modulate the efficacy and toxicity of chemotherapeutic agents such as irinotecan.<ref>{{cite journal |last1=Alexander |first1=James L. |last2=Wilson |first2=Ian D. |last3=Teare |first3=Julian |last4=Marchesi |first4=Julian R. |last5=Nicholson |first5=Jeremy K. |last6=Kinross |first6=James M. |title=Gut microbiota modulation of chemotherapy efficacy and toxicity |journal=Nature Reviews Gastroenterology & Hepatology |date=June 2017 |volume=14 |issue=6 |pages=356–365 |doi=10.1038/nrgastro.2017.20 |pmid=28270698 |hdl=10044/1/77636 |url=https://orca.cardiff.ac.uk/id/eprint/100186/ |hdl-access=free }}</ref> This effect is derived from the microbiome-encoded β-glucuronidase enzymes which recover the active form of the irinotecan causing gastrointestinal toxicity.<ref>{{cite journal |last1=Brandi |first1=Giovanni |last2=Dabard |first2=Jean |last3=Raibaud |first3=Pierre |last4=Di Battista |first4=Monica |last5=Bridonneau |first5=Chantal |last6=Pisi |first6=Anna Maria |last7=Morselli Labate |first7=Antonio Maria |last8=Pantaleo |first8=Maria Abbondanza |last9=De Vivo |first9=Antonello |last10=Biasco |first10=Guido |title=Intestinal microflora and digestive toxicity of irinotecan in mice. |journal=Clinical Cancer Research |date=15 February 2006 |volume=12 |issue=4 |pages=1299–1307 |doi=10.1158/1078-0432.CCR-05-0750 |pmid=16489087 }}</ref>

===== Secondary metabolites ===== This microbial community in the gut has a huge biochemical capability to produce distinct secondary metabolites that are sometimes produced from the metabolic conversion of dietary foods such as fibers, endogenous biological compounds such as indole or bile acids.<ref>{{Cite journal |last1=Koh |first1=Ara |last2=De Vadder |first2=Filipe |last3=Kovatcheva-Datchary |first3=Petia |last4=Bäckhed |first4=Fredrik |date=June 2016 |title=From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites |journal=Cell |volume=165 |issue=6 |pages=1332–1345 |doi=10.1016/j.cell.2016.05.041 |pmid=27259147 |doi-access=free }}</ref><ref>{{cite journal |last1=Konopelski |first1=Piotr |last2=Ufnal |first2=Marcin |title=Indoles - Gut Bacteria Metabolites of Tryptophan with Pharmacotherapeutic Potential |journal=Current Drug Metabolism |date=14 September 2018 |volume=19 |issue=10 |pages=883–890 |doi=10.2174/1389200219666180427164731 |pmid=29708069 }}</ref><ref name="Collins et al Bile acids and the gut microbiota">{{cite journal |last1=Collins |first1=Stephanie L. |last2=Stine |first2=Jonathan G. |last3=Bisanz |first3=Jordan E. |last4=Okafor |first4=C. Denise |last5=Patterson |first5=Andrew D. |title=Bile acids and the gut microbiota: metabolic interactions and impacts on disease |journal=Nature Reviews Microbiology |date=April 2023 |volume=21 |issue=4 |pages=236–247 |doi=10.1038/s41579-022-00805-x |pmid=36253479 }}</ref> Microbial metabolites especially short chain fatty acids (SCFAs) and secondary bile acids (BAs) play important roles for the human in health and disease states.<ref>{{cite journal |last1=Yang |first1=Wenjing |last2=Yu |first2=Tianming |last3=Huang |first3=Xiangsheng |last4=Bilotta |first4=Anthony J. |last5=Xu |first5=Leiqi |last6=Lu |first6=Yao |last7=Sun |first7=Jiaren |last8=Pan |first8=Fan |last9=Zhou |first9=Jia |last10=Zhang |first10=Wenbo |last11=Yao |first11=Suxia |last12=Maynard |first12=Craig L. |last13=Singh |first13=Nagendra |last14=Dann |first14=Sara M. |last15=Liu |first15=Zhanju |last16=Cong |first16=Yingzi |title=Intestinal microbiota-derived short-chain fatty acids regulation of immune cell IL-22 production and gut immunity |journal=Nature Communications |date=8 September 2020 |volume=11 |issue=1 |page=4457 |doi=10.1038/s41467-020-18262-6 |pmid=32901017 |pmc=7478978 |bibcode=2020NatCo..11.4457Y }}</ref><ref>{{cite journal |last1=Murugesan |first1=Selvasankar |last2=Nirmalkar |first2=Khemlal |last3=Hoyo-Vadillo |first3=Carlos |last4=García-Espitia |first4=Matilde |last5=Ramírez-Sánchez |first5=Daniela |last6=García-Mena |first6=Jaime |title=Gut microbiome production of short-chain fatty acids and obesity in children |journal=European Journal of Clinical Microbiology & Infectious Diseases |date=April 2018 |volume=37 |issue=4 |pages=621–625 |doi=10.1007/s10096-017-3143-0 |pmid=29196878 }}</ref><ref name=":7" />

One of the most important bacterial metabolites produced by the gut microbiota is secondary bile acids (BAs).<ref name="Collins et al Bile acids and the gut microbiota"/> These metabolites are produced by the bacterial biotransformation of the primary bile acids such as cholic acid (CA) and chenodeoxycholic acid (CDCA) into secondary bile acids (BAs) lithocholic acid (LCA) and deoxy cholic acid (DCA) respectively.<ref name=":6">{{cite journal |last1=Jones |first1=Brian V. |last2=Begley |first2=Máire |last3=Hill |first3=Colin |last4=Gahan |first4=Cormac G. M. |last5=Marchesi |first5=Julian R. |title=Functional and comparative metagenomic analysis of bile salt hydrolase activity in the human gut microbiome |journal=Proceedings of the National Academy of Sciences |date=9 September 2008 |volume=105 |issue=36 |pages=13580–13585 |doi=10.1073/pnas.0804437105 |pmid=18757757 |pmc=2533232 |bibcode=2008PNAS..10513580J |doi-access=free }}</ref> Primary bile acids which are synthesized by hepatocytes and stored in the gall bladder possess hydrophobic characters. These metabolites are subsequently metabolized by the gut microbiota into secondary metabolites with increased hydrophobicity.<ref name=":6" /> Bile salt hydrolases (BSH) which are conserved across gut microbiota phyla such as ''Bacteroides'', ''Firmicutes'', and ''Actinobacteria'' responsible for the first step of secondary bile acids metabolism.<ref name=":6" /> Secondary bile acids (BAs) such as DCA and LCA have been demonstrated to inhibit both ''Clostridioides difficile'' germination and outgrowth.<ref name=":7">{{cite journal |last1=Thanissery |first1=Rajani |last2=Winston |first2=Jenessa A. |last3=Theriot |first3=Casey M. |title=Inhibition of spore germination, growth, and toxin activity of clinically relevant C. difficile strains by gut microbiota derived secondary bile acids |journal=Anaerobe |date=June 2017 |volume=45 |pages=86–100 |doi=10.1016/j.anaerobe.2017.03.004 |pmid=28279860 |pmc=5466893 }}</ref>

====Dysbiosis====

The gut microbiota is important for maintaining homeostasis in the intestine. Development of intestinal cancer is associated with an imbalance in the natural microflora (dysbiosis).<ref name="Cao2017">{{cite journal | vauthors = Cao H, Xu M, Dong W, Deng B, Wang S, Zhang Y, Wang S, Luo S, Wang W, Qi Y, Gao J, Cao X, Yan F, Wang B | title = Secondary bile acid-induced dysbiosis promotes intestinal carcinogenesis | journal = International Journal of Cancer | volume = 140 | issue = 11 | pages = 2545–2556 | date = June 2017 | pmid = 28187526 | doi = 10.1002/ijc.30643 | doi-access = free }}</ref> The secondary bile acid deoxycholic acid is associated with alterations of the microbial community that lead to increased intestinal carcinogenesis.<ref name = Cao2017/> Increased exposure of the colon to secondary bile acids resulting from dysbiosis can cause DNA damage, and such damage can produce carcinogenic mutations in cells of the colon.<ref name="Bernstein2022">{{cite journal | vauthors = Bernstein H, Bernstein C | title = Bile acids as carcinogens in the colon and at other sites in the gastrointestinal system | journal = Experimental Biology and Medicine | volume = 248 | issue = 1 | pages = 79–89 | date = January 2023 | pmid = 36408538 | pmc = 9989147 | doi = 10.1177/15353702221131858 }}</ref> The high density of bacteria in the colon (about 1012 per ml.) that are subject to dysbiosis compared to the relatively low density in the small intestine (about 102 per ml.) may account for the greater than 10-fold higher incidence of cancer in the colon compared to the small intestine.<ref name = Bernstein2022/>

=== Gut–brain axis === {{Main|Gut–brain axis}}

The gut microbiota contributes to digestion and immune modulation, as it plays a role in the gut-brain axis, where microbial metabolites such as short-chain fatty acids and neurotransmitters influence brain function and behavior. The gut–brain axis is the biochemical signaling that takes place between the gastrointestinal tract and the central nervous system.<ref name="2014Wangrev" /> That term has been expanded to include the role of the gut flora in the interplay; the term "microbiome––brain axis" is sometimes used to describe paradigms explicitly including the gut flora.<ref name="2014Wangrev" /><ref name="Mayer2014rev">{{Cite journal |last1=Mayer |first1=E. A |last2=Knight |first2=R |last3=Mazmanian |first3=S. K |last4=Cryan |first4=J. F |last5=Tillisch |first5=K |year=2014 |title=Gut Microbes and the Brain: Paradigm Shift in Neuroscience |journal=Journal of Neuroscience |volume=34 |issue=46 |pages=15490–15496 |doi=10.1523/JNEUROSCI.3299-14.2014 |pmc=4228144 |pmid=25392516}}</ref><ref name="DinanandCryan2015">{{Cite journal |last1=Dinan |first1=Timothy G |last2=Cryan |first2=John F |year=2015 |title=The impact of gut microbiota on brain and behavior |journal=Current Opinion in Clinical Nutrition and Metabolic Care |volume=18 |issue=6 |pages=552–558 |doi=10.1097/MCO.0000000000000221 |pmid=26372511 }}</ref> Broadly defined, the gut-brain axis includes the central nervous system, neuroendocrine and neuroimmune systems including the hypothalamic–pituitary–adrenal axis (HPA axis), sympathetic and parasympathetic arms of the autonomic nervous system including the enteric nervous system, the vagus nerve, and the gut microbiota.<ref name="2014Wangrev" /><ref name="DinanandCryan2015" />

A 2016 systematic review of preclinical studies and small human trials conducted with certain commercially available strains of probiotic bacteria found that ''Bifidobacterium'' and ''Lactobacillus'' genera (''B. longum'', ''B. breve'', ''B. infantis'', ''L. helveticus'', ''L. rhamnosus'', ''L. plantarum'', and ''L. casei''), were of interest for certain central nervous system disorders.<ref name="CNS SystRev 2016">{{Cite journal |last1=Wang |first1=Huiying |last2=Lee |first2=In-Seon |last3=Braun |first3=Christoph |last4=Enck |first4=Paul |year=2016 |title=Effect of Probiotics on Central Nervous System Functions in Animals and Humans: A Systematic Review |journal=Journal of Neurogastroenterology and Motility |volume=22 |issue=4 |pages=589–605 |doi=10.5056/jnm16018 |pmc=5056568 |pmid=27413138}}</ref>

== Alterations in microbiota balance ==

=== Effects of antibiotic use ===

Altering the numbers of gut bacteria, for example by taking broad-spectrum antibiotics, may affect the host's health and ability to digest food.<ref name="Carman">{{Cite journal |last1=Carman |first1=Robert J. |last2=Simon |first2=Mary Alice |last3=Fernández |first3=Haydée |last4=Miller |first4=Margaret A. |last5=Bartholomew |first5=Mary J. |year=2004 |title=Ciprofloxacin at low levels disrupts colonization resistance of human fecal microflora growing in chemostats |journal=Regulatory Toxicology and Pharmacology |volume=40 |issue=3 |pages=319–326 |doi=10.1016/j.yrtph.2004.08.005 |pmid=15546686}}</ref> Antibiotics can cause antibiotic-associated diarrhea by irritating the bowel directly, changing the levels of microbiota, or allowing pathogenic bacteria to grow.<ref name="Beaugerie L and Petit JC" /> Another harmful effect of antibiotics is the increase in numbers of antibiotic-resistant bacteria found after their use, which, when they invade the host, cause illnesses that are difficult to treat with antibiotics.<ref name=Carman/>

Changing the numbers and species of gut microbiota can reduce the body's ability to ferment carbohydrates and metabolize bile acids and may cause diarrhea. Carbohydrates that are not broken down may absorb too much water and cause runny stools, or lack of SCFAs produced by gut microbiota could cause diarrhea.<ref name="Beaugerie L and Petit JC" />

A reduction in levels of native bacterial species also disrupts their ability to inhibit the growth of harmful species such as ''C. difficile'' and ''Salmonella'' Kedougou, and these species can get out of hand, though their overgrowth may be incidental and not be the true cause of diarrhea.<ref name="Guarner and Malagelada 2003b" /><ref name="Beaugerie L and Petit JC" /><ref name=Carman/> Emerging treatment protocols for C. difficile infections involve fecal microbiota transplantation of donor feces (see Fecal transplant).<ref>{{cite journal |last1=Hvas |first1=Christian Lodberg |last2=Baunwall |first2=Simon Mark Dahl |last3=Erikstrup |first3=Christian |title=Faecal microbiota transplantation: A life-saving therapy challenged by commercial claims for exclusivity |journal=eClinicalMedicine |date=July 2020 |volume=24 |article-number=100436 |doi=10.1016/j.eclinm.2020.100436 |pmc=7334803 |pmid=32642633 }}</ref> Initial reports of treatment describe success rates of 90%, with few side effects. Efficacy is speculated to result from restoring bacterial balances of bacteroides and firmicutes classes of bacteria.<ref name="Brandt">{{Cite journal |last1=Brandt |first1=Lawrence J. |last2=Borody |first2=Thomas Julius |last3=Campbell |first3=Jordana |year=2011 |title=Endoscopic Fecal Microbiota Transplantation |journal=Journal of Clinical Gastroenterology |volume=45 |issue=8 |pages=655–657 |doi=10.1097/MCG.0b013e3182257d4f |pmid=21716124 |doi-access=free }}</ref>

The composition of the gut microbiome also changes in severe illnesses, due not only to antibiotic use but also to such factors as ischemia of the gut, failure to eat, and immune compromise. Negative effects from this have led to interest in selective digestive tract decontamination, a treatment to kill only pathogenic bacteria and allow the re-establishment of healthy ones.<ref name="Knight">{{Cite journal |last1=Knight |first1=DJW |last2=Girling |first2=KJ |year=2003 |title=Gut flora in health and disease |journal=The Lancet |volume=361 |issue=9371 |pages=512–519 |doi=10.1016/S0140-6736(03)13438-1 |pmid=12781578 |doi-access=free }}</ref>

Antibiotics alter the population of the microbiota in the gastrointestinal tract, and this may change the intra-community metabolic interactions, modify caloric intake by using carbohydrates, and globally affect host metabolic, hormonal, and immune homeostasis.<ref name= cho2012/>

There is reasonable evidence that taking probiotics containing ''Lactobacillus'' species may help prevent antibiotic-associated diarrhea and that taking probiotics with ''Saccharomyces'' (e.g., ''Saccharomyces boulardii '') may help to prevent ''Clostridioides difficile'' infection following systemic antibiotic treatment.<ref name="JFP2016rev">{{Cite journal |last1=Schneiderhan |first1=J |last2=Master-Hunter |first2=T |last3=Locke |first3=A |year=2016 |title=Targeting gut flora to treat and prevent disease |journal=The Journal of Family Practice |volume=65 |issue=1 |pages=34–38 |pmid=26845162}}</ref>

=== Pregnancy ===

The gut microbiota of a woman changes as pregnancy advances, with the changes similar to those seen in metabolic syndromes such as diabetes. The change in gut microbiota causes no ill effects. The newborn's gut microbiota resemble the mother's first-trimester samples. The diversity of the microbiome decreases from the first to third trimester, as the numbers of certain species go up.<ref name="Mueller 109–117">{{Cite journal |last1=Mueller |first1=Noel T. |last2=Bakacs |first2=Elizabeth |last3=Combellick |first3=Joan |last4=Grigoryan |first4=Zoya |last5=Dominguez-Bello |first5=Maria G. |year=2015 |title=The infant microbiome development: mom matters |journal=Trends in Molecular Medicine |volume=21 |issue=2 |pages=109–117 |doi=10.1016/j.molmed.2014.12.002 |pmc=4464665 |pmid=25578246}}</ref><ref>{{Cite journal |last1=Baker |first1=Monya |year=2012 |title=Pregnancy alters resident gut microbes |journal=Nature |doi=10.1038/nature.2012.11118 |doi-access=free }}</ref>

=== Probiotics, prebiotics, synbiotics, and pharmabiotics === Probiotics contain live microorganisms. When consumed, they are believed to provide health benefits by altering the microbiome composition.<ref name=":10">{{Cite journal |last1=Horta-Baas |first1=Gabriel |last2=Sandoval-Cabrera |first2=Antonio |last3=Romero-Figueroa |first3=María del Socorro |date=2021-07-03 |title=Modification of Gut Microbiota in Inflammatory Arthritis: Highlights and Future Challenges |url=https://link.springer.com/article/10.1007/s11926-021-01031-9 |journal=Current Rheumatology Reports |language=en |volume=23 |issue=8 |page=67 |doi=10.1007/s11926-021-01031-9 |pmid=34218340 |issn=1534-6307|url-access=subscription }}</ref><ref name="Expert">{{Cite journal |last1=Hill |first1=Colin |last2=Guarner |first2=Francisco |last3=Reid |first3=Gregor |last4=Gibson |first4=Glenn R |last5=Merenstein |first5=Daniel J |last6=Pot |first6=Bruno |last7=Morelli |first7=Lorenzo |last8=Canani |first8=Roberto Berni |last9=Flint |first9=Harry J |last10=Salminen |first10=Seppo |last11=Calder |first11=Philip C |last12=Sanders |first12=Mary Ellen |year=2014 |title=The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic |journal=Nature Reviews Gastroenterology & Hepatology |volume=11 |issue=8 |pages=506–514 |doi=10.1038/nrgastro.2014.66 |pmid=24912386 |doi-access=free|hdl=2164/4189 |hdl-access=free }}</ref><ref name="bridging">{{Cite journal |last1=Rijkers |first1=Ger T |last2=De Vos |first2=Willem M |last3=Brummer |first3=Robert-Jan |last4=Morelli |first4=Lorenzo |last5=Corthier |first5=Gerard |last6=Marteau |first6=Philippe |year=2011 |title=Health benefits and health claims of probiotics: Bridging science and marketing |journal=British Journal of Nutrition |volume=106 |issue=9 |pages=1291–1296 |doi=10.1017/S000711451100287X |pmid=21861940 |doi-access=free}}</ref> Current research explores using probiotics as a way to restore the microbial balance of the intestine by stimulating the immune system and inhibiting pro-inflammatory cytokines.<ref name=":10" />

With regard to gut microbiota, prebiotics are typically non-digestible, fiber compounds that pass undigested through the upper part of the gastrointestinal tract and stimulate the growth or activity of advantageous gut flora by acting as substrate for them.<ref name="gibson">{{Cite journal |last1=Gibson |first1=Glenn R |year=2004 |title=Fibre and effects on probiotics (the prebiotic concept) |journal=Clinical Nutrition Supplements |volume=1 |issue=2 |pages=25–31 |doi=10.1016/j.clnu.2004.09.005}}</ref><ref name="2015defRev">{{Cite journal |last1=Hutkins |first1=Robert W |last2=Krumbeck |first2=Janina A |last3=Bindels |first3=Laure B |last4=Cani |first4=Patrice D |last5=Fahey |first5=George |last6=Goh |first6=Yong Jun |last7=Hamaker |first7=Bruce |last8=Martens |first8=Eric C |last9=Mills |first9=David A |last10=Rastal |first10=Robert A |last11=Vaughan |first11=Elaine |last12=Sanders |first12=Mary Ellen |year=2016 |title=Prebiotics: Why definitions matter |journal=Current Opinion in Biotechnology |volume=37 |pages=1–7 |doi=10.1016/j.copbio.2015.09.001 |pmc=4744122 |pmid=26431716}}</ref>

Synbiotics refers to food ingredients or dietary supplements combining probiotics and prebiotics in a form of synergism.<ref>{{Cite journal |last1=Pandey |first1=Kavita. R |last2=Naik |first2=Suresh. R |last3=Vakil |first3=Babu. V |year=2015 |title=Probiotics, prebiotics and synbiotics- a review |journal=Journal of Food Science and Technology |volume=52 |issue=12 |pages=7577–7587 |doi=10.1007/s13197-015-1921-1 |pmc=4648921 |pmid=26604335}}</ref>

The term "pharmabiotics" is used in various ways, to mean: pharmaceutical formulations (standardized manufacturing that can obtain regulatory approval as a drug) of probiotics, prebiotics, or synbiotics;<ref>{{Cite journal |last1=Broeckx |first1=Géraldine |last2=Vandenheuvel |first2=Dieter |last3=Claes |first3=Ingmar J.J |last4=Lebeer |first4=Sarah |last5=Kiekens |first5=Filip |year=2016 |title=Drying techniques of probiotic bacteria as an important step towards the development of novel pharmabiotics |url=https://repository.uantwerpen.be/docman/irua/9d9f03/132884.pdf |journal=International Journal of Pharmaceutics |volume=505 |issue=1–2 |pages=303–318 |doi=10.1016/j.ijpharm.2016.04.002 |pmid=27050865 |hdl-access=free |hdl=10067/1328840151162165141}}</ref> probiotics that have been genetically engineered or otherwise optimized for best performance (shelf life, survival in the digestive tract, etc.);<ref>{{Cite journal |last1=Sleator |first1=Roy D |last2=Hill |first2=Colin |year=2009 |title=Rational Design of Improved Pharmabiotics |journal=Journal of Biomedicine and Biotechnology |volume=2009 |article-number=275287 |doi=10.1155/2009/275287 |pmc=2742647 |pmid=19753318 |doi-access=free}}</ref> and the natural products of gut flora metabolism (vitamins, etc.).<ref>{{Cite journal |last1=Patterson |first1=Elaine |last2=Cryan |first2=John F |last3=Fitzgerald |first3=Gerald F |last4=Ross |first4=R. Paul |last5=Dinan |first5=Timothy G |last6=Stanton |first6=Catherine |year=2014 |title=Gut microbiota, the pharmabiotics they produce and host health |journal=Proceedings of the Nutrition Society |volume=73 |issue=4 |pages=477–489 |doi=10.1017/S0029665114001426 |pmid=25196939 |doi-access=free}}</ref>

There is some evidence that treatment with some probiotic strains of bacteria may be effective in treatment of irritable bowel syndrome, inflammatory bowel disease, and abdominal bloating.<ref name="FordQuigley2014">{{cite journal |doi=10.1038/ajg.2014.202 |pmid=25070051 |title=Efficacy of Prebiotics, Probiotics and Synbiotics in Irritable Bowel Syndrome and Chronic Idiopathic Constipation: Systematic Review and Meta-analysis |journal=The American Journal of Gastroenterology |volume=109 |issue=10 |pages=1547–1561; quiz 1546, 1562 |year=2014 |last1=Ford |first1=Alexander C |last2=Quigley |first2=Eamonn M M |last3=Lacy |first3=Brian E |last4=Lembo |first4=Anthony J |last5=Saito |first5=Yuri A |last6=Schiller |first6=Lawrence R |last7=Soffer |first7=Edy E |last8=Spiegel |first8=Brennan M R |last9=Moayyedi |first9=Paul }}</ref><ref name=Ghouri2014>{{cite journal |doi=10.2147/CEG.S27530 |pmid=25525379 |pmc=4266241 |title=Systematic review of randomized controlled trials of probiotics, prebiotics, and synbiotics in inflammatory bowel disease |journal=Clinical and Experimental Gastroenterology |volume=7 |pages=473–487 |year=2014 |last1=Dupont |first1=Andrew |last2=Richards |last3=Jelinek |first3=Katherine A |last4=Krill |first4=Joseph |last5=Rahimi |first5=Erik |last6=Ghouri |first6=Yezaz |doi-access=free }}</ref><ref>{{cite journal |doi=10.1111/1751-2980.12087 |pmid=23848393 |title=Recent progress on the role of gut microbiota in the pathogenesis of inflammatory bowel disease |journal=Journal of Digestive Diseases |volume=14 |issue=10 |pages=513–517 |year=2013 |last1=Yu |first1=Cheng Gong |last2=Huang |first2=Qin |doi-access=free }}</ref><ref>{{Cite journal |last1=Crucillà |first1=Salvatore |last2=Caldart |first2=Federico |last3=Michelon |first3=Marco |last4=Marasco |first4=Giovanni |last5=Costantino |first5=Andrea |date=2024-08-14 |title=Functional Abdominal Bloating and Gut Microbiota: An Update |journal=Microorganisms |volume=12 |issue=8 |page=1669 |doi=10.3390/microorganisms12081669 |doi-access=free |pmc=11357468 |pmid=39203511 }}</ref> Those organisms most likely to result in a decrease of symptoms have included: * ''Bifidobacterium breve'' * ''Bifidobacterium infantis'' * ''Enterococcus faecium'' * ''Lactobacillus plantarum'' * ''Lactobacillus reuteri'' * ''Lactobacillus rhamnosus'' * ''Lactobacillus salivarius'' * ''Propionibacterium freudenreichii'' * ''Saccharomyces boulardii'' * ''Escherichia coli Nissle 1917'' * ''Streptococcus thermophilus''

=== Research === Tests for whether non-antibiotic drugs may impact human gut-associated bacteria were performed by ''in vitro'' analysis on more than 1000 marketed drugs against 40 gut bacterial strains, demonstrating that 24% of the drugs inhibited the growth of at least one of the bacterial strains.<ref>{{cite journal |doi=10.1038/nature25979 |pmid=29555994 |pmc=6108420 |title=Extensive impact of non-antibiotic drugs on human gut bacteria |journal=Nature |volume=555 |issue=7698 |pages=623–628 |year=2018 |last1=Maier |first1=Lisa |last2=Pruteanu |first2=Mihaela |last3=Kuhn |first3=Michael |last4=Zeller |first4=Georg |last5=Telzerow |first5=Anja |last6=Anderson |first6=Exene Erin |last7=Brochado |first7=Ana Rita |last8=Fernandez |first8=Keith Conrad |last9=Dose |first9=Hitomi |last10=Mori |first10=Hirotada |last11=Patil |first11=Kiran Raosaheb |last12=Bork |first12=Peer |last13=Typas |first13=Athanasios |bibcode=2018Natur.555..623M }}</ref>

== Role in disease ==

Bacteria in the digestive tract can contribute to and be affected by disease in various ways. The presence or overabundance of some kinds of bacteria may contribute to inflammatory disorders such as inflammatory bowel disease.<ref name="Guarner and Malagelada 2003b" /> Additionally, metabolites from certain members of the gut flora may influence host signalling pathways, contributing to disorders such as obesity and colon cancer.<ref name="Guarner and Malagelada 2003b" /> Some gut bacteria may also cause infections and sepsis, for example when they are allowed to pass from the gut into the rest of the body.<ref name="Guarner and Malagelada 2003b" />

=== Ulcers === ''Helicobacter pylori'' infection can initiate formation of stomach ulcers when the bacteria penetrate the stomach epithelial lining, then causing an inflammatory phagocytotic response.<ref name="kamboj">{{cite journal |last1=Kamboj |first1=Amrit K. |last2=Cotter |first2=Thomas G. |last3=Oxentenko |first3=Amy S. |title=Helicobacter pylori |journal=Mayo Clinic Proceedings |date=April 2017 |volume=92 |issue=4 |pages=599–604 |doi=10.1016/j.mayocp.2016.11.017 |pmid=28209367 }}</ref> In turn, the inflammation damages parietal cells which release excessive hydrochloric acid into the stomach and produce less of the protective mucus.<ref name="hopkins">{{cite web |title=Peptic ulcer disease |url=https://www.hopkinsmedicine.org/gastroenterology_hepatology/_pdfs/esophagus_stomach/peptic_ulcer_disease.pdf |publisher=The Johns Hopkins University School of Medicine |access-date=21 October 2020 |date=2013}}</ref> Injury to the stomach lining, leading to ulcers, develops when gastric acid overwhelms the defensive properties of cells and inhibits endogenous prostaglandin synthesis, reduces mucus and bicarbonate secretion, reduces mucosal blood flow, and lowers resistance to injury.<ref name=hopkins/> Reduced protective properties of the stomach lining increase vulnerability to further injury and ulcer formation by stomach acid, pepsin, and bile salts.<ref name=kamboj/><ref name=hopkins/>

===Bowel perforation=== Normally-commensal bacteria can harm the host if they extrude from the intestinal tract.<ref name=Sommer2013rev/><ref name=Faderl2015rev/> Translocation, which occurs when bacteria leave the gut through its mucosal lining, can occur in a number of different diseases.<ref name=Faderl2015rev/> If the gut is perforated, bacteria invade the interstitium, causing a potentially fatal infection.<ref name=Prescotts/>{{rp|715}}

=== Inflammatory bowel diseases === The two main types of inflammatory bowel diseases, Crohn's disease and ulcerative colitis, are chronic inflammatory disorders of the gut; the causes of these diseases are unknown and issues with the gut flora and its relationship with the host have been implicated in these conditions.<ref name=Shen2016rev/><ref name="BurischJess2013">{{cite journal |doi=10.1016/j.crohns.2013.01.010 |pmid=23395397 |title=The burden of inflammatory bowel disease in Europe |journal=Journal of Crohn's and Colitis |volume=7 |issue=4 |pages=322–337 |year=2013 |last1=Burisch |first1=Johan |last2=Jess |first2=Tine |last3=Martinato |first3=Matteo |last4=Lakatos |first4=Peter L |doi-access=free }}</ref><ref>{{cite journal |doi=10.1016/j.diabet.2016.04.004 |pmid=27179626 |title=Impact of gut microbiota on diabetes mellitus |journal=Diabetes & Metabolism |volume=42 |issue=5 |pages=303–315 |year=2016 |last1=Blandino |first1=G |last2=Inturri |first2=R |last3=Lazzara |first3=F |last4=Di Rosa |first4=M |last5=Malaguarnera |first5=L }}</ref><ref name=2016BoulangeRev>{{cite journal |doi=10.1186/s13073-016-0303-2|pmid=27098727|pmc=4839080|title=Impact of the gut microbiota on inflammation, obesity, and metabolic disease|journal=Genome Medicine|volume=8|issue=1|page=42|year=2016|last1=Boulangé|first1=Claire L|last2=Neves|first2=Ana Luisa|last3=Chilloux|first3=Julien|last4=Nicholson|first4=Jeremy K|last5=Dumas|first5=Marc-Emmanuel |doi-access=free }}</ref> Additionally, it appears that interactions of gut flora with the gut–brain axis have a role in IBD, with physiological stress mediated through the hypothalamic–pituitary–adrenal axis driving changes to intestinal epithelium and the gut flora in turn releasing factors and metabolites that trigger signaling in the enteric nervous system and the vagus nerve.<ref name=Saxena2016/>

The diversity of gut flora appears to be significantly diminished in people with inflammatory bowel diseases compared to healthy people; additionally, in people with ulcerative colitis, Proteobacteria and Actinobacteria appear to dominate; in people with Crohn's, ''Enterococcus faecium'' and several Proteobacteria appear to be over-represented.<ref name=Saxena2016/>

There is reasonable evidence that correcting gut flora imbalances by taking probiotics with ''Lactobacilli'' and ''Bifidobacteria'' can reduce visceral pain and gut inflammation in IBD.<ref name="JFP2016rev" />

=== Irritable bowel syndrome === Irritable bowel syndrome is a result of stress and chronic activation of the HPA axis; its symptoms include abdominal pain, changes in bowel movements, and an increase in proinflammatory cytokines. Overall, studies have found that the luminal and mucosal microbiota are changed in irritable bowel syndrome individuals, and these changes can relate to the type of irritation such as diarrhea or constipation. Also, there is a decrease in the diversity of the microbiome with low levels of fecal Lactobacilli and Bifidobacteria, high levels of facultative anaerobic bacteria such as ''Escherichia coli'', and increased ratios of Firmicutes: Bacteroidetes.<ref name="DinanandCryan2015" />

=== Asthma === With asthma, two hypotheses have been posed to explain its rising prevalence in the developed world. The hygiene hypothesis posits that children in the developed world are not exposed to enough microbes and thus may contain lower prevalence of specific bacterial taxa that play protective roles.<ref name=":2">{{cite journal |doi=10.1126/scitranslmed.aab2271 |pmid=26424567 |title=Early infancy microbial and metabolic alterations affect risk of childhood asthma |journal=Science Translational Medicine |volume=7 |issue=307 |pages=307ra152 |year=2015 |last1=Arrieta |first1=Marie-Claire |last2=Stiemsma |first2=Leah T |last3=Dimitriu |first3=Pedro A |last4=Thorson |first4=Lisa |last5=Russell |first5=Shannon |last6=Yurist-Doutsch |first6=Sophie |last7=Kuzeljevic |first7=Boris |last8=Gold |first8=Matthew J |last9=Britton |first9=Heidi M |last10=Lefebvre |first10=Diana L |last11=Subbarao |first11=Padmaja |last12=Mandhane |first12=Piush |last13=Becker |first13=Allan |last14=McNagny |first14=Kelly M |last15=Sears |first15=Malcolm R |last16=Kollmann |first16=Tobias |last17=Mohn |first17=William W |last18=Turvey |first18=Stuart E |last19=Brett Finlay |first19=B |doi-access=free }}</ref> The second hypothesis focuses on the Western pattern diet, which lacks whole grains and fiber and has an overabundance of simple sugars.<ref name="Shen2016rev" /> Both hypotheses converge on the role of short-chain fatty acids (SCFAs) in immunomodulation. These bacterial fermentation metabolites are involved in immune signalling that prevents the triggering of asthma and lower SCFA levels are associated with the disease.<ref name=":2" /><ref name=":3">{{cite journal |doi=10.1186/s13223-016-0173-6 |pmid=28077947 |pmc=5217603 |title=Asthma and the microbiome: Defining the critical window in early life |journal=Allergy, Asthma & Clinical Immunology |volume=13 |article-number=3 |year=2017 |last1=Stiemsma |first1=Leah T |last2=Turvey |first2=Stuart E |doi-access=free }}</ref> Lacking protective genera such as ''Lachnospira'', ''Veillonella'', ''Rothia'' and ''Faecalibacterium'' has been linked to reduced SCFA levels.<ref name=":2" /> Further, SCFAs are the product of bacterial fermentation of fiber, which is low in the Western pattern diet.<ref name="Shen2016rev" /><ref name=":3" /> SCFAs offer a link between gut flora and immune disorders, and as of 2016, this was an active area of research.<ref name="Shen2016rev" /> Similar hypotheses have also been posited for the rise of food and other allergies.<ref name=":02">{{cite journal |doi=10.1007/s00405-016-4058-6 |pmid=27115907 |title=The possible mechanisms of the human microbiome in allergic diseases |journal=European Archives of Oto-Rhino-Laryngology |volume=274 |issue=2 |pages=617–626 |year=2016 |last1=Ipci |first1=Kagan |last2=Altıntoprak |first2=Niyazi |last3=Muluk |first3=Nuray Bayar |last4=Senturk |first4=Mehmet |last5=Cingi |first5=Cemal }}</ref>

=== Diabetes mellitus type 1 === The connection between the gut microbiota and diabetes mellitus type 1 has also been linked to SCFAs, such as butyrate and acetate. Diets yielding butyrate and acetate from bacterial fermentation show increased Treg expression.<ref>{{cite journal |last1=Mariño |first1=Eliana |last2=Richards |first2=James L |last3=McLeod |first3=Keiran H |last4=Stanley |first4=Dragana |last5=Yap |first5=Yu Anne |last6=Knight |first6=Jacinta |last7=McKenzie |first7=Craig |last8=Kranich |first8=Jan |last9=Oliveira |first9=Ana Carolina |last10=Rossello |first10=Fernando J |last11=Krishnamurthy |first11=Balasubramanian |last12=Nefzger |first12=Christian M |last13=Macia |first13=Laurence |last14=Thorburn |first14=Alison |last15=Baxter |first15=Alan G |last16=Morahan |first16=Grant |last17=Wong |first17=Lee H |last18=Polo |first18=Jose M |last19=Moore |first19=Robert J |last20=Lockett |first20=Trevor J |last21=Clarke |first21=Julie M |last22=Topping |first22=David L |last23=Harrison |first23=Leonard C |last24=Mackay |first24=Charles R |title=Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes |journal=Nature Immunology |date=May 2017 |volume=18 |issue=5 |pages=552–562 |doi=10.1038/ni.3713 |pmid=28346408 }}</ref> Treg cells downregulate effector T cells, which in turn reduces the inflammatory response in the gut.<ref>{{cite journal |last1=Bettelli |first1=Estelle |last2=Carrier |first2=Yijun |last3=Gao |first3=Wenda |last4=Korn |first4=Thomas |last5=Strom |first5=Terry B. |last6=Oukka |first6=Mohamed |last7=Weiner |first7=Howard L. |last8=Kuchroo |first8=Vijay K. |title=Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells |journal=Nature |date=May 2006 |volume=441 |issue=7090 |pages=235–238 |doi=10.1038/nature04753 |pmid=16648838 }}</ref> Butyrate is an energy source for colon cells. butyrate-yielding diets thus decrease gut permeability by providing sufficient energy for the formation of tight junctions.<ref name=":4">{{cite journal |last1=Säemann |first1=Marcus D. |last2=Böhmig |first2=Georg A. |last3=Österreicher |first3=Christoph H. |last4=Burtscher |first4=Helmut |last5=Parolini |first5=Ornella |last6=Diakos |first6=Christos |last7=Stöckl |first7=Johannes |last8=Hörl |first8=Walter H. |last9=Zlabinger |first9=Gerhard J. |title=Anti-inflammatory effects of sodium butyrate on human monocytes: potent inhibition of IL-12 and up-regulation of IL-10 production |journal=The FASEB Journal |date=December 2000 |volume=14 |issue=15 |pages=2380–2382 |doi=10.1096/fj.00-0359fje |doi-access=free |pmid=11024006 }}</ref> Additionally, butyrate has also been shown to decrease insulin resistance, suggesting gut communities low in butyrate-producing microbes may increase chances of acquiring diabetes mellitus type 2.<ref name=":5">{{cite journal |doi=10.2337/db08-1637 |pmid=19366864 |pmc=2699871 |title=Butyrate Improves Insulin Sensitivity and Increases Energy Expenditure in Mice |journal=Diabetes |volume=58 |issue=7 |pages=1509–1517 |year=2009 |last1=Gao |first1=Z |last2=Yin |first2=J |last3=Zhang |first3=J |last4=Ward |first4=R. E |last5=Martin |first5=R. J |last6=Lefevre |first6=M |last7=Cefalu |first7=W. T |last8=Ye |first8=J }}</ref> Butyrate-yielding diets may also have potential colorectal cancer suppression effects.<ref name=":4" /> === Type 2 diabetes === The gut microbiota are very important for the host health because they play role in degradation of non-digestible polysaccharides (fermentation of resistant starch, oligosaccharides, inulin) strengthening gut integrity or shaping the intestinal epithelium, harvesting energy, protecting against pathogens, and regulating host immunity.<ref>{{Cite journal|last=Ibrahim|first=Nesma|date=2018-07-01|title=Gut Microbiota and Type 2 Diabetes Mellitus: What is The Link ?|url=http://aeji.journals.ekb.eg/article_9950.html|journal=Afro-Egyptian Journal of Infectious and Endemic Diseases|language=en|volume=6|issue=2|pages=112–119|doi=10.21608/aeji.2018.9950|s2cid=3900880 |issn=2090-7184|doi-access=free}}</ref><ref>{{Cite journal|last1=Thursby|first1=Elizabeth|last2=Juge|first2=Nathalie|date=2017-06-01|title=Introduction to the human gut microbiota|journal=Biochemical Journal|language=en|volume=474|issue=11|pages=1823–1836|doi=10.1042/BCJ20160510|issn=0264-6021|pmc=5433529|pmid=28512250}}</ref>

Several studies showed that the gut bacterial composition in diabetic patients became altered with increased levels of ''Lactobacillus gasseri'', ''Streptococcus mutans'' and Clostridiales members, with decrease in butyrate-producing bacteria such as ''Roseburia intestinalis'' and ''Faecalibacterium prausnitzii.''<ref name=":1">{{Cite journal|last1=Muñoz-Garach|first1=Araceli|last2=Diaz-Perdigones|first2=Cristina|last3=Tinahones|first3=Francisco J.|date=December 2016|title=Microbiota y diabetes mellitus tipo 2|journal=Endocrinología y Nutrición|language=es|volume=63|issue=10|pages=560–568|doi=10.1016/j.endonu.2016.07.008|pmid=27633134}}</ref><ref>{{Cite journal|last1=Blandino|first1=G.|last2=Inturri|first2=R.|last3=Lazzara|first3=F.|last4=Di Rosa|first4=M.|last5=Malaguarnera|first5=L.|date=2016-11-01|title=Impact of gut microbiota on diabetes mellitus|url=|journal=Diabetes & Metabolism|language=en|volume=42|issue=5|pages=303–315|doi=10.1016/j.diabet.2016.04.004|pmid=27179626|issn=1262-3636}}</ref> This alteration is due to many factors such as antibiotic abuse, diet, and age''.''

The decrease in butyrate production is associated with defects in intestinal permeability, which could lead to endotoxemia, which is the increased level of circulating Lipopolysaccharides from gram negative bacterial cells wall. It is found that endotoxemia has association with development of insulin resistance.<ref name=":1" />

In addition that butyrate production affects serotonin level.<ref name=":1" /> Elevated serotonin level has contribution in obesity, which is known to be a risk factor for development of diabetes.

===Cancer===

The human gut microbial composition is modulated by dietary bile acids.<ref name = Fogelson2023>{{cite journal |vauthors=Fogelson KA, Dorrestein PC, Zarrinpar A, Knight R |title=The gut microbial bile acid modulation and its relevance to digestive health and diseases |journal=Gastroenterology |volume=164 |issue=7 |pages=1069–1085 |date=June 2023|pmc=10205675|pmid=36841488 |doi=10.1053/j.gastro.2023.02.022 |url=}}</ref><ref name = Bernstein2023>{{cite journal |vauthors=Bernstein H, Bernstein C |title=Bile acids as carcinogens in the colon and at other sites in the gastrointestinal system |journal=Experimental Biology and Medicine (Maywood) |volume=248 |issue=1 |pages=79–89 |date=January 2023 |pmid=36408538|pmc= 9989147|doi=10.1177/15353702221131858}}</ref> There appears to be a metabolic link between cancer associated gut microbes and a fat- and meat rich diet.<ref>{{cite journal |vauthors=Wirbel J, Pyl PT, Kartal E, Zych K, Kashani A, Milanese A, Fleck JS, Voigt AY, Palleja A, Ponnudurai R, Sunagawa S, Coelho LP, Schrotz-King P, Vogtmann E, Habermann N, Niméus E, Thomas AM, Manghi P, Gandini S, Serrano D, Mizutani S, Shiroma H, Shiba S, Shibata T, Yachida S, Yamada T, Waldron L, Naccarati A, Segata N, Sinha R, Ulrich CM, Brenner H, Arumugam M, Bork P, Zeller G |title=Meta-analysis of fecal metagenomes reveals global microbial signatures that are specific for colorectal cancer |journal=Nat Med |volume=25 |issue=4 |pages=679–689 |date=April 2019 |pmid=30936547 |doi=10.1038/s41591-019-0406-6 |pmc=7984229 |url=|hdl=11572/232872 |hdl-access=free }}</ref> In rodents, elevated levels of bile acids produced by the gut microbiota in response to a high fat diet are associated with an increased the risk of colorectal cancer.<ref name = Bernstein2023/> The secondary bile acid deoxycholic acid, produced from the primary bile acid cholic acid by the gut microbiota, is elevated in the colonic contents of humans in response to a high fat diet.<ref name = Fogelson2023/><ref name = Bernstein2023/> In populations that have a high incidence of colorectal cancer fecal concentrations of bile acids, particularly deoxycholic acid produced by the action of gut microbiota, are higher.<ref name = Fogelson2023/><ref name = Bernstein2023/>

===Development and antibiotics=== The colonization of the human gut microbiota may start already before birth.<ref>Vandenplas, Y., Carnielli, V. P., Ksiazyk, J., Luna, M. S., Migacheva, N., Mosselmans, J. M., ... & Wabitsch, M. (2020), Factors affecting early-life intestinal microbiota development. Nutrition, 78, 110812.</ref> There are multiple factors in the environment that affects the development of the microbiota with birthmode being one of the most impactful.<ref>Korpela K, Helve O, Kolho KL, Saisto T, Skogberg K, Dikareva E, Stefanovic V, Salonen A, Andersson S, de Vos WM. Maternal Fecal Microbiota Transplantation in Cesarean-Born Infants Rapidly Restores Normal Gut Microbial Development: A Proof-of-Concept Study. Cell. 2020 Oct 15;183(2):324-334.e5. doi: 10.1016/j.cell.2020.08.047. Epub 2020 Oct 1. PMID 33007265.</ref>

Another factor that has been observed to cause huge changes in the gut microbiota, particularly in children, is the use of antibiotics, associating with health issues such as higher BMI,<ref>Korpela, K., Salonen, A., Saxen, H., Nikkonen, A., Peltola, V., Jaakkola, T., ... & Kolho, K. L. (2020). Antibiotics in early life associate with specific gut microbiota signatures in a prospective longitudinal infant cohort. Pediatric Research, 1-6</ref><ref>Schei, K., Simpson, M. R., Avershina, E., Rudi, K., Øien, T., Júlíusson, P. B., ... & Ødegård, R. A. (2020). Early Gut Fungal and Bacterial Microbiota and Childhood Growth. Frontiers in pediatrics, 8, 658</ref> and further an increased risk towards metabolic diseases such as obesity.<ref>Korpela, K., Salonen, A., Virta, L. J., Kekkonen, R. A., Forslund, K., Bork, P., & De Vos, W. M. (2016). Intestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children. Nature communications, 7, 10410</ref> In infants it was observed that amoxicillin and macrolides cause significant shifts in the gut microbiota characterized by a change in the bacterial classes Bifidobacteria, Enterobacteria and Clostridia.<ref>Korpela, K., Salonen, A., Saxen, H., Nikkonen, A., Peltola, V., Jaakkola, T., ... & Kolho, K. L. (2020). Antibiotics in early life associate with specific gut microbiota signatures in a prospective longitudinal infant cohort. Pediatric Research, 1-6.</ref> A single course of antibiotics in adults causes changes in both the bacterial and fungal microbiota, with even more persistent changes in the fungal communities.<ref name="Seelbinder, B. 2020">Seelbinder, B., Chen, J., Brunke, S., Vazquez-Uribe, R., Santhaman, R., Meyer, A. C., ... & Panagiotou, G. (2020). Antibiotics create a shift from mutualism to competition in human gut communities with a longer-lasting impact on fungi than bacteria. Microbiome, 8(1), 1-20</ref> The bacteria and fungi live together in the gut and there is most likely a competition for nutrient sources present.<ref>Cabral, D. J., Penumutchu, S., Norris, C., Morones-Ramirez, J. R., & Belenky, P. (2018). Microbial competition between Escherichia coli and Candida albicans reveals a soluble fungicidal factor. Microbial cell, 5(5), 249</ref><ref>Peleg, A. Y., Hogan, D. A., & Mylonakis, E. (2010). Medically important bacterial–fungal interactions. Nature Reviews Microbiology, 8(5), 340-349</ref> Seelbinder ''et al''. found that commensal bacteria in the gut regulate the growth and pathogenicity of ''Candida albicans'' by their metabolites, particularly by propionate, acetic acid and 5-dodecenoate.<ref name="Seelbinder, B. 2020"/> ''Candida'' has previously been associated with IBD<ref>Sokol H, Leducq V, Aschard H, Pham H P, Jegou S, Landman C, Cohen D, Liguori G, Bourrier A, Nion-Larmurier I, Cosnes J, Seksik P, Langella P, Skurnik D, Richard ML, Beaugerie L. Fungal microbiota dysbiosis in IBD. Gut 2017;66:1039–1048. doi: 10.1136/gutjnl-2015-310746</ref> and further it has been observed to be increased in non-responders to a biological drug, infliximab, given to IBD patients with severe IBD.<ref>Rebecka Ventin-Holmberg, Anja Eberl, Schahzad Saqib, Katri Korpela, Seppo Virtanen, Taina Sipponen, Anne Salonen, Päivi Saavalainen, Eija Nissilä, Bacterial and Fungal Profiles as Markers of Infliximab Drug Response in Inflammatory Bowel Disease, Journal of Crohn's and Colitis, 2020;, jjaa252, https://doi.org/10.1093/ecco-jcc/jjaa252</ref> Propionate and acetic acid are both short-chain fatty acids (SCFAs) that have been observed to be beneficial to gut microbiota health.<ref>El Hage, R., Hernandez-Sanabria, E., Calatayud Arroyo, M., Props, R., & Van de Wiele, T. (2019). Propionate-producing consortium restores antibiotic-induced dysbiosis in a dynamic in vitro model of the human intestinal microbial ecosystem. Frontiers in microbiology, 10, 1206.</ref><ref>Tian, X., Hellman, J., Horswill, A. R., Crosby, H. A., Francis, K. P., & Prakash, A. (2019). Elevated gut microbiome-derived propionate levels are associated with reduced sterile lung inflammation and bacterial immunity in mice. Frontiers in microbiology, 10, 159.</ref><ref>Li, Y., Faden, H. S., & Zhu, L. (2020). The response of the gut microbiota to dietary changes in the first two years of life. Frontiers in pharmacology, 11, 334.</ref> When antibiotics affect the growth of bacteria in the gut, there might be an overgrowth of certain fungi, which might be pathogenic when not regulated.<ref name="Seelbinder, B. 2020"/> ===Blood–brain barrier dysfunction=== The gut microbiome regulates the function of the blood–brain barrier (BBB) throughout life, at least partially due to microbial metabolites.<ref name="Tang et al"> {{cite journal | vauthors = Tang W, Zhu H, Feng Y, Guo R, Wan D | title = The Impact of Gut Microbiota Disorders on the Blood–Brain Barrier | journal = Infection and Drug Resistance | volume = 13 | pages = 3351–3363 | date = 2020 | pmid = 33061482 | doi = 10.2147/IDR.S254403 | pmc = 7532923 | doi-access = free }}</ref> The BBB is a selectively permeable membrane that tightly regulates the transfer of substances between the circulation and the brain parenchyma.<ref name="Langen et al"> {{cite journal | vauthors = Langen UH, Ayloo S, Gu C | title = Development and Cell Biology of the Blood-Brain Barrier | journal = Annual Review of Cell and Developmental Biology | volume = 35 | date = 2019| pages = 591–613 | pmid = 31299172 | doi = 10.1146/annurev-cellbio-100617-062608 | pmc = 8934576 }}</ref> During development, germ-free mice exhibit increased BBB permeability from embryonic stages through adulthood with reduced tight junction proteins, while colonization with mature microbiota restores barrier function through SCFAs like butyrate.<ref name="Braniste et al"> {{cite journal | vauthors = Braniste V, Al-Asmakh M, Kowal C, Anuar F, Abbaspour A, Tóth M, Korecka A, Bakocevic N, Ng LG, Kundu P, Gulyás B, Halldin C, Hultenby K, Nilsson H, Hebert H, Volpe BT, Diamond B, Pettersson S | title = The gut microbiota influences blood-brain barrier permeability in mice | journal = Science Translational Medicine | volume = 6 | pages = 263ra158 | date = 2016-11-19 | issue = 263 | pmid = 25411471 | doi = 10.1126/scitranslmed.3009759 | pmc = 4396848 }}</ref> This developmental impact persists, as mice with gut microbiota associated with preterm birth show early-life BBB hyperpermeability and cognitive deficits, whereas those with microbiota associated with full-term birth maintain an intact BBB.<ref name="Zemmel et al"> {{cite journal | vauthors = Zemmel ZM, Fan X, Yueyue Y, Markiewicz E, Tsai HM, Lu L, Little JC, Ramaswamy R, Andrews B, Claud EC, Lu J | title = Early-life gut microbiome maturity regulates blood–brain barrier and cognitive development | journal = Gut Microbes | volume = 17 | article-number = 2551879 | date = 2025 | issue = 1 | pmid = 40886152 | doi = 10.1080/19490976.2025.2551879 | pmc = 12416178 | doi-access = free }}</ref> During aging, altered microbiota composition with increased ''Firmicutes''/''Bacteroidetes'' ratio correlates with compromised BBB function, reduced P-glycoprotein activity, and cognitive impairment.<ref name="Hoffman et al"> {{cite journal | vauthors = Hoffman JD, Parikh I, Green SJ, Chlipala G, Mohney RB, Keaton M, Bauer B, Hartz A, Lin AL| title = Age Drives Distortion of Brain Metabolic, Vascular and Cognitive Functions, and the Gut Microbiome | journal = Frontiers in Aging Neuroscience | volume = 9 | date = 2017 | article-number = 298 | pmid = 28993728 | doi = 10.3389/fnagi.2017.00298 | pmc = 5622159 | doi-access = free}}</ref> These effects may be mediated by microbial metabolites including SCFAs that enhance barrier integrity and methylamines, where trimethylamine ''N''-oxide protects BBB function while its precursor trimethylamine disrupts it.<ref name="Hoyles et al"> {{cite journal | vauthors = Hoyles L, Pontifex MG, Rodriguez-Ramiro I, Anis-Alavi MA, Jelane KS, Snelling T, Solito E, Fonseca S, Carvalho AL, Carding SR, Müller M, Glen RC, Vauzour D, McArthur S | title = Regulation of blood–brain barrier integrity by microbiome-associated methylamines and cognition by trimethylamine N-oxide | journal = Microbiome | volume = 9 | date = 2021 | issue = 1 | article-number = 235 | pmid = 34836554 | doi = 10.1186/s40168-021-01181-z | pmc = 8626999 | doi-access = free}}</ref><ref name="Knox et al"> {{cite journal | vauthors = Knox EG, Aburto MR, Clarke G, Cryan JF, O'Driscoll CM | title = The blood-brain barrier in aging and neurodegeneration | journal = Molecular Psychiatry | volume = 27 | date = 2022 | issue = 6 | pages = 2659–2673 | pmid = 35361905 | doi = 10.1038/s41380-022-01511-z | pmc = 9156404 | doi-access = free}}</ref><ref name="Parker et al"> {{cite journal | vauthors = Parker A, Fonseca S, Carding C | title = Gut microbes and metabolites as modulators of blood-brain barrier integrity and brain health | journal = Gut Microbes | volume = 11 | issue = 2 | date = 2020 | article-number = 1638722 | pmid = 31368397 | doi = 10.1080/19490976.2019.1638722 | pmc = 7053956 | doi-access = free}}</ref><ref name="Kern et al"> {{cite journal | vauthors = Kern L, Mastandrea I, Melekhova A, Elinav E | title = Mechanisms by which microbiome-derived metabolites exert their impacts on neurodegeneration | journal = Cell Chemical Biology | volume = 32 | issue = 2 | date = 2025 | pages = 25–45 | pmid = 39326420 | doi = 10.1016/j.chembiol.2024.08.014}}</ref>

=== Obesity and metabolic syndrome === The gut flora have been implicated in obesity and metabolic syndrome due to a key role in the digestive process; the Western pattern diet appears to drive and maintain changes in the gut flora that in turn change how much energy is derived from food and how that energy is used.<ref name=2016BoulangeRev/><ref>{{cite journal |doi=10.1016/j.dsx.2016.01.024 |pmid=26916014 |title=Gut microbiome and metabolic syndrome |journal=Diabetes & Metabolic Syndrome: Clinical Research & Reviews |volume=10 |issue=2 |pages=S150–157 |year=2016 |last1=Mazidi |first1=Mohsen |last2=Rezaie |first2=Peyman |last3=Kengne |first3=Andre Pascal |last4=Mobarhan |first4=Majid Ghayour |last5=Ferns |first5=Gordon A }}</ref> One aspect of a healthy diet that is often lacking in the Western-pattern diet is fiber and other complex carbohydrates that a healthy gut flora require flourishing; changes to gut flora in response to a Western-pattern diet appear to increase the amount of energy generated by the gut flora which may contribute to obesity and metabolic syndrome.<ref name=JFP2016rev/> There is also evidence that microbiota influence eating behaviours based on the preferences of the microbiota, which can lead to the host consuming more food eventually resulting in obesity. It has generally been observed that with higher gut microbiome diversity, the microbiota will spend energy and resources on competing with other microbiota and less on manipulating the host. The opposite is seen with lower gut microbiome diversity, and these microbiotas may work together to create host food cravings.<ref name="Alcocketal2014">{{cite journal |doi=10.1002/bies.201400071 |pmid=25103109 |pmc=4270213 |title=Is eating behavior manipulated by the gastrointestinal microbiota? Evolutionary pressures and potential mechanisms |journal=BioEssays |volume=36 |issue=10 |pages=940–949 |year=2014 |last1=Alcock |first1=Joe |last2=Maley |first2=Carlo C |last3=Aktipis |first3=C. Athena }}</ref>

Additionally, the liver plays a dominant role in blood glucose homeostasis by maintaining a balance between the uptake and storage of glucose through the metabolic pathways of glycogenesis and gluconeogenesis. Intestinal lipids regulate glucose homeostasis involving a gut–brain–liver axis. The direct administration of lipids into the upper intestine increases the long chain fatty acyl-coenzyme A (LCFA-CoA) levels in the upper intestines and suppresses glucose production even under subdiaphragmatic vagotomy or gut vagal deafferentation. This interrupts the neural connection between the brain and the gut and blocks the upper intestinal lipids' ability to inhibit glucose production. The gut–brain–liver axis and gut microbiota composition can regulate the glucose homeostasis in the liver and provide potential therapeutic methods to treat obesity and diabetes.<ref name="Chen2013rev">{{cite journal |doi=10.1007/s13238-013-3017-x |pmid=23686721 |pmc=4875553 |title=The role of gut microbiota in the gut-brain axis: Current challenges and perspectives |journal=Protein & Cell |volume=4 |issue=6 |pages=403–414 |year=2013 |last1=Chen |first1=Xiao |last2=d'Souza |first2=Roshan |last3=Hong |first3=Seong-Tshool }}</ref>

Just as gut flora can function in a feedback loop that can drive the development of obesity, there is evidence that restricting intake of calories (i.e., dieting) can drive changes to the composition of the gut flora.<ref name=2016BoulangeRev/>

== Other animals == The composition of the human gut microbiome is similar to that of the other great apes. However, humans' gut biota has decreased in diversity and changed in composition since our evolutionary split from ''Pan''.<ref name="ReferenceC">{{cite journal |last1=Moeller |first1=Andrew H. |last2=Li |first2=Yingying |last3=Mpoudi Ngole |first3=Eitel |last4=Ahuka-Mundeke |first4=Steve |last5=Lonsdorf |first5=Elizabeth V. |last6=Pusey |first6=Anne E. |last7=Peeters |first7=Martine |last8=Hahn |first8=Beatrice H. |last9=Ochman |first9=Howard |title=Rapid changes in the gut microbiome during human evolution |journal=Proceedings of the National Academy of Sciences |date=18 November 2014 |volume=111 |issue=46 |pages=16431–16435 |doi=10.1073/pnas.1419136111 |pmid=25368157 |pmc=4246287 |bibcode=2014PNAS..11116431M |doi-access=free }}</ref> Humans display increases in Bacteroidetes, a bacterial phylum associated with diets high in animal protein and fat, and decreases in Methanobrevibacter and Fibrobacter, groups that ferment complex plant polysaccharides.<ref name="ReferenceC"/> These changes are the result of the combined dietary, genetic, and cultural changes humans have undergone since evolutionary divergence from ''Pan'' (chimpanzees and bonobos).{{citation needed|date=March 2023}}

In addition to humans and vertebrates, some insects also have complex and diverse gut microbiota that play key nutritional roles.<ref name="Engel">{{cite journal |last1=Engel |first1=P. |last2=Moran |first2=N. |year=2013 |title=The gut microbiota of insects–diversity in structure and function |journal=FEMS Microbiology Reviews |volume=37 |issue=5 |pages=699–735 |doi=10.1111/1574-6976.12025 |pmid=23692388|doi-access=free }}</ref> Microbial communities associated with termites can constitute a majority of the weight of the individuals and perform important roles in the digestion of lignocellulose and nitrogen fixation.<ref>{{cite journal |last1=Brune |first1=A. |year=2014 |title=Symbiotic digestion of lignocellulose in termite guts |journal=Nature Reviews Microbiology |volume=12 |issue=3 |pages=168–180 |doi=10.1038/nrmicro3182 |pmid=24487819 }}</ref> It is known that the disruption of gut microbiota of termites using agents like antibiotics<ref>{{cite journal |last1=Rosengaus |first1=Rebeca B. |last2=Zecher |first2=Courtney N. |last3=Schultheis |first3=Kelley F. |last4=Brucker |first4=Robert M. |last5=Bordenstein |first5=Seth R. |title=Disruption of the Termite Gut Microbiota and Its Prolonged Consequences for Fitness |journal=Applied and Environmental Microbiology |date=July 2011 |volume=77 |issue=13 |pages=4303–4312 |doi=10.1128/AEM.01886-10 |pmc=3127728 |pmid=21571887 |bibcode=2011ApEnM..77.4303R }}</ref> or boric acid<ref>{{cite journal |last1=Ashbrook |first1=Aaron R |last2=Schwarz |first2=Melbert |last3=Schal |first3=Coby |last4=Mikaelyan |first4=Aram |title=Lethal disruption of the bacterial gut community in Eastern subterranean termite caused by boric acid |journal=Journal of Economic Entomology |date=14 October 2024 |volume=117 |issue=6 |pages=2599–2607 |doi=10.1093/jee/toae221 |pmid=39401329 |doi-access=free |pmc=11682946 }}</ref> (a common agent used in preventative treatment) causes severe damage to digestive function and leads to the rise of opportunistic pathogens.<ref name=":1" /> These communities are host-specific, and closely related insect species share comparable similarities in gut microbiota composition.<ref name="ReferenceA">{{cite journal |last1=Dietrich |first1=C. |last2=Köhler |first2=T. |last3=Brune |first3=A. |year=2014 |title=The cockroach origin of the termite gut microbiota: patterns in bacterial community structure reflect major evolutionary events |journal=Applied and Environmental Microbiology |volume=80 |issue=7 |pages=2261–2269 |doi=10.1128/AEM.04206-13 |pmid=24487532 |pmc=3993134|bibcode=2014ApEnM..80.2261D }}</ref><ref name="ReferenceB">{{cite journal |last1=Mikaelyan |first1=A. |last2=Dietrich |first2=C. |last3=Köhler |first3=T. |last4=Poulsen |first4=M. |last5=Sillam-Dussès |first5=D. |last6=Brune |first6=A. |year=2015 |title=Diet is the primary determinant of bacterial community structure in the guts of higher termites |journal=Molecular Ecology |volume=24 |issue=20 |pages=5824–5895 |doi=10.1111/mec.13376 |pmid=26348261|bibcode=2015MolEc..24.5284M }}</ref> In cockroaches, gut microbiota have been shown to assemble in a deterministic fashion, irrespective of the inoculum;<ref>{{cite journal |last1=Mikaelyan |first1=A. |last2=Thompson |first2=C. |last3=Hofer |first3=M. |last4=Brune |first4=A. |year=2016 |title=The deterministic assembly of complex bacterial communities in germ-free cockroach guts |journal=Applied and Environmental Microbiology |volume=82 |issue=4 |pages=1256–1263 |doi=10.1128/AEM.03700-15 |pmid=26655763|pmc=4751828 }}</ref> the reason for this host-specific assembly remains unclear. Bacterial communities associated with insects like termites and cockroaches are determined by a combination of forces, primarily diet, but there is some indication that host phylogeny may also be playing a role in the selection of lineages.<ref name="ReferenceA" /><ref name="ReferenceB" />

For more than 51 years it has been known that the administration of low doses of antibacterial agents promotes the growth of farm animals to increase weight gain.<ref name=cho2012>{{cite journal |doi=10.1038/nature11400 |title=Antibiotics in early life alter the murine colonic microbiome and adiposity |year=2012 |last1=Cho |first1=I. |last2=Yamanishi |first2=S. |last3=Cox |first3=L. |last4=Methé |first4=B. A. |last5=Zavadil |first5=J. |last6=Li |first6=K. |last7=Gao |first7=Z. |last8=Mahana |first8=D. |last9=Raju |first9=K. |last10=Teitler |first10=I. |last11=Li |first11=H. |last12=Alekseyenko |first12=A. V. |last13=Blaser |first13=M. J. |journal=Nature |volume=488 |issue=7413 |pages=621–626 |pmid=22914093 |pmc=3553221|bibcode=2012Natur.488..621C }}</ref>

In a study carried out on mice the ratio of ''Firmicutes'' and ''Lachnospiraceae'' was significantly elevated in animals treated with subtherapeutic doses of different antibiotics. By analyzing the caloric content of faeces and the concentration of small chain fatty acids (SCFAs) in the GI tract, it was concluded that the changes in the composition of microbiota lead to an increased capacity to extract calories from otherwise indigestible constituents, and to an increased production of SCFAs. These findings provide evidence that antibiotics perturb not only the composition of the GI microbiome but also its metabolic capabilities, specifically with respect to SCFAs.<ref name= cho2012/>

==Notes== {{reflist|group=note}}

== References == {{reflist|colwidth=30em}}

== Further reading == ; Review articles * {{cite journal |doi=10.1002/mnfr.201000451 |title=The impact of pre- and/or probiotics on human colonic metabolism: Does it affect human health? |year=2011 |last1=De Preter |first1=Vicky |last2=Hamer |first2=Henrike M |last3=Windey |first3=Karen |last4=Verbeke |first4=Kristin |journal=Molecular Nutrition & Food Research |volume=55 |pages=46–57 |pmid=21207512 |issue=1}} * {{cite journal |doi=10.1155/2015/931574 |pmid=25759850 |pmc=4352473 |title=Intestinal Microbiota as Modulators of the Immune System and Neuroimmune System: Impact on the Host Health and Homeostasis |journal=Journal of Immunology Research |volume=2015 |article-number=931574 |year=2015 |last1=Maranduba |first1=Carlos Magno da Costa |last2=De Castro |first2=Sandra Bertelli Ribeiro |last3=Souza |first3=Gustavo Torres de |last4=Rossato |first4=Cristiano |last5=Da Guia |first5=Francisco Carlos |last6=Valente |first6=Maria Anete Santana |last7=Rettore |first7=João Vitor Paes |last8=Maranduba |first8=Claudinéia Pereira |last9=Souza |first9=Camila Maurmann de |last10=Carmo |first10=Antônio Márcio Resende do |last11=MacEdo |first11=Gilson Costa |last12=Silva |first12=Fernando de Sá |doi-access=free }} * {{cite journal |doi=10.2147/BTT.S19099 |title=Gut microbiota: Next frontier in understanding human health and development of biotherapeutics |year=2011 |last1=Prakash |first1=Satya |last2=Rodes |first2=Laetitia |last3=Coussa-Charley |first3=Michael |last4=Tomaro-Duchesneau |first4=Catherine |last5=Tomaro-Duchesneau |first5=Catherine |last6=Coussa-Charley |last7=Rodes |journal=Biologics: Targets and Therapy |pages=71–86 |pmid=21847343 |volume=5 |pmc=3156250 |doi-access=free }} * {{cite journal |doi=10.1126/science.1208344 |title=Linking Long-Term Dietary Patterns with Gut Microbial Enterotypes |year=2011 |last1=Wu |first1=G. D. |last2=Chen |first2=J. |last3=Hoffmann |first3=C. |last4=Bittinger |first4=K. |last5=Chen |first5=Y.-Y. |last6=Keilbaugh |first6=S. A. |last7=Bewtra |first7=M. |last8=Knights |first8=D. |last9=Walters |first9=W. A. |last10=Knight |first10=R. |last11=Sinha |first11=R. |last12=Gilroy |first12=E. |last13=Gupta |first13=K. |last14=Baldassano |first14=R. |last15=Nessel |first15=L. |last16=Li |first16=H. |last17=Bushman |first17=F. D. |last18=Lewis |first18=J.D. |journal=Science |volume=334 |issue=6052 |pages=105–108 |pmid=21885731 |pmc=3368382|bibcode=2011Sci...334..105W }}

{{DEFAULTSORT:Gut Flora}} Category:Gut flora Category:Bacteriology Category:Digestive system Category:Bacillota Category:Environmental microbiology Category:Microbiomes