View source for Template:Tryptophan metabolism by human microbiota

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| image = Microbiota-derived 3-Indolepropionic acid-notext.svg
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| header = {{{header|Tryptophan metabolism by {{when pagename is|Human microbiota=human gastrointestinal microbiota|other=[[Biology:Human microbiota#Gut|human gastrointestinal microbiota]]}} <small>(</small>{{navbar|mini=1|t|e|template=Tryptophan metabolism by human microbiota}}<small>)</small>}}}
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| alt = Tryptophan metabolism diagram
| caption = {{{caption|This diagram shows the biosynthesis of [[bioactive compound]]s ({{when pagename is|Indole=indole|other=[[Chemistry:Indole|indole]]}} and certain other derivatives) from {{when pagename is|Tryptophan=[[Chemistry:Tryptophan|other=Trypto]]phan|tryptophan]]}} by bacteria in the gut.<ref name="Microbial biosynthesis of bioactive compounds" /> Indole is produced from tryptophan by bacteria that express [[Biology:Tryptophanase|tryptophanase]].<ref name="Microbial biosynthesis of bioactive compounds" /> {{when pagename is|Clostridium sporogenes=''Clostridium sporogenes''|other=''[[Biology:Clostridium sporogenes|Clostridium sporogenes]]''}} metabolizes tryptophan into indole and subsequently {{when pagename is|3-Indolepropionic acid={{nowrap|3-indolepropionic}} acid|other=[[Chemistry:3-Indolepropionic acid|{{nowrap|3-indolepropionic}} acid]]}} (IPA),<ref name="Microbiome IPA">{{cite journal | vauthors = Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA, Peters EC, Siuzdak G|authorlink7=Gary Siuzdak | title = Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 106 | issue = 10 | pages = 3698–3703 | date = March 2009 | pmid = 19234110 | pmc = 2656143 | doi = 10.1073/pnas.0812874106 | quote = {{when pagename is|3-Indolepropionic acid=Production of IPA was shown to be completely dependent on the presence of gut microflora and could be established by colonization with the bacterium Clostridium sporogenes.&nbsp;... Conversely, a different set of enteric bacteria has been implicated in the metabolic transformation of indole to indole-3-propionic acid (IPA) (27). IPA, also identified only in the plasma of conv mice, has been shown to be a powerful antioxidant (28)&nbsp;... Although the presence of IPA in mammals has long been ascribed in the literature to bacterial metabolic processes, this conclusion was based on either the production of IPA in ex vivo cultures of individual bacterial species (31) or observed decreases in IPA levels in animals after administration of antibiotics (32). In our own survey of IPA production by representative members of the intestinal flora, only Clostridium sporogenes was found to produce IPA in culture (Table S2). Based on these results, individual GF mice were intentionally colonized with C. sporogenes strain ATCC 15579, and blood samples were taken at several intervals after colonization. IPA was undetectable in the samples taken shortly after introduction of the microbes, and was first observed in the serum 5 days after colonization, reaching plateau values comparable with conv mice by day 10. These colonization studies demonstrate that the introduction of enteric bacteria capable of IPA production in vivo into the gastrointestinal tract is sufficient to introduce IPA into the bloodstream of the host. Also, other GF animals were injected i.p. with either IPA (at 10, 20, or 40 mg/kg) or sterile PBS vehicle, and their serum concentrations of IPA were measured over time. As seen in Table S3, the high serum levels of IPA observed 1 h after injection decreased more than 90% within 5 h, showing that IPA is rapidly cleared from the blood, and that its presence in the serum of conv animals must result from continuous production from 1 or more bacterial species associated with the mammalian gut.|other=Production of IPA was shown to be completely dependent on the presence of gut microflora and could be established by colonization with the bacterium ''Clostridium sporogenes''.}}}}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2656143/figure/F2/ IPA metabolism diagram]</ref> a highly potent [[neuroprotective]] [[Biology:Antioxidant|antioxidant]] that scavenges [[Chemistry:Hydroxyl radical|hydroxyl radical]]s.<ref name="Microbial biosynthesis of bioactive compounds" /><ref name="Human metabolome IPA">{{cite web|title=3-Indolepropionic acid|website=Human Metabolome Database|publisher=University of Alberta|accessdate=12 June 2018|url=http://www.hmdb.ca/metabolites/HMDB02302|quote=Indole-3-propionate (IPA), a deamination product of tryptophan formed by symbiotic bacteria in the gastrointestinal tract of mammals and birds. 3-Indolepropionic acid has been shown to prevent oxidative stress and death of primary neurons and neuroblastoma cells exposed to the amyloid beta-protein in the form of amyloid fibrils, one of the most prominent neuropathologic features of Alzheimer's disease. 3-Indolepropionic acid also shows a strong level of neuroprotection in two other paradigms of oxidative stress. ({{PMID|10419516}})&nbsp;... More recently it has been found that higher indole-3-propionic acid levels in serum/plasma are associated with reduced likelihood of type 2 diabetes and with higher levels of consumption of fiber-rich foods ({{PMID|28397877}})<br />Origin: {{•}} Endogenous {{•}} Microbial}}</ref><ref name="Indolepropionic acid scavenging">{{cite journal | vauthors = Chyan YJ, Poeggeler B, Omar RA, Chain DG, Frangione B, Ghiso J, Pappolla MA | title = Potent neuroprotective properties against the Alzheimer beta-amyloid by an endogenous melatonin-related indole structure, indole-3-propionic acid | journal = J. Biol. Chem. | volume = 274 | issue = 31 | pages = 21937–21942 | date = July 1999 | pmid = 10419516 | doi = 10.1074/jbc.274.31.21937| quote = [Indole-3-propionic acid (IPA)] has previously been identified in the plasma and cerebrospinal fluid of humans, but its functions are not known.&nbsp;... In kinetic competition experiments using free radical-trapping agents, the capacity of IPA to scavenge hydroxyl radicals exceeded that of melatonin, an indoleamine considered to be the most potent naturally occurring scavenger of free radicals. In contrast with other antioxidants, IPA was not converted to reactive intermediates with pro-oxidant activity.}}</ref> IPA binds to the [[Biology:Pregnane X receptor|pregnane X receptor]] (PXR) in intestinal cells, thereby facilitating mucosal homeostasis and [[Biology:Intestinal permeability|barrier function]].<ref name="Microbial biosynthesis of bioactive compounds" /> Following [[Absorption (pharmacokinetics)|absorption]] from the intestine and [[Medicine:Distribution (pharmacology)|distribution]] to the brain, IPA confers a neuroprotective effect against [[cerebral ischemia]] and [[Medicine:Alzheimer's disease|Alzheimer's disease]].<ref name="Microbial biosynthesis of bioactive compounds" /> {{when pagename is|Lactobacillus=''Lactobacillus''|other=''[[Biology:Lactobacillus|Lactobacillus]]''}} species metabolize tryptophan into {{when pagename is|Indole-3-carboxaldehyde=indole-3-carboxaldehyde|other=[[Chemistry:Indole-3-carboxaldehyde|indole-3-aldehyde}}]] (I3A) which acts on the [[Biology:Aryl hydrocarbon receptor|aryl hydrocarbon receptor (]]AhR) in intestinal immune cells, in turn increasing [[interleukin-22]] (IL-22) production.<ref name="Microbial biosynthesis of bioactive compounds" /> Indole itself [[Medicine:Secretagogue|triggers the secretion]] of [[Biology:Glucagon-like peptide-1|glucagon-like peptide-1]] (GLP-1) in [[Biology:Enteroendocrine cell#L cell|intestinal L cells]] and acts as a [[Biology:Ligand (biochemistry)|ligand]] for AhR.<ref name="Microbial biosynthesis of bioactive compounds" /> Indole can also be metabolized by the liver into {{when pagename is|Indoxyl sulfate=[[Chemistry:Indoxyl sulfate|other=Indoxyl sulfa]]te|indoxyl sulfate}}]], a compound that is toxic in high concentrations and associated with [[Medicine:Vascular disease|vascular disease]] and [[renal dysfunction]].<ref name="Microbial biosynthesis of bioactive compounds" /> AST-120 ([[activated charcoal]]), an intestinal [[Chemistry:Sorbent|sorbent t]]hat is [[Oral administrat[[Physics:[[Physics:Ion|taken by mouth,]]Chemistry:Adsorption|adsorbs i]]ndole, in turn decreasing the concentration of indoxyl sulfate in blood plasma.<ref name="Microbial biosynthesis of bioactive compounds">{{cite journal | vauthors = Zhang LS, Davies SS | title = Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions | journal = Genome Med | volume = 8 | issue = 1 | pages = 46 | date = April 2016 | pmid = 27102537 | pmc = 4840492 | doi = 10.1186/s13073-016-0296-x | quote = ''Lactobacillus'' spp. convert tryptophan to indole-3-aldehyde (I3A) through unidentified enzymes [125]. ''Clostridium sporogenes'' convert tryptophan to IPA [6], likely via a tryptophan deaminase.&nbsp;... IPA also potently scavenges hydroxyl radicals}}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4840492/table/Tab2/ Table 2: Microbial metabolites: their synthesis, mechanisms of action, and effects on health and disease]<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4840492/figure/Fig1/ Figure 1: Molecular mechanisms of action of indole and its metabolites on host physiology and disease]</ref>
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<!--The text annotations are (mostly) sorted into groups by vertical position and then within groups by horizontal position -->
{{annotation|205|3|[[Chemistry:Tryptophan|Tryptophan]]}}

{{annotation|127|65|[[Biology:Clostridium sporogenes|''Clostridium<br />sporogenes'']]|annot-text-align=center|font-size=12}}
{{annotation|252|85|[[Biology:Lactobacillus|Lacto-<br/>bacilli]]|font-size=12}}
{{annotation|292|60|[[Biology:Tryptophanase|Tryptophanase]]-<br />expressing<br />bacteria|text-align=center|font-size=12}}

{{annotation|148|116|[[Chemistry:3-Indolepropionic acid|IPA]]|font-size=14}}
{{annotation|236|131|[[Chemistry:Indole-3-carboxaldehyde|I3A]]|font-size=14}}
{{annotation|318|115|[[Chemistry:Indole|Indole]]|font-size=14}}
{{annotation|470|174|[[Biology:Liver|Liver]]|text-align=center|font-size=18}}

{{annotation|37|301|[[Biology:Human brain|Brain]]|font-size=18}}
{{annotation|133|352|[[Chemistry:3-Indolepropionic acid|IPA]]|font-size=14}}
{{annotation|236|299|[[Chemistry:Indole-3-carboxaldehyde|I3A]]|font-size=14}}
{{annotation|328|269|[[Chemistry:Indole|Indole]]|font-size=14}}
{{annotation|413|261|[[Chemistry:Indoxyl sulfate|Indoxyl<br />sulfate]]|text-align=center|font-size=12}}
{{annotation|350|318|[[Activated charcoal|<span style="color:red">AST-120</span>]]|font-size=14}}
{{annotation|281|346|[[Biology:Aryl hydrocarbon receptor|AhR]]|font-size=12}}
{{annotation|269|297|Intestinal<br />[[immune cells|immune<br />cells]]|text-align=center|font-size=11}}

{{annotation|40|209|[[Intestinal epithelium|Intestinal<br />epithelium]]|text-align=center|font-size=18}}
{{annotation|161.5|231|[[Biology:Pregnane X receptor|PXR]]|font-size=11}}
{{annotation|144|255|Mucosal homeostasis:<br />↓[[Biology:Tumor necrosis factor alpha|TNF-α]]<br />↑[[Biology:Tight junction|Junction]] protein-<br />coding [[Biology:Messenger RNA|mRNA]]s|font-size=10}}

{{annotation|252.5|237|[[Biology:Enteroendocrine cell#L cell|L cell]]|font-size=12}}
{{annotation|249|265|[[Biology:Glucagon-like peptide-1|GLP-1]]|font-size=12}}
{{annotation|335|227|[[Biology:Tight junction|T J]]|font-size=12}}

{{annotation|15|390|[[Neuroprotectant]]:<br />↓Activation of [[glial cell]]s and [[Biology:Astrocyte|astrocyte]]s<br />↓[[4-Hydroxy-2-nonenal]] levels<br />↓[[DNA damage]]<br />–[[Biology:Antioxidant|Antioxidant]]<br />–Inhibits [[β-amyloid]] fibril formation|font-size=10}}

{{annotation|243|370|Maintains mucosal reactivity:<br />↑[[Interleukin 22|IL-22]] production|font-size=10}}

{{annotation|458|290|Associated with [[Medicine:Vascular disease|vascular disease]]:<br />↑[[Biology:Oxidative stress|Oxidative stress]]<br />↑[[Smooth muscle cell]] [[Biology:Cell proliferation|proliferation]]<br />↑[[Aorta|Aortic wall]] thickness and [[aortic calcification|calcification]]|font-size=10}}

{{annotation|458|391|Associated with [[Medicine:Chronic kidney disease|chronic kidney disease]]:<br />↑[[Renal dysfunction]]<br />–[[Uremic toxin]]|font-size=10}}

{{annotation|381|448|[[Kidney]]s|font-size=18}}
}}<noinclude>

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==Reflist==
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