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Cited by 210Gut microbiota and healthDementia and Cognitive Impairment ResearchTryptophan and brain disorders

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Microbial-derived metabolites as a risk factor of age-related cognitive decline and dementia

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Connell, Emily, Le Gall, Gwenaelle, Pontifex, Matthew G., Sami, Saber, Cryan, John F., Clarke, Gerard, Müller, Michael, Vauzour, David·2022·Molecular Neurodegeneration
DOI 10.1186/s13024-022-00548-6PMC PMC9204954
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Abstract

A consequence of our progressively ageing global population is the increasing prevalence of worldwide age-related cognitive decline and dementia. In the absence of effective therapeutic interventions, identifying risk factors associated with cognitive decline becomes increasingly vital. Novel perspectives suggest that a dynamic bidirectional communication system between the gut, its microbiome, and the central nervous system, commonly referred to as the microbiota-gut-brain axis, may be a contributing factor for cognitive health and disease. However, the exact mechanisms remain undefined. Microbial-derived metabolites produced in the gut can cross the intestinal epithelial barrier, enter systemic circulation and trigger physiological responses both directly and indirectly affecting the central nervous system and its functions. Dysregulation of this system (i.e., dysbiosis) can modulate cytotoxic metabolite production, promote neuroinflammation and negatively impact cognition. In this review, we explore critical connections between microbial-derived metabolites (secondary bile acids, trimethylamine-N-oxide (TMAO), tryptophan derivatives and others) and their influence upon cognitive function and neurodegenerative disorders, with a particular interest in their less-explored role as risk factors of cognitive decline.

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Fig. 1 Microbial metabolites can directly and indirectly modulate the CNS through immune, neuronal and direct metabolite mediated pathways within the microbiota-gut-brain axis. In the gut lumen, dietary products can be metabolised by microbiota into neuroactive compounds, including neurotransmitters, (e.g., serotonin, dopamine), amino acids (e.g., tryptophan, tryptamine) and other microbial-derived metabolites (e.g., short-chain fatty acids, trimethylamine (TMA)). These compounds subsequently communicate with the central nervous system either directly, travelling through the portal vein, liver and crossing the blood–brain barrier, or indirectly via the production of neurotransmitters by enterochromaffin cells (ECC) or immune pathways (stimulated immune cells produce cytokines that can enter the blood or stimulate the vagus nerve)
Fig. 1 Microbial metabolites can directly and indirectly modulate the CNS through immune, neuronal and direct metabolite mediated pathways within the microbiota-gut-brain axis. In the gut lumen, dietary products can be metabolised by microbiota into neuroactive compounds, including neurotransmitters, (e.g., serotonin, dopamine), amino acids (e.g., tryptophan, tryptamine) and other microbial-derived metabolites (e.g., short-chain fatty acids, trimethylamine (TMA)). These compounds subsequently communicate with the central nervous system either directly, travelling through the portal vein, liver and crossing the blood–brain barrier, or indirectly via the production of neurotransmitters by enterochromaffin cells (ECC) or immune pathways (stimulated immune cells produce cytokines that can enter the blood or stimulate the vagus nerve)CC BY · PubMed Central
Fig. 2 Bile acids, TMAO and tryptophan metabolic pathways and their links to the brain. Primary bile acids are produced from cholesterol breakdown in the liver. They can be conjugated with taurine or glycine residues before travelling to the gut, where they are deconjugated and converted to secondary bile acids via microbial action. Bile acids have been found in the brain of humans and rodents suggesting they can cross the blood–brain barrier via either diffusion (unconjugated) or active transport (conjugated) and influence the central nervous system. TMAO is produced via a two-stage process. TMA is first formed from the microbial conversion of choline in the gut. TMA then travels to the liver, where the FMO1/3 enzyme converts it to TMAO. Recent evidence found TMAO in human brains, indicating it can cross the blood–brain barrier. Tryptophan can be metabolised via three key pathways. Firstly, via gut microbial action, tryptophan can be converted via the indole pathway into numerous indole derivatives, or into the amino acid, tryptamine. Indoles and tryptamine are known to cross the BBB. Secondly, around 3% of dietary tryptophan is metabolised into serotonin and melatonin via numerous enzymes in the serotonin pathway. Notably, serotonin produced in the gut cannot cross the blood–brain barrier. However, the serotonin precursor, 5-hydroxytryptophan, and serotonin derivatives, N-acetylserotonin and melatonin, can cross the blood–brain barrier and influence the central nervous system. Finally, the majority of tryptophan (~ 90–95%) is metabolised via the kynurenine pathway, of which 90% occurs in the liver. This pathway is initiated by the TDO enzyme in the liver and the IDO enzyme in the brain. Only kynurenine, 3-hydroxykynurenine and tryptophan itself can cross the blood–brain barrier. However, once in the brain, tryptophan can be metabolised via both the kynurenine and serotonin pathways to form the pathway’s intermediates
Fig. 2 Bile acids, TMAO and tryptophan metabolic pathways and their links to the brain. Primary bile acids are produced from cholesterol breakdown in the liver. They can be conjugated with taurine or glycine residues before travelling to the gut, where they are deconjugated and converted to secondary bile acids via microbial action. Bile acids have been found in the brain of humans and rodents suggesting they can cross the blood–brain barrier via either diffusion (unconjugated) or active transport (conjugated) and influence the central nervous system. TMAO is produced via a two-stage process. TMA is first formed from the microbial conversion of choline in the gut. TMA then travels to the liver, where the FMO1/3 enzyme converts it to TMAO. Recent evidence found TMAO in human brains, indicating it can cross the blood–brain barrier. Tryptophan can be metabolised via three key pathways. Firstly, via gut microbial action, tryptophan can be converted via the indole pathway into numerous indole derivatives, or into the amino acid, tryptamine. Indoles and tryptamine are known to cross the BBB. Secondly, around 3% of dietary tryptophan is metabolised into serotonin and melatonin via numerous enzymes in the serotonin pathway. Notably, serotonin produced in the gut cannot cross the blood–brain barrier. However, the serotonin precursor, 5-hydroxytryptophan, and serotonin derivatives, N-acetylserotonin and melatonin, can cross the blood–brain barrier and influence the central nervous system. Finally, the majority of tryptophan (~ 90–95%) is metabolised via the kynurenine pathway, of which 90% occurs in the liver. This pathway is initiated by the TDO enzyme in the liver and the IDO enzyme in the brain. Only kynurenine, 3-hydroxykynurenine and tryptophan itself can cross the blood–brain barrier. However, once in the brain, tryptophan can be metabolised via both the kynurenine and serotonin pathways to form the pathway’s intermediatesCC BY · PubMed Central
Fig. 3 Key potential pathways through which microbial-derived metabolites influence cognitive function. An illustration of the main underlying mechanisms linking microbial metabolites and the brain. Dietary-derived precursor molecules can be metabolised by gut microbiota to form bioactive metabolites. These microbial-derived metabolites can influence gut permeability, blood–brain barrier function, neuroinflammation, vagus nerve activation, neurogenesis and excitotoxicity affecting the regulation of the microbiota-gut-brain axis and cognitive function. The green colour highlights a protective and beneficial effect, whereas red indicates a detrimental effect. Acronyms: BBB: blood–brain barrier; DCA: deoxycholic acid; ECC: enterochromaffin cells; FMO: flavin-containing monooxygenase; GABA: γ-aminobutyric acid; IA: indole-3- acrylic acid; IAA: indole-3- acetic acid; IAld: indole-3-aldehyde; ILA: indole-3-lactic acid; I3S: indoxyl-3-sulfate; KYNA; kynurenic acid; LCA: lithocholic acid; NMDAR: N-methyl-D-aspartate receptor; QUIN; quinolinic acid; TMA: trimethylamine; TMAO: trimethylamine N-oxide; TUDCA: tauroursodeoxycholic acid
Fig. 3 Key potential pathways through which microbial-derived metabolites influence cognitive function. An illustration of the main underlying mechanisms linking microbial metabolites and the brain. Dietary-derived precursor molecules can be metabolised by gut microbiota to form bioactive metabolites. These microbial-derived metabolites can influence gut permeability, blood–brain barrier function, neuroinflammation, vagus nerve activation, neurogenesis and excitotoxicity affecting the regulation of the microbiota-gut-brain axis and cognitive function. The green colour highlights a protective and beneficial effect, whereas red indicates a detrimental effect. Acronyms: BBB: blood–brain barrier; DCA: deoxycholic acid; ECC: enterochromaffin cells; FMO: flavin-containing monooxygenase; GABA: γ-aminobutyric acid; IA: indole-3- acrylic acid; IAA: indole-3- acetic acid; IAld: indole-3-aldehyde; ILA: indole-3-lactic acid; I3S: indoxyl-3-sulfate; KYNA; kynurenic acid; LCA: lithocholic acid; NMDAR: N-methyl-D-aspartate receptor; QUIN; quinolinic acid; TMA: trimethylamine; TMAO: trimethylamine N-oxide; TUDCA: tauroursodeoxycholic acidCC BY · PubMed Central

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Metadata

Authors
Connell, E., Le Gall, G., Pontifex, M. G., Sami, S., Cryan, J. F., Clarke, G., Müller, M., & Vauzour, D.
Affiliations
  • University of East Anglia (GB)
  • University College Cork (IE)
Corresponding author
Vauzour, David
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2022-06-17
Volume
17
Issue
1
Pages
43-43
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-022-00548-6
PMC
PMC9204954
OpenAlex
W4283020259
Cited by
208
References
369
Citations by year
2026: 41 · 2025: 60 · 2024: 57 · 2023: 38 · 2022: 12
FWCI
4.39
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UEA Digital Repository (University of East Anglia) (acceptedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Lenus, The Irish Health Repository (Dr Steevens Hospital Library) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords
age-related cognitive decline, dementia, microbiota-gut-brain axis, dysbiosis, secondary bile acids, trimethylamine N-oxide, tryptophan derivatives, neuroinflammation, neurodegenerative diseases, gut microbiota, risk factors
MeSH terms
Gastrointestinal Microbiome, Aging, Dementia, Humans, Risk Factors, Cognitive Dysfunction

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