Abstract
Introduction
A rapidly growing body of data documents associations between disease of the brain and small molecules generated by gut-microbiota (GMB). While such metabolites can affect brain function through a variety of mechanisms, the most direct action would be on the central nervous system (CNS) itself.
Objective
Identify indolic and phenolic GMB-dependent small molecules that reach bioactive concentrations in primate CNS.
Methods
We conducted a PubMed search for metabolomic studies of the primate CNS [brain tissue or cerebrospinal fluid (CSF)] and then selected for phenolic or indolic metabolites that (i) had been quantified, (ii) were GMB-dependent. For each chemical we then conducted a search for studies of bioactivity conducted in vitro in human cells of any kind or in CNS cells from the mouse or rat.
Results
36 metabolites of interests were identified in primate CNS through targeted metabolomics. Quantification was available for 31/36 and in vitro bioactivity for 23/36. The reported CNS range for 8 metabolites 2-(3-hydroxyphenyl)acetic acid, 2-(4-hydroxyphenyl)acetic acid, 3-(3-hydroxyphenyl)propanoic acid, (E)-3-(3,4-dihydroxyphenyl)prop-2-enoic acid [caffeic acid], 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2-acetamido-3-(1H-indol-3-yl)propanoic acid [N-acetyltryptophan], 1H-indol-3-yl hydrogen sulfate [indoxyl-3-sulfate] overlapped with a bioactive concentration. However, the number and quality of relevant studies of CNS neurochemistry as well as of bioactivity were highly limited. Structural isomers, multiple metabolites and potential confounders were inadequately considered.
Conclusion
The potential direct bioactivity of GMB-derived indolic and phenolic molecules on primate CNS remains largely unknown. The field requires additional strategies to identify and prioritize screening of the most promising small molecules that enter the CNS.
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References
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GEJ conceived the study and wrote the first draft of the manuscript. DX conducted the data extraction. All authors read, provided critical review, and approved the final manuscript.
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Curtis J. Donskey has received research funding from Clorox, Pfizer, and PDI. All other authors report no relevant conflicts of interest.
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Jaskiw, G.E., Xu, D., Obrenovich, M.E. et al. Small phenolic and indolic gut-dependent molecules in the primate central nervous system: levels vs. bioactivity. Metabolomics 18, 8 (2022). https://doi.org/10.1007/s11306-021-01866-4
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DOI: https://doi.org/10.1007/s11306-021-01866-4