Although there have been sporadic studies targeting a few microbial molecules or chemical classes in this regard, as represented by α-synuclein 10, 3,4-dihydroxyphenylacetate 7, and bile acids 11, many of these still have yet to be validated as a gut-brain mediator. Despite such interest, surprisingly, molecular underpinnings for such microbiota-gut-brain axis are unclear. Gut microbes, in close proximity to numerous local neurons and immune cells, may either act on the ENS in situ to signal the CNS remotely, or more likely, they synthesize or transform molecular cues that can translocate from gut lumen to systemic circulation, and possibly cross the blood-brain barrier (BBB) and affect CNS directly 9. It has been postulated that at least two routes are involved 8, namely (i) the vagus nerves (neuronal) that connect the central nervous system (CNS) and enteric nervous system (ENS, the “second brain”) and (ii) the circulatory system (humoral) encompassing blood and lymphatic circulation. In a recent work by Valles-Colomer and colleagues 7, analyses of a large human cohort correlating fecal metagenomic features with indicators of quality of life and depression identified microbial strains, pathways, and metabolites pertaining to mental health and gut-brain interaction, providing the first population-scale evidence linking microbiota to mental health outcomes.ĭespite the emerging data, whether and how microbiota controls brain function remains largely undefined. For example, using maternal immune activation (MIA) mouse, a model of autism spectrum disorder (ASD), Hsiao and colleagues discovered 6 that both ASD-mimicking GI barrier defects and behavioral abnormalities MIA offspring exhibited were restored through colonizing human commensal Bacteroidetes fragilis, supporting a gut-microbiota-brain connection for autism. Interestingly, recent studies support that microbiota also harbors novel neuroactive potential with links to neurological and/or psychiatric disorders, as further encapsulated as the “microbiota-gut-brain axis” 5. Complex, dynamic, and metabolically active by nature, these commensal microbes have been discovered to constantly interact with the host as a crucial mediator for physiological processes spanning energy harvest 2, immune cell development 3, and gut epithelial homeostasis 4. The mammalian body and particularly the gastrointestinal (GI) tract is inhabited by hundreds of trillions of microbes, collectively termed the microbiota 1. Our findings may be valuable for future research probing microbial influences on host metabolism and gut-brain communication. Gender-specific characteristics of these landscapes are discussed. Multicompartmental comparative analyses single out microbiota-derived metabolites potentially implicated in interorgan transport and the gut-brain axis, as exemplified by indoxyl sulfate and trimethylamine- N-oxide.
Results revealed for all three matrices metabolomic signatures owing to microbiota, yielding hundreds of identified metabolites including 533 altered for feces, 231 for sera, and 58 for brain with numerous significantly enriched pathways involving aromatic amino acids and neurotransmitters. Here we use high-coverage metabolomics to comparatively profile feces, blood sera, and cerebral cortical brain tissues of germ-free C57BL/6 mice and their age-matched conventionally raised counterparts. While emerging studies support that microbiota regulates brain function with a few molecular cues suggested, the overall biochemical landscape of the “microbiota-gut-brain axis” remains largely unclear. The mammalian gut harbors a complex and dynamic microbial ecosystem: the microbiota.
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