Neuromicrobiology, an emerging neurometabolic facet of the gut microbiome?

Abstract

The concept of the gut microbiome is emerging as a metabolic interactome influenced by diet, xenobiotics, genetics, and other environmental factors that affect the host's absorption of nutrients, metabolism, and immune system. Beyond nutrient digestion and production, the gut microbiome also functions as personalized polypharmacy, where bioactive metabolites that our microbes excrete or conjugate may reach systemic circulation and impact all organs, including the brain. Appreciable evidence shows that gut microbiota produce diverse neuroactive metabolites, particularly neurotransmitters (and their precursors), stimulating the local nervous system (i.e., enteric and vagus nerves) and affecting brain function and cognition. Several studies have demonstrated correlations between the gut microbiome and the central nervous system sparking an exciting new research field, neuromicrobiology. Microbiome-targeted interventions are seen as promising adjunctive treatments (pre-, pro-, post-, and synbiotics), but the mechanisms underlying host-microbiome interactions have yet to be established, thus preventing informed evidence-based therapeutic applications. In this paper, we review the current state of knowledge for each of the major classes of microbial neuroactive metabolites, emphasizing their biological effects on the microbiome, gut environment, and brain. Also, we discuss the biosynthesis, absorption, and transport of gut microbiota-derived neuroactive metabolites to the brain and their implication in mental disorders.

Keywords: GABA; SCFAs; dopamine; gut microbiome; gut-brain axis; microbial neurometabolites; neurotransmitter; serotonin.

Figure 1

Top-down and bottom-up pathways between the gut microbiota and the brain. Right side: Gut microbiota-derived neurotransmitters and their precursor in the gut microbiome-brain axis; left side: the hypothalamus-pituitary–adrenal axis.

Figure 2

Phylogenetic diversity of neurotransmitter-producing bacteria. Sequences are based on published whole-genome or partial sequences from the NCBI Reference Sequence (NCBI RefSeq Targeted Loci Project, Direct Submission, National Center for Biotechnology, Information, NIH, Bethesda, MD 20894, USA). GeneBank accession numbers for the 16S rRNA sequence are shown in the bracket. The phylogenetic tree was constructed using MEGA 11 software (version 11.0.10). Briefly, the evolutionary history was inferred using the Neighbor-Joining method (Saitou and Nei, 1987). The bootstrap consensus tree inferred from 1,000 replicates represents the evolutionary history of the taxa analyzed (Felsenstein, 1992). Branches corresponding to partitions reproduced in less than 50% of bootstrap replicates are collapsed. The evolutionary distances were computed using the Tamura 3-parameter method (Tamura, 1992) and are in the units of the number of base substitutions per site. This analysis involved 34 nucleotide sequences. All ambiguous positions were removed for each sequence pair (pairwise deletion option). There were a total of 1,606 positions in the final dataset. Evolutionary analyses were conducted in MEGA11 (Tamura et al., 2021).

Figure 3

The role of microbially-produced B vitamins in CNS and gut microbiome.

Figure 4

The transportation pathways of gut microbiota-derived neuroactive compounds to the brain. (A) Indirect transportation: gut microbiome regulates or induces host biosynthesis of neurotransmitters in cells like serotonin (5-HT) through tryptophan hydroxylase 1 (Tph1) or GABA through glutamate decarboxylase (GAD). (B) Microbial extracellular vesicle transportation: MEVs may bind to the cell receptor and deliver their contents to the host cell, activate a cell response, or be fully incorporated into the host cell’s cytoplasm. (C) Direct transport: Microbially modulated neurotransmitters could interact with receptors or circulate systemically to reach the blood–brain barrier.