Tryptophan Metabolism by Gut Microbiome and Gut-Brain-Axis: An in silico Analysis

Harrisham Kaur, Chandrani Bose, Sharmila S Mande, Harrisham Kaur, Chandrani Bose, Sharmila S Mande

Abstract

The link between gut microbiome and brain is being slowly acknowledged due to the speculated role of resident gut microbial community in altering the functions of gut-brain axis (GBA). Recently, a number of microbial metabolites (referred to as neuro-active metabolites) produced through tryptophan metabolism have been suggested to influence the GBA. In view of this, the current study focuses on microbial tryptophan metabolism pathways which produce neuro-active metabolites. An in silico analysis was performed on bacterial genomes as well as publicly available gut microbiome data. The results provide a comprehensive catalog of the analyzed pathways across bacteria. The analysis indicates an enrichment of tryptophan metabolism pathways in five gut-associated phyla, namely, Actinobacteria, Firmicutes, Bacteroidetes, Proteobacteria, and Fusobacteria. Further, five genera, namely, Clostridium, Burkholderia, Streptomyces, Pseudomonas, and Bacillus have been predicted to be enriched in terms of number of the analyzed tryptophan metabolism pathways, suggesting a higher potential of these bacterial groups to metabolize tryptophan in gut. Analysis of available microbiome data corresponding to gut samples from patients of neurological diseases and healthy individuals suggests probable association of different sets of tryptophan metabolizing bacterial pathways with the etiology of different diseases. The insights obtained from the present study are expected to provide directions toward designing of microbiome based diagnostic and therapeutic approaches for neurological diseases/disorders.

Keywords: genome mining; gut microbiome; gut-brain axis; in silico; neurological disorders; tryptophan metabolism.

Copyright © 2019 Kaur, Bose and Mande.

Figures

FIGURE 1
FIGURE 1
Schematic representation of tryptophan metabolism pathways leading to production of neuro-active compounds. The pathways correspond to metabolism of tryptophan (indicated in green font inside an oval) for production of six neuro-active compounds namely, indole, tryptamine, kynurenine, quinolinate, indole acetic acid, and indole propionic acid. These six compounds have been indicated in green font. The intermediate compounds of the pathways have been represented in black font. For each pathway, the EC numbers and the functional domains of the participating enzymes have been indicated in blue and red colors, respectively.
FIGURE 2
FIGURE 2
Tryptophan metabolism pathways for neuro-active compound production across bacterial phyla. Distribution of six neuro-active compound production pathways across bacterial phyla comprising of completely sequenced bacterial genomes. Each cell represents the proportion of strains predicted to harbor a pathway for a particular phylum.
FIGURE 3
FIGURE 3
The count of gut bacteria at phyla, genera, and strain levels predicted to possess each of the six analyzed pathways. The pathways pertain to metabolism of tryptophan (indicated in black font inside an oval) for production of six neuro-active compounds namely, indole, tryptamine, kynurenine, quinolinate, indole acetic acid, and indole propionic acid. These six compounds have been indicated in green font. The intermediate compounds of the pathways have been represented in black font. The bar plot depicting phyla-count, genera-count and strain-count for each pathway has been placed behind or below the corresponding neuro-active compound.
FIGURE 4
FIGURE 4
Tryptophan metabolism pathways for neuro-active compound production in bacterial genera found in gut. Distribution of six neuro-active compound production pathways across genera comprising of completely sequenced bacterial genomes found in human gut. Each cell represents “SCORBPEO” (Score for Bacterial Production of Neuro-active Compounds) value corresponding to the pathways in these genera. “SCORBPEO” indicates the relative capabilities for production of a particular neuro-active compound of any genus, evaluated based on the number of pathway containing strains, the database size of the respective genus, and enrichment of the pathway in gut-associated strains of the genus.
FIGURE 5
FIGURE 5
Distribution of tryptophan transporters in gut bacteria. (A) Pie-chart depicting the proportion of indole producing gut bacteria predicted to have tryptophan transporters versus those not utilizing the same. (B) Venn diagram representing the distribution profile of three known transporters namely, TnaB, Mtr, and AroP in gut bacteria. (C) Heat-map showing the proportion of strains in each of the five gut bacterial genera predicted to utilize the three tryptophan transporters (TnaB, Mtr, and AroP).
FIGURE 6
FIGURE 6
Schematic representation of the insights obtained from genomic analysis in context of tryptophan metabolism pathways in gut bacteria and their probable connection to brain. The six neuro-active compounds produced through bacterial tryptophan metabolism are depicted using various shapes as shown in the legend provided inside the figure. For each compound, the top three genera with respect to the “SCORBPEO” value are shown within rectangles having solid borders. For example, bacterial genera such as Klebsiella, Staphylococcus, Ralstonia, etc., produce indole acetic acid (IAA) in the large intestine through tryptophan metabolism. Probable ways by which each of the six compounds may alter the functioning of GBA (as collated from literature) have been indicated by yellow rectangles having dotted border. For instance, IAA may affect the interaction between gut and brain by acting as inter-cellular signaling molecule and immune system modulator. Apart from such mechanisms mediated by tryptophan metabolism products, sequestration of tryptophan by gut bacteria may have a direct impact on brain tryptophan level, which in turn can affect brain function.
FIGURE 7
FIGURE 7
Tryptophan metabolism pathways in differentially abundant genera in gut microbiome of patients suffering from neurological diseases and healthy individuals. Each panel corresponds to a set of microbiome data obtained from patients of a neurological disease and matched healthy individuals. The genera differentially enriched in diseased cohorts have been shown with orange bars, while those differentially abundant in healthy cohorts have been shown with cyan bars. The pathways that have been predicted in differentially abundant genera in diseased or healthy individuals have been represented by Sankey diagrams. The width of the pathway-genus association represents the “SCORBPEO” value of the genus for the respective pathway.

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