Genomic reconstruction of short-chain fatty acid production by the human gut microbiota

Abstract

Short-chain fatty acids (SCFAs) including acetate, formate, propionate, and butyrate are the end products of dietary fiber and host glycan fermentation by the human gut microbiota (HGM). SCFAs produced in the column are of utmost importance for host physiology and health. Butyrate and propionate improve gut health and play a key role in the neuroendocrine and immune systems. Prediction of HGM metabolic potential is important for understanding the influence of diet and HGM-produced metabolites on human health. We conducted a detailed metabolic reconstruction of pathways for the synthesis of SCFAs and L- and D-lactate, as additional fermentation products, in a reference set of 2,856 bacterial genomes representing strains of >800 known HGM species. The reconstructed butyrate and propionate pathways included four and three pathway variants, respectively, that start from different metabolic precursors. Altogether, we identified 48 metabolic enzymes, including five alternative enzymes in propionate pathways, and propagated their occurrences across all studied genomes. We established genomic signatures for reconstructed pathways and classified genomes according to their simplified binary phenotypes encoding the ability (“1”) or inability (“0”) of a given organism to produce SCFAs. The resulting binary phenotypes combined into a binary phenotype matrix were used to assess the SCFA synthesis potential of HGM samples from several public metagenomic studies. We report baseline and variance for Community Phenotype Indices calculated for SCFAs production capabilities in 16S metagenomic samples of intestinal microbiota from two large national cohorts (American Gut Project, UK twins), the Hadza hunter-gatherers, and the young children cohort of infants with high-risk for type 1 diabetes. We further linked the predicted SCFA metabolic capabilities with available SCFA concentrations both for in vivo fecal samples and in vitro fermentation samples from previous studies. Finally, we analyzed differential representation of individual SCFA pathway genes across several WGS metagenomic datasets. The obtained collection of SCFA pathway genes and phenotypes enables the predictive metabolic phenotype profiling of HGM datasets and enhances the in silico methodology to study cross-feeding interactions in the gut microbiomes.

Fucosylated Human Milk Oligosaccharides Drive Structure‐Specific Syntrophy between Bifidobacterium infantis and Eubacterium hallii within a Modeled Infant Gut Microbiome

“…The Paraclostridium genus is characterized to produce butyrate through the degradation of lysine and succinate, similar to Lachnoclostridium . [ 66 ] The mechanisms and community dynamics that promote expansion of Paraclostridium during 2ʹFL fermentation and Lachnoclostridium during DFL fermentation are unclear as they both appear to expand into the butyrate‐producing niche left vacated by E. hallii .…”

Alteration of Community Metabolism by Prebiotics and Medicinal Herbs

“…To predict the metabolic potential of microbial taxa identified via 16S rRNA enumeration, we used a subsystem-based approach implemented in the microbial community of SEED, an application of the SEED genomic platform [23] as we have described previously [14]. Curated across human gut microbial genomes, metabolic subsystems include biochemical pathways classified into two categories: (i) the biosynthesis of vitamins, amino acids, and cofactors [24,25], and (ii) production of SCFAs [26]. To analyze the glycosyl hydrolase (GH) and polysaccharide lyase (PL) gene family abundance in profiled taxa, we obtained the distribution of carbohydrate active enzymes (CAZymes) in the analyzed reference genomes using the dbCAN2 tool [25] and observed the production of SCFAs.…”

“…For example, Bifidobacterium predominantly generates lactate, whereas Bacteroides predominantly generate propionate. We used genome reconstruction using 2865 gut reference genomes [26] to identify taxa with the coding potential to generate major fermentation products. We previously reported herb-induced alterations of SCFAs [19], and so the focus here is on prebiotic fibers (Figure 4).…”

Systemic Metabolic Depletion of Intestine Microbiome Undermines Melanoma Immunotherapy Effectiveness

“…For acetate, we considered six possible synthesis pathways, including the WL pathway and a recently discovered pathway involving succinyl-CoA:acetate CoA-transferase and succinyl-CoA synthetase [52, 87, 88]. Meanwhile, for butyrate and propionate, we explored four and three possible synthetic pathways, respectively [89, 90] (refer to Supplementary Table S15 for details). We assembled a reference catalog of gene products for each pathway, resulting in 4563 AA sequences for acetate pathways, 2744 for butyrate pathways, and 415 for propionate pathways.…”