Abstract
The gut contains an enormous diversity of simple as well as complex molecules from highly diverse food sources, together with host-secreted molecules. This presents a large metabolic opportunity for the gut microbiota, but little is known about how gut microbes are able to catabolize this large chemical diversity. Recently, Fe-S flavoenzymes were found to be key in the transformation of bile acids, catalysing the key step in the 7α-dehydroxylation pathway that allows gut bacteria to transform cholic acid into deoxycholic acid, an exclusively microbe-derived molecule with major implications for human health. While this enzyme family has also been implicated in a limited number of other catalytic transformations, little is known about the extent to which it is of more global importance in gut microbial metabolism. Here, we perform a large-scale computational genomic analysis to show that this enzyme superfamily has undergone a remarkable expansion in Clostridiales, and occurs throughout a diverse array of >1000 different families of putative metabolic gene clusters. Analysis of the enzyme content of these gene clusters suggests that they encode pathways with a wide range of predicted substrate classes, including saccharides, amino acids/peptides and lipids. Altogether, these results indicate a potentially important role of this protein superfamily in the human gut, and our dataset provides significant opportunities for the discovery of novel pathways that may have significant effects on human health.
Highlights
The gene set of the human gut microbiota vastly exceeds the human gene repertoire[1,2], which allows microbes to complement human metabolism by degrading undigested polysaccharides, lipids, and peptides that reach the large intestine[3]
The metabolic potential of gut bacteria greatly exceeds the genetic potential of the human host
Bacteria can benefit from utilizing a diverse range of substrates that reach the digestive tract
Summary
The gene set of the human gut microbiota vastly exceeds the human gene repertoire[1,2], which allows microbes to complement human metabolism by degrading undigested polysaccharides, lipids, and peptides that reach the large intestine[3]. The identification of these molecules and the elucidation of their producing pathways is crucial to assess the causes and consequences of certain microbiome-associated phenotypes. Another example of exclusively microbiome-derived molecules are the secondary bile acids (BA): deoxycholic acid (DCA) and lithocholic acid (LCA). While the primary bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA) are synthesized by the liver[7], they are transformed into DCA or LCA by colonic bacteria during enterohepatic circulation[8] These molecules have been proposed to act as inhibitors of C. difficile outgrowth[9], as well as to induce the development of colon cancer[10,11] and cholesterol gallstone disease[12]. The participation of Fe-S flavoenzymes in the key reductive steps of the pathway is consistent with a role for this pathway in using primary bile acids as terminal electron acceptors for an anaerobic electron transport pathway, constituting a unique metabolic niche within the gut community
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