Substrate availability and dietary fibre regulate metabolism of tryptophan by human gut microbes

Abstract

AbstractTryptophan is catabolized by gut microbes, resulting in a wide range of metabolites implicated in both beneficial and adverse host effects. However, it remains elusive how the gut microbial tryptophan metabolism is governed either towards indole, associated with adverse effects in chronic kidney disease, or towards indolelactic acid (ILA) and indolepropionic acid (IPA), associated with protective effects in type 2 diabetes and inflammatory bowel disease. Here, we used human fecal cultures in combination with a controlled three-species model to test competition for tryptophan, and measured the resulting metabolites bothin vitroand in gnotobiotic mice colonized with the three species. We revealed that the generation of specific tryptophan-derived metabolites was not predominantly determined by the abundance of tryptophan metabolizing bacteria, but rather by substrate-dependent regulation of specific metabolic pathways.In vitroandin vivo, indole-producingEscherichia coliand ILA- and IPA-producingClostridium sporogenescompeted for tryptophan. Importantly, the fibre degradingBacteroides thetaiotaomicronaffected this competition by cross-feeding monosaccharides toE. coli, which inhibited indole production through catabolite repression, and thereby made more tryptophan available toC. sporogenes, increasing ILA and IPA production. We thus present the first mechanistic explanation for why consumption of fermentable fibres suppress indole production but promote the generation of other tryptophan metabolites associated with health benefits. We conclude that the availability of tryptophan and dietary fibre regulates gut microbiome tryptophan metabolism pathways, and consequently influences the balance between the different tryptophan catabolites generated. This balance has implications for host-microbial cross-talk affecting human health.