Host and gut microbial tryptophan metabolism and type 2 diabetes: an integrative analysis of host genetics, diet, gut microbiome and circulating metabolites in cohort studies

Abstract

ObjectiveTryptophan can be catabolised to various metabolites through host kynurenine and microbial indole pathways. We aimed to examine relationships of host and microbial tryptophan metabolites with incident type 2 diabetes (T2D), host genetics, diet and gut microbiota.MethodWe analysed associations between circulating levels of 11 tryptophan metabolites and incident T2D in 9180 participants of diverse racial/ethnic backgrounds from five cohorts. We examined host genome-wide variants, dietary intake and gut microbiome associated with these metabolites.ResultsTryptophan, four kynurenine-pathway metabolites (kynurenine, kynurenate, xanthurenate and quinolinate) and indolelactate were positively associated with T2D risk, while indolepropionate was inversely associated with T2D risk. We identified multiple host genetic variants, dietary factors, gut bacteria and their potential interplay associated with these T2D-relaetd metabolites. Intakes of fibre-rich foods, but not protein/tryptophan-rich foods, were the dietary factors most strongly associated with tryptophan metabolites. The fibre-indolepropionate association was partially explained by indolepropionate-associated gut bacteria, mostly fibre-using Firmicutes. We identified a novel association between a host functional LCT variant (determining lactase persistence) and serum indolepropionate, which might be related to a host gene-diet interaction on gut Bifidobacterium, a probiotic bacterium significantly associated with indolepropionate independent of other fibre-related bacteria. Higher milk intake was associated with higher levels of gut Bifidobacterium and serum indolepropionate only among genetically lactase non-persistent individuals.ConclusionHigher milk intake among lactase non-persistent individuals, and higher fibre intake were associated with a favourable profile of circulating tryptophan metabolites for T2D, potentially through the host–microbial cross-talk shifting tryptophan metabolism toward gut microbial indolepropionate production.

Metabolomics in Diabetes and Diabetic Complications: Insights from Epidemiological Studies

“…Over the past two decades, metabolomics has been widely utilized in large epidemiological studies, and some metabolites/pathways have been identified and validated to be associated with insulin metabolism or being predictive of diabetes across different studies [ 35 ]. Table 2 summarizes the findings from some of key prospective studies [ 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ].…”

“…Using untargeted LC-MS, more microbial metabolites have been found to be predictive of incident diabetes in the METSIM study [ 63 ]. Studies integrating metabolomics with genetics and gut microbiota have been implemented to explore the interplay between genetic variants, dietary intake, gut microbiome and metabolites in diabetes and its complications [ 65 , 103 ].…”

New Insights Into Gut-Bacteria-Derived Indole and Its Derivatives in Intestinal and Liver Diseases

“…Recently, some researchers have found that IPA was the metabolite most significantly and consistently related to the intake of fiber and inversely associated with the risk of type 2 diabetes ( de Mello et al, 2017 ). The associated mechanism can be partially explained by the host functional LCT variant and fiber intake interaction on the gut bacteria shifting tryptophan metabolism ( de Mello et al, 2017 ; Qi et al, 2021 ). In addition to carbohydrates, dietary cholesterol was reported to drive the formation of nonalcoholic fatty liver disease–associated hepatocellular carcinoma by inducing changes in mouse gut microbiota and metabolites.…”

Metabolomics Meets Nutritional Epidemiology: Harnessing the Potential in Metabolomics Data

“…In a recent analysis that was conducted among more than 9000 free-living individuals participating in five cohort studies, investigators demonstrated that the circulating levels of indolepropionate, a tryptophan metabolite produced by gut bacteria, were robustly associated with a lower type 2 diabetes risk [30]. A further genome-wide association analysis demonstrated that variants in the LCT gene that encodes lactase predicted levels of indolepropionate.…”