Dietary Intake, Tryptophan Metabolism, and Genetic Associations in Incident Type 2 Diabetes

Investigators assessed the association between circulating levels of tryptophan metabolites and incident T2D via genetic variants, diet, and gut microbiome.

Among patients with type 2 diabetes (T2D), increased dietary fiber intake was associated with more favorable levels of circulating tryptophan metabolites. These findings, from an analysis of large cohort data, were published in Gut.

Data were sourced from the Hispanic Community Health Study/Study of Latinos, Atherosclerosis Risk in Communities Study, Framingham Heart Study, Women’s Health Initiative, and Prevención con Dieta Mediterránea Study. Individuals (N=9180) from diverse backgrounds were assessed for incident T2D, circulating metabolites, dietary intake, gut microbiome via stool samples, and genetics.

Incident T2D, after adjusting for cofactors, was positively associated with tryptophan (P <.001), xanthurenate (P <.001), indolelactate (P =.001), kynurenine (P =.016), and kynurenate (P =.046) and negatively associated with indolepropionate (P =.006). Indolepropionate was the only metabolite not associated with other metabolites (Spearman’s r, -0.05-0.06).

Genetic analysis identified 13 loci which were associated with 9 out of 11 tryptophan metabolites (P <4.5´10-9). Six of these loci had previously been associated.

The heritability of these loci was 13.0% for serotonin, 10.7% for indolepropionate, and 7.4% for kynurenine. On the basis of the significant loci and heritability, indolepropionate had a potentially causal relationship with incident T2D (genetic causality proportion, 76%; P =1.6´10-24).

Serum indolepropionate was associated with increased consumption of vegetables, fruits, whole grains, legumes, and nuts and decreased consumption of refined grains and red meat. Indolepropionate was most strongly associated with higher fiber intake (P =7.3´10-60). Tryptophan metabolites were found to mediate the relationship between diet quality and incident T2D (proportion mediated, 61.5%; P =.01).

The investigators observed that 21 gut microbiota genera were significantly associated with indolepropionate (false discovery rate [FDR], <.05). These genera included Firmicutes (n=16), Actinobacteria (n=3), and Bacteroidetes (n=2). Fifteen of these genera were also associated with increased fiber intake (FDR, <.05) and were found to have a mediating effect between fiber intake and indolepropionate (proportion mediated, 22.3%; P =.003).

This analysis may have been limited by the design of some of the underlying studies. For example, 1 cohort collected dietary details and serum samples 7 years before stool samples. Unknown changes to dietary behaviors may have caused erroneous relationships to be made.

Incident T2D may be associated with a complex relationship involving tryptophan metabolism, genetics, and dietary intake. Additional studies are needed to assess the extent of host-microbial cross-talk and its role in T2D.


Qi Q, Li J, Yu B, et al. 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. Gut. Published online June 14, 2021. doi: 10.1136/gutjnl-2021-324053