Gut microorganisms and their metabolites modulate the severity of acute colitis in a tryptophan metabolism-dependent...

Growing evidence shows that nutrient metabolism affects inflammatory bowel diseases (IBD) development. Previously, we showed that deficiency of indoleamine 2,3-dioxygenase 1 (Ido1), a tryptophan-catabolizing enzyme, reduced the severity of dextran sulfate sodium (DSS)-induced colitis in mice. However, the roles played by intestinal microbiota in generating the differences in disease progression between Ido1^+/+ and Ido1^-/- mice are unknown. Therefore, we aimed to investigate the interactions between the intestinal microbiome and host IDO1 in governing intestinal inflammatory responses.

Microbial 16s rRNA sequencing was conducted in Ido1^+/+ and Ido1^-/- mice after DSS treatment. Bacteria-derived tryptophan metabolites were measured in urine. Transcriptome analysis revealed the effects of the metabolite and IDO1 expression in HCT116 cells. Colitis severity of Ido1^+/+ was compared to Ido1^-/- mice following fecal microbiota transplantation (FMT).

Microbiome analysis through 16S-rRNA gene sequencing showed that IDO1 deficiency increased intestinal bacteria that use tryptophan preferentially to produce indolic compounds. Urinary excretion of 3-indoxyl sulfate, a metabolized form of gut bacteria-derived indole, was significantly higher in Ido1^-/- than in Ido1^+/+ mice. Transcriptome analysis showed that tight junction transcripts were significantly increased by indole treatment in HCT116 cells; however, the effects were diminished by IDO1 overexpression. Using FMT experiments, we demonstrated that bacteria from Ido1^-/- mice could directly attenuate the severity of DSS-induced colitis.

Our results provide evidence that a genetic defect in utilizing tryptophan affects intestinal microbiota profiles, altering microbial metabolites, and colitis development. This suggests that the host and intestinal microbiota communicate through shared nutrient metabolic networks.