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


METHODS
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).


RESULTS
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.


CONCLUSIONS
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.
['Shin|Ji-Hee|JH|', 'Lee|Young-Kwan|YK|', 'Shon|Woo-Jeong|WJ|', 'Kim|Bora|B|', 'Jeon|Che Ok|CO|', 'Cho|Joo-Youn|JY|', 'Morse|Herbert C|HC|', 'Choi|Eun Young|EY|', 'Shin|Dong-Mi|DM|']
D000818:Animals D003092:Colitis D016264:Dextran Sulfate D004195:Disease Models, Animal D000069196:Gastrointestinal Microbiome D015212:Inflammatory Bowel Diseases D051379:Mice D008810:Mice, Inbred C57BL D012336:RNA, Ribosomal, 16S D014364:Tryptophan
Colitis Tryptophan Indoleamine 2,3-dioxygenase 1 Indole Gut microbiota