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

Abstract

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.

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Acknowledgements

This research was supported by the Seoul National University Research Grant.

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Affiliations

Authors

Contributions

This study was designed, directed, and coordinated by D-MS, EYC, and J-HS. HCM, D-MS, and EYC supervised the project. J-HS, W-JS, and Y-KL acquired data and performed the animal experiments. Detection of metabolites in urine was analyzed by BK and J-YC. J-HS analyzed and interpreted data. JHS and DMS wrote the main paper, and Y-KL and BK wrote the Materials and Methods section. COJ gave technical and material support. All authors discussed the results and implications and commented on the manuscript at all stages.

Corresponding authors

Correspondence to Eun Young Choi or Dong-Mi Shin.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The protocol of this study was approved by the Institutional Animal Care and Use Committee of the Institute of Laboratory Animal Resources, Seoul National University (Institutional Animal Care and Use Committee permit number: SNU-150119-5).

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Cite this article

Shin, JH., Lee, YK., Shon, WJ. et al. Gut microorganisms and their metabolites modulate the severity of acute colitis in a tryptophan metabolism-dependent manner. Eur J Nutr 59, 3591–3601 (2020). https://doi.org/10.1007/s00394-020-02194-4

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Keywords

  • Gut microbiota
  • Indoleamine 2,3-dioxygenase 1
  • Colitis
  • Indole
  • Tryptophan