Indole-3-carbinol prevents colitis and associated microbial dysbiosis in an IL-22-dependent manner.

Philip B Busbee,Nicholas Dopkins,Udai Singh,William Becker,Saurabh Chatterjee,Prakash S Nagarkatti,Kathryn Miranda,Chaunbing Tang,Haider Alrafas,Mitzi Nagarkatti,Lorenzo Menzel

doi:10.1172/jci.insight.127551

Abstract

Colitis, an inflammatory bowel disease, is caused by a variety of factors, but luminal microbiota are thought to play crucial roles in disease development and progression. Indole is produced by gut microbiota and is believed to protect the colon from inflammatory damage. In the current study, we investigated whether indole-3-carbinol (I3C), a naturally occurring plant product found in numerous cruciferous vegetables, can prevent colitis-associated microbial dysbiosis and attempted to identify the mechanisms. Treatment with I3C led to repressed colonic inflammation and prevention of microbial dysbiosis caused by colitis, increasing a subset of gram-positive bacteria known to produce butyrate. I3C was shown to increase production of butyrate, and when mice with colitis were treated with butyrate, there was reduced colonic inflammation accompanied by suppression of Th17 and induction of Tregs, protection of the mucus layer, and upregulation in Pparg expression. Additionally, IL-22 was increased only after I3C but not butyrate administration, and neutralization of IL-22 prevented the beneficial effects of I3C against colitis, as well as blocked I3C-mediated dysbiosis and butyrate induction. This study suggests that I3C attenuates colitis primarily through induction of IL-22, which leads to modulation of gut microbiota that promote antiinflammatory butyrate.

Highlights

Colitis is a disorder characterized by chronic inflammation and tissue destruction within the colon and intestinal tract
In a murine DSS-induced colitis model, researchers found a significant increase in Bacteroidales, which correlated with intestinal mucin degradation, whereas Clostridiales decreased during inflammation, correlating with a reduction in butyrate [36, 37]
In human inflammatory bowel disease (IBD) patients, certain bacteria seem to become more prominent when compared with healthy controls, such as members of the family Enterobacteriaceae, Bacteriodaceae, and Bacteriodes [38,39,40,41,42]. 16S rRNA gene profiles of mucosal tissue samples from ulcerative colitis patients found that this patient population had higher abundances of Prevotella and Bacteriodes [43]

Summary

Introduction

Colitis is a disorder characterized by chronic inflammation and tissue destruction within the colon and intestinal tract. Ulcerative colitis and Crohn’s disease are 2 forms of colitis defined by the affected areas of inflammation and depth of destruction in the gastrointestinal tissue [1]. The inflammation associated with the disease is regulated to the colon and rectum, with damage occurring at the superficial epithelial surface, whereas in Crohn’s disease, the inflammation can be found throughout the gastrointestinal tract and often extends deeper into the colonic tissue layer [2]. Acetic acid is known to induce colitis in animal models [5, 6], whereas butyrate, the conjugate base form of butyric acid, was shown to reduce symptoms in ulcerative colitis patients by acting as an energy source for colonic epithelial cells for healing [7].

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