AUTHOR=Kahalehili Heather M. , Newman Nolan K. , Pennington Jamie M. , Kolluri Siva K. , Kerkvliet Nancy I. , Shulzhenko Natalia , Morgun Andrey , Ehrlich Allison K. TITLE=Dietary Indole-3-Carbinol Activates AhR in the Gut, Alters Th17-Microbe Interactions, and Exacerbates Insulitis in NOD Mice JOURNAL=Frontiers in Immunology VOLUME=11 YEAR=2021 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.606441 DOI=10.3389/fimmu.2020.606441 ISSN=1664-3224 ABSTRACT=

The diet represents one environmental risk factor controlling the progression of type 1 diabetes (T1D) in genetically susceptible individuals. Consequently, understanding which specific nutritional components promote or prevent the development of disease could be used to make dietary recommendations in prediabetic individuals. In the current study, we hypothesized that the immunoregulatory phytochemcial, indole-3-carbinol (I3C) which is found in cruciferous vegetables, will regulate the progression of T1D in nonobese diabetic (NOD) mice. During digestion, I3C is metabolized into ligands for the aryl hydrocarbon receptor (AhR), a transcription factor that when systemically activated prevents T1D. In NOD mice, an I3C-supplemented diet led to strong AhR activation in the small intestine but minimal systemic AhR activity. In the absence of this systemic response, the dietary intervention led to exacerbated insulitis. Consistent with the compartmentalization of AhR activation, dietary I3C did not alter T helper cell differentiation in the spleen or pancreatic draining lymph nodes. Instead, dietary I3C increased the percentage of CD4+RORγt+Foxp3- (Th17 cells) in the lamina propria, intraepithelial layer, and Peyer’s patches of the small intestine. The immune modulation in the gut was accompanied by alterations to the intestinal microbiome, with changes in bacterial communities observed within one week of I3C supplementation. A transkingdom network was generated to predict host-microbe interactions that were influenced by dietary I3C. Within the phylum Firmicutes, several genera (Intestinimonas, Ruminiclostridium 9, and unclassified Lachnospiraceae) were negatively regulated by I3C. Using AhR knockout mice, we validated that Intestinimonas is negatively regulated by AhR. I3C-mediated microbial dysbiosis was linked to increases in CD25high Th17 cells. Collectively, these data demonstrate that site of AhR activation and subsequent interactions with the host microbiome are important considerations in developing AhR-targeted interventions for T1D.