Regulation of Bacteroides acidifaciens by the aryl hydrocarbon receptor in IL-22-producing immune cells has sex-dependent consequential impact on colitis.

Colitis is an inflammatory bowel disease (IBD) characterized by immune cell dysregulation and alterations in the gut microbiome. In our previous report, we showed a natural product in cruciferous vegetables and ligand of the aryl hydrocarbon receptor (AhR), indole-3-carbinol (I3C), was able to reduce colitis-induced disease severity and microbial dysbiosis in an interleukin-22 (IL-22) dependent manner. In the current study, we performed single-cell RNA sequencing (scRNAseq) from colonocytes during colitis induction and supplementation with I3C and show how this treatment alters expression of genes involved in IL-22 signaling. To further define the role of IL-22 signaling in I3C-mediated protection during colitis and disease-associated microbial dysbiosis, we generated mice with AhR deficiency in RAR-related orphan receptor c (Rorc)-expressing cells (AhR ΔRorc ) which depletes this receptor in immune cells involved in production of IL-22. Colitis was induced in wildtype (WT), AhR ΔRorc , and littermate (LM) mice with or without I3C treatment. Results showed AhR ΔRorc mice lost the efficacy effects of I3C treatment which correlated with a loss of ability to increase IL-22 by innate lymphoid type 3 (ILC3s), not T helper 22 (Th22) cells. 16S rRNA microbiome profiling studies showed AhR ΔRorc mice were unable to regulate disease-associated increases in Bacteroides, which differed between males and females. Lastly, inoculation with a specific disease-associated Bacteroides species, Bacteroides acidifaciens (B. acidifaciens), was shown to exacerbate colitis in females, but not males. Collectively, this report highlights the cell and sex-specific role of AhR in regulating microbes that can impact colitis disease.

Mitchell C ，Staley S ，Williams MC ，Saxena A ，Bogdon R ，Roark K ，Hailey M ，Miranda K ，Becker W ，Dopkins N ，Pena MM ，Hogan KM ，Baird M ，Wilson K ，Nagarkatti P ，Nagarkatti M ，Busbee PB ... -  《Frontiers in Immunology》

Dietary Indole-3-Carbinol Activates AhR in the Gut, Alters Th17-Microbe Interactions, and Exacerbates Insulitis in NOD Mice.

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.

Kahalehili HM ，Newman NK ，Pennington JM ，Kolluri SK ，Kerkvliet NI ，Shulzhenko N ，Morgun A ，Ehrlich AK ... -  《Frontiers in Immunology》

Involvement of Intestinal Epithelium Aryl Hydrocarbon Receptor Expression and 3, 3'-Diindolylmethane in Colonic Tertiary Lymphoid Tissue Formation.

Garcia-Villatoro EL ，Bomstein ZS ，Allred KF ，Callaway ES ，Safe S ，Chapkin RS ，Jayaraman A ，Allred CD ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

Aryl Hydrocarbon Receptor Regulates Muc2 Production Independently of IL-22 during Colitis.

Saxena A ，Mitchell C ，Bogdon R ，Roark K ，Wilson K ，Staley S ，Hailey M ，Williams MC ，Rutkovsky A ，Nagarkatti P ，Nagarkatti M ，Busbee PB ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

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

Busbee PB ，Menzel L ，Alrafas HR ，Dopkins N ，Becker W ，Miranda K ，Tang C ，Chatterjee S ，Singh U ，Nagarkatti M ，Nagarkatti PS ... -  《JCI Insight》