AUTHOR=Mitchell Chandani , Staley Shanieka , Williams Michal Claire , Saxena Archana , Bogdon Raymond , Roark Kasie , Hailey Michele , Miranda Kathryn , Becker William , Dopkins Nicholas , Pena Maria Marjorette , Hogan Kristen M. , Baird Maredith , Wilson Kiesha , Nagarkatti Prakash , Nagarkatti Mitzi , Busbee Philip Brandon 

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

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1444045

DOI=10.3389/fimmu.2024.1444045

ISSN=1664-3224

ABSTRACT=<sec><title>Introduction</title><p>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.</p></sec><sec><title>Methods</title><p>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<sup><italic>ΔRorc</italic></sup>) which depletes this receptor in immune cells involved in production of IL-22. Colitis was induced in wildtype (WT), AhR<sup><italic>ΔRorc</italic></sup>, and littermate (LM) mice with or without I3C treatment. </p></sec><sec><title>Results</title><p>Results showed AhR<sup><italic>ΔRorc</italic></sup> 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<sup><italic>ΔRorc</italic></sup> 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, <italic>Bacteroides acidifaciens</italic> (<italic>B. acidifaciens</italic>), was shown to exacerbate colitis in females, but not males. </p></sec><sec><title>Discussion</title><p>Collectively, this report highlights the cell and sex-specific role of AhR in regulating microbes that can impact colitis disease.</p></sec>