Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States.
Department of Biological Sciences, College of Arts and Sciences, University of South Carolina, Columbia, SC, United States.
Front Immunol. 2024 Aug 20;15:1444045. doi: 10.3389/fimmu.2024.1444045. eCollection 2024.
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 ) which depletes this receptor in immune cells involved in production of IL-22. Colitis was induced in wildtype (WT), AhR , and littermate (LM) mice with or without I3C treatment.
Results showed AhR 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 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, (), 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.
结肠炎是一种炎症性肠病（IBD），其特征是免疫细胞失调和肠道微生物组的改变。在我们之前的报告中，我们展示了十字花科蔬菜中的一种天然产物和芳烃受体（AhR）的配体，吲哚-3-甲醇（I3C），能够以白细胞介素-22（IL-22）依赖的方式减轻结肠炎引起的疾病严重程度和微生物失调。
在目前的研究中，我们对结肠炎诱导期间和用 I3C 补充后的结肠细胞进行了单细胞 RNA 测序（scRNAseq），并展示了这种治疗如何改变参与 IL-22 信号的基因的表达。为了进一步确定 IL-22 信号在 I3C 介导的结肠炎保护和疾病相关微生物失调中的作用，我们生成了 RAR 相关孤儿受体 c（Rorc）表达细胞中 AhR 缺陷的小鼠（AhR ），该受体在参与 IL-22 产生的免疫细胞中耗竭该受体。在野生型（WT）、AhR 和同窝（LM）小鼠中诱导结肠炎，并用或不用 I3C 处理。
结果表明，AhR 小鼠失去了 I3C 治疗的疗效，这与先天淋巴样细胞 3（ILC3s）而不是辅助性 T 细胞 22（Th22）细胞增加 IL-22 的能力丧失有关。16S rRNA 微生物组分析研究表明，AhR 小鼠无法调节与疾病相关的增加的拟杆菌，这在男性和女性之间有所不同。最后，接种一种特定的与疾病相关的拟杆菌物种（），在女性中加剧了结肠炎，但在男性中没有。
总的来说，本报告强调了 AhR 在调节可能影响结肠炎疾病的微生物方面的细胞和性别特异性作用。
