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,我们显示了十字花科蔬菜中的天然产物和芳烃受体(AhR)的配体,吲哚-3-甲醇(I3C),能够以白介素-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菌群失调。
■在当前的研究中,我们在结肠炎诱导和补充I3C期间对结肠细胞进行了单细胞RNA测序(scRNAseq),并显示了这种治疗如何改变IL-22信号传导相关基因的表达.为了进一步定义IL-22信号在I3C介导的结肠炎和疾病相关微生物菌群失调保护中的作用,我们在RAR相关的孤儿受体c(Rorc)表达细胞(AhRΔRorc)中产生了AhR缺乏的小鼠,该小鼠在参与IL-22产生的免疫细胞中消耗了该受体。在野生型(WT)中诱导结肠炎,AhRΔRorc,和有或没有I3C处理的同窝(LM)小鼠。
■结果显示AhRΔRorc小鼠失去了I3C治疗的功效作用,这与先天淋巴样3型(ILC3)增加IL-22的能力丧失有关,不是T辅助细胞22(Th22)。16SrRNA微生物组分析研究表明,AhRΔRorc小鼠无法调节拟杆菌的疾病相关增加,男性和女性之间的差异。最后,接种特定的疾病相关拟杆菌物种,酸化拟杆菌(B.酸化),被证明会加剧女性的结肠炎,但不是男性。
■集体,本报告强调了AhR在调节可影响结肠炎疾病的微生物中的细胞和性别特异性作用.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: Collectively, this report highlights the cell and sex-specific role of AhR in regulating microbes that can impact colitis disease.