Department of Pediatrics, Baylor College of Medicine, Houston, Texas; Section of Gastroenterology, Hepatology, and Nutrition, Texas Children's Hospital, Houston, Texas.
Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas; Department of Pathology, Texas Children's Hospital, Houston, Texas.
Am J Pathol. 2021 Apr;191(4):704-719. doi: 10.1016/j.ajpath.2021.01.009. Epub 2021 Jan 28.
The intestinal microbiota influences the development and function of the mucosal immune system. However, the exact mechanisms by which commensal microbes modulate immunity is not clear. We previously demonstrated that commensal Bacteroides ovatus ATCC 8384 reduces mucosal inflammation. Herein, we aimed to identify immunomodulatory pathways employed by B. ovatus. In germ-free mice, mono-association with B. ovatus shifted the CD11b/CD11c and CD103/CD11c dendritic cell populations. Because indole compounds are known to modulate dendritic cells, B. ovatus cell-free supernatant was screened for tryptophan metabolites by liquid chromatography-tandem mass spectrometry and larger quantities of indole-3-acetic acid were detected. Analysis of cecal and fecal samples from germ-free and B. ovatus mono-associated mice confirmed that B. ovatus could elevate indole-3-acetic acid concentrations in vivo. Indole metabolites have previously been shown to stimulate immune cells to secrete the reparative cytokine IL-22. Addition of B. ovatus cell-free supernatant to immature bone marrow-derived dendritic cells stimulated IL-22 secretion. The ability of IL-22 to drive repair in the intestinal epithelium was confirmed using a physiologically relevant human intestinal enteroid model. Finally, B. ovatus shifted the immune cell populations in trinitrobenzene sulfonic acid-treated mice and up-regulated colonic IL-22 expression, effects that correlated with decreased inflammation. Our data suggest that B. ovatus-produced indole-3-acetic acid promotes IL-22 production by immune cells, yielding beneficial effects on colitis.
肠道微生物群影响黏膜免疫系统的发育和功能。然而，共生微生物调节免疫的确切机制尚不清楚。我们之前证明共生拟杆菌 ATCC 8384 可减少黏膜炎症。在此，我们旨在确定拟杆菌使用的免疫调节途径。在无菌小鼠中，与拟杆菌单一致联会改变 CD11b/CD11c 和 CD103/CD11c 树突状细胞群体。因为吲哚化合物已知可调节树突状细胞，所以通过液相色谱-串联质谱法筛选拟杆菌无细胞上清液中的色氨酸代谢物，并检测到更多的吲哚-3-乙酸。无菌和拟杆菌单一致联小鼠的盲肠和粪便样本分析证实，拟杆菌可在体内提高吲哚-3-乙酸浓度。吲哚代谢物先前已被证明可刺激免疫细胞分泌修复性细胞因子 IL-22。将拟杆菌无细胞上清液添加到未成熟的骨髓来源的树突状细胞中可刺激 IL-22 分泌。使用生理相关的人肠类器官模型证实了 IL-22 驱动肠上皮修复的能力。最后，拟杆菌改变了三硝基苯磺酸处理小鼠中的免疫细胞群体，并上调了结肠 IL-22 的表达，这些作用与炎症减轻相关。我们的数据表明，拟杆菌产生的吲哚-3-乙酸可促进免疫细胞产生 IL-22，对结肠炎产生有益影响。
