Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA.
Department of Pharmaceutics, University of Washington, Seattle, WA 98195, USA.
Immunity. 2018 Dec 18;49(6):1103-1115.e6. doi: 10.1016/j.immuni.2018.11.018.
Retinoic acid (RA), a vitamin A metabolite, regulates transcriptional programs that drive protective or pathogenic immune responses in the intestine, in a manner dependent on RA concentration. Vitamin A is obtained from diet and is metabolized by intestinal epithelial cells (IECs), which operate in intimate association with microbes and immune cells. Here we found that commensal bacteria belonging to class Clostridia modulate RA concentration in the gut by suppressing the expression of retinol dehydrogenase 7 (Rdh7) in IECs. Rdh7 expression and associated RA amounts were lower in the intestinal tissue of conventional mice, as compared to germ-free mice. Deletion of Rdh7 in IECs diminished RA signaling in immune cells, reduced the IL-22-dependent antimicrobial response, and enhanced resistance to colonization by Salmonella Typhimurium. Our findings define a regulatory circuit wherein bacterial regulation of IEC-intrinsic RA synthesis protects microbial communities in the gut from excessive immune activity, achieving a balance that prevents colonization by enteric pathogens.
视黄酸（RA）是一种维生素 A 代谢物，可调节肠道中保护性或致病性免疫反应的转录程序，其方式取决于 RA 浓度。维生素 A 可从饮食中获得，并由肠道上皮细胞（IEC）代谢，这些细胞与微生物和免疫细胞密切相关。在这里，我们发现属于梭菌纲的共生细菌通过抑制 IEC 中视黄醇脱氢酶 7（Rdh7）的表达来调节肠道中的 RA 浓度。与无菌小鼠相比，常规小鼠的肠道组织中 Rdh7 的表达和相关 RA 含量较低。IEC 中 Rdh7 的缺失减少了免疫细胞中的 RA 信号转导，降低了 IL-22 依赖性抗菌反应，并增强了对鼠伤寒沙门氏菌定植的抵抗力。我们的研究结果定义了一个调节回路，其中细菌调节 IEC 内在 RA 合成可保护肠道中的微生物群落免受过度免疫活性的影响，从而达到防止肠道病原体定植的平衡。
