Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Sci Immunol. 2019 Apr 19;4(34). doi: 10.1126/sciimmunol.aaw4341.
Bacterial dysbiosis is associated with Crohn's disease (CD), a chronic intestinal inflammatory disorder thought to result from an abnormal immune response against intestinal bacteria in genetically susceptible individuals. However, it is unclear whether dysbiosis is a cause or consequence of intestinal inflammation and whether overall dysbiosis or specific bacteria trigger the disease. Here, we show that the combined deficiency of NOD2 and phagocyte NADPH oxidase, two CD susceptibility genes, triggers early-onset spontaneous T1-type intestinal inflammation in mice with the pathological hallmarks of CD. Disease was induced by , a Gram-negative mucus-dwelling anaerobe. NOD2 and CYBB deficiencies led to marked accumulation of , which was associated with impaired neutrophil recruitment and killing of the bacterium by luminal neutrophils. Maternal immunoglobulins against protected mutant mice from disease during breastfeeding. Our results indicate that a specific intestinal microbe triggers CD-like disease in the presence of impaired clearance of the bacterium by innate immunity.
细菌失调与克罗恩病（CD）有关，CD 是一种慢性肠道炎症性疾病，据认为是由于遗传易感个体对肠道细菌的异常免疫反应引起的。然而，目前尚不清楚细菌失调是肠道炎症的原因还是结果，以及整体失调还是特定细菌引发了这种疾病。在这里，我们表明，两种 CD 易感性基因 NOD2 和吞噬细胞 NADPH 氧化酶的联合缺乏会导致具有 CD 病理特征的小鼠中出现早发性自发性 T1 型肠道炎症。疾病是由革兰氏阴性黏液栖居厌氧菌引起的。NOD2 和 CYBB 的缺乏导致大量积累 ，这与中性粒细胞募集受损和腔道中性粒细胞对细菌的杀伤能力受损有关。针对 的母体免疫球蛋白在哺乳期保护突变小鼠免受疾病侵害。我们的结果表明，在先天免疫清除细菌能力受损的情况下，特定的肠道微生物会引发类似 CD 的疾病。
