Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
Institute of Molecular Life Science and Swiss Institute of Bioinformatics, University of Zurich, Zurich, Switzerland.
J Clin Invest. 2019 May 20;129(6):2527-2541. doi: 10.1172/JCI123263.
The gut microbiota is crucial for our health, and well-balanced interactions between the host's immune system and the microbiota are essential to prevent chronic intestinal inflammation, as observed in inflammatory bowel diseases (IBD). A variant in protein tyrosine phosphatase non-receptor type 22 (PTPN22) is associated with reduced risk of developing IBD, but promotes the onset of autoimmune disorders. While the role of PTPN22 in modulating molecular pathways involved in IBD pathogenesis is well studied, its impact on shaping the intestinal microbiota has not been addressed in depth. Here, we demonstrate that mice carrying the PTPN22 variant (619W mice) were protected from acute dextran sulfate sodium (DSS) colitis, but suffered from pronounced inflammation upon chronic DSS treatment. The basal microbiota composition was distinct between genotypes, and DSS-induced dysbiosis was milder in 619W mice than in WT littermates. Transfer of microbiota from 619W mice after the first DSS cycle into treatment-naive 619W mice promoted colitis, indicating that changes in microbial composition enhanced chronic colitis in those animals. This indicates that presence of the PTPN22 variant affects intestinal inflammation by modulating the host's response to the intestinal microbiota.
肠道微生物群对我们的健康至关重要，宿主免疫系统和微生物群之间的平衡相互作用对于预防慢性肠道炎症至关重要，如炎症性肠病 (IBD) 中观察到的那样。蛋白酪氨酸磷酸酶非受体型 22 (PTPN22) 的变异与降低 IBD 发病风险有关，但会促进自身免疫性疾病的发生。虽然 PTPN22 在调节涉及 IBD 发病机制的分子途径中的作用已得到充分研究，但它对肠道微生物群的影响尚未得到深入研究。在这里，我们证明携带 PTPN22 变异体 (619W 小鼠) 的小鼠对急性葡聚糖硫酸钠 (DSS) 结肠炎具有保护作用，但在慢性 DSS 处理时会发生明显的炎症。两种基因型之间的基础微生物群组成存在差异，并且在 619W 小鼠中，DSS 诱导的菌群失调比 WT 同窝仔鼠更为轻微。将第一次 DSS 循环后来自 619W 小鼠的微生物群转移到未经治疗的 619W 小鼠中，会促进结肠炎，表明微生物组成的变化增强了这些动物的慢性结肠炎。这表明 PTPN22 变异体的存在通过调节宿主对肠道微生物群的反应来影响肠道炎症。
