Department of Chemical and Pharmaceutical Engineering, Huaqiao University, Xiamen, Fujian, China.
Department of Colorectal Cancer Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China.
Biomed J. 2023 Oct;46(5):100580. doi: 10.1016/j.bj.2023.01.004. Epub 2023 Feb 8.
Inflammatory bowel disease (IBD) is a chronic, life-threatening inflammatory disease of gastrointestinal tissue characterized by inflammation of the gut. Recent studies have shown that gut microbiota is involved in the pathophysiology of IBD. However, it is unknown whether direct inhibition of NLR family pyrin domain containing 3 (NLRP3) inflammasome regulates IBD and alters gut microbiota.
Here, the NLRP3 expression was evaluated in the colon of IBD subjects. Then, we investigated the effects of NLRP3 inhibition by MCC950 on the gut microbiota and IBD-like symptoms induced by dextran sulfate sodium (DSS).
Firstly, NLRP3 and IL-1β levels were increased in patients with IBD as compared with healthy individuals. Then, the animal experiment showed that NLRP3 inhibition by MCC950 significantly attenuated IBD-like symptoms such as diarrhea and colonic inflammation in DSS-induced mice. In addition, NLRP3 inhibition inhibited NLRP3/ASC/caspase-1/IL-1β signaling pathway in the colon, which was over-activated by DSS. Furthermore, MCC950 increased the abundance of phylum Firmicutes, decreased the abundance of phylum Bacteroidetes, and increased the Firmicutes/Bacteroidetes ratio, indicating that the inhibition of NLRP3 inflammasome could regulate the abundance of intestinal flora. According to correlation analysis, NLRP3 might produce its functional role in the regulation of oxidation indicators by changing the gut microbiota composition, especially the phylum Bacteroidota, genus Lactobacillus and species Lactobacillus reuteri.
This study suggests that NLRP3 inflammasome inhibition attenuates IBD-like symptoms by regulating gut microbiota, and provides a basis for the clinical application of NLRP3 as a target for the treatment of IBD.
炎症性肠病（IBD）是一种慢性、危及生命的胃肠道组织炎症性疾病，以肠道炎症为特征。最近的研究表明，肠道微生物群参与了 IBD 的病理生理学。然而，尚不清楚直接抑制 NOD、LRR 和富含pyrin 结构域蛋白 3（NLRP3）炎症小体是否调节 IBD 并改变肠道微生物群。
本研究评估了 IBD 患者结肠中 NLRP3 的表达。然后，我们研究了 NLRP3 抑制剂 MCC950 对葡聚糖硫酸钠（DSS）诱导的肠道微生物群和 IBD 样症状的影响。
首先，与健康个体相比，IBD 患者的 NLRP3 和 IL-1β 水平升高。然后，动物实验表明，DSS 诱导的小鼠中 NLRP3 抑制通过 MCC950 显著减轻 IBD 样症状，如腹泻和结肠炎症。此外，NLRP3 抑制抑制了 NLRP3/ASC/caspase-1/IL-1β 信号通路，该通路在 DSS 作用下过度激活。此外，MCC950 增加了厚壁菌门的丰度，降低了拟杆菌门的丰度，并增加了厚壁菌门/拟杆菌门的比例，表明 NLRP3 炎症小体的抑制可以调节肠道菌群的丰度。根据相关性分析，NLRP3 可能通过改变肠道菌群组成，特别是拟杆菌门、乳杆菌属和雷氏乳杆菌，来发挥其在氧化指标调节中的功能作用。
本研究表明，NLRP3 炎症小体抑制通过调节肠道微生物群减轻 IBD 样症状，为 NLRP3 作为治疗 IBD 的靶点的临床应用提供了依据。
