Ulcerative colitis (UC) is a chronic and relapsing inflammatory disorder, which has an increased incidence worldwide. The NLRP3 inflammasome has recently been assigned as a promising target for several inflammatory diseases including bowel inflammation. We aimed to investigate the potential complementary effects of combined therapy of metformin and MCC950 in dextran sodium sulfate (DSS)-induced colitis in rats. Metformin/MCC950 mitigated colon shortening, disease activity index (DAI), and macroscopic damage index (MDI). It also improved the colon histology picture and reduced the inflammation score. In addition, metformin/MCC950 augmented the antioxidant defense machinery and attenuated the myeloperoxidase (MPO) activity. Moreover, the levels of the pro-inflammatory mediators tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) were reduced. This pharmacological activity might be attributed to interrupting the priming signal of the NLRP3 inflammasome activation through inactivating Toll-like receptor 4 (TLR4)/nuclear transcription factor kappa-B (NF-κB) signalling (effect of metformin) as well as interrupting the activation signal through potent inhibition of NLRP3 expression and caspase-1 (effect of MCC950). As a result, significant inhibition of the production of the bioactive IL-1β and IL-18 occurred, and hence the pyroptosis process was inhibited. Moreover, the metformin/MCC950 leads to the induction of autophagy by AMP-activated protein kinase (AMPK)-dependent mechanisms leading to the accumulation of Beclin-1 and a substantial decline in the levels of p62 SQSTM1 (effect of metformin). The observed impeding effect on HSP90 along with inducing autophagy (effect of metformin) suggests that NLRP3 is prone to autophagic degradation. In conclusion, we reveal that the combination of metformin with MCC950 has a protective role in DSS-induced colitis and might become a candidate in a promising approach for the future treatment of human UC.

溃疡性结肠炎 (UC) 是一种慢性复发性炎症性疾病，其在世界范围内的发病率不断增加。NLRP3 炎症小体最近被指定为几种炎症性疾病（包括肠道炎症）的有希望的靶点。我们旨在研究二甲双胍和 MCC950 联合治疗对葡聚糖硫酸钠 (DSS) 诱导的大鼠结肠炎的潜在补充作用。二甲双胍/MCC950 减轻了结肠缩短、疾病活动指数 (DAI) 和宏观损伤指数 (MDI)。它还改善了结肠组织学图片并降低了炎症评分。此外，二甲双胍/MCC950 增强了抗氧化防御机制并减弱了髓过氧化物酶 (MPO) 活性。此外，促炎介质肿瘤坏死因子α（TNFα）和白细胞介素6（IL-6）的水平降低。这种药理活性可能归因于通过灭活 Toll 样受体 4 (TLR4)/核转录因子 kappa-B (NF-κB) 信号（二甲双胍的作用）以及中断激活来中断 NLRP3 炎症小体激活的启动信号通过有效抑制 NLRP3 表达和 caspase-1（MCC950 的作用）产生信号。结果，显着抑制了生物活性 IL-1β 和 IL-18 的产生，从而抑制了细胞焦亡过程。此外，二甲双胍/MCC950 会通过 AMP 活化蛋白激酶 (AMPK) 依赖性机制诱导自噬，从而导致 Beclin-1 的积累和 p62 SQSTM1 水平的大幅下降（二甲双胍的作用）。观察到的对 HSP90 的阻碍作用以及诱导自噬（二甲双胍的作用）表明 NLRP3 易于自噬降解。总之，我们揭示了二甲双胍与 MCC950 的组合在 DSS 诱导的结肠炎中具有保护作用，并可能成为未来治疗人类 UC 的一种有前途的方法的候选者。