Decreased expression of the NLRP6 inflammasome is associated with increased intestinal permeability and inflammation in obesity with type 2 diabetes

Abstract

Background Obesity-associated dysfunctional intestinal permeability contributes to systemic chronic infammation leading to the development of metabolic diseases. The infammasomes constitute essential components in the regulation of intestinal homeostasis. We aimed to determine the impact of the infammasomes in the regulation of gut barrier dysfunction and metabolic infammation in the context of obesity and type 2 diabetes (T2D). Methods Blood samples obtained from 80 volunteers (n=20 normal weight, n=21 OB without T2D, n=39 OB with T2D) and a subgroup of jejunum samples were used in a case–control study. Circulating levels of intestinal damage markers and expression levels of infammasomes as well as their main efectors (IL-1β and IL-18) and key infammation-related genes were analyzed. The impact of infammation-related factors, diferent metabolites and Akkermansia muciniphila in the regulation of infammasomes and intestinal integrity genes was evaluated. The efect of blocking NLRP6 by using siRNA in infammation was also studied. Results Increased circulating levels (P<0.01) of the intestinal damage markers endotoxin, LBP, and zonulin in patients with obesity decreased (P<0.05) after weight loss. Patients with obesity and T2D exhibited decreased (P<0.05) jejunum gene expression levels of NLRP6 and its main efector IL18 together with increased (P<0.05) mRNA levels of infammatory markers. We further showed that while NLRP6 was primarily localized in goblet cells, NLRP3 was localized in the intestinal epithelial cells. Additionally, decreased (P<0.05) mRNA levels of Nlrp1, Nlrp3 and Nlrp6 in the small intestinal tract obtained from rats with diet-induced obesity were found. NLRP6 expression was regulated by taurine, parthenolide and A. muciniphila in the human enterocyte cell line CCL-241. Finally, a signifcant decrease (P<0.01) in the expression and release of MUC2 after the knockdown of NLRP6 was observed. Conclusions The increased levels of intestinal damage markers together with the downregulation of NLRP6 and IL18 in the jejunum in obesity-associated T2D suggest a defective infammasome sensing, driving to an impaired epithelial intestinal barrier that may regulate the progression of multiple obesity-associated comorbidities