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Objective: Roux-en-Y gastric bypass (RYGB) could affect immunological activity after surgery. We examined the role of RYGB on the NOD-like receptor pyrin domain containing-6 (NLRP6) in the intestine after surgery in rat models. Methods: Expression of intestinal NLRP6 in the lean, obesity, RYGB, and sham-pair fed (PF) groups was analyzed by quantitative RT-PCR, Western blotting, and immunohistochemistry. Gut microbiota abundance was determined by 16S rRNA sequencing. Cohousing experiments were conducted to analyze the effects of gut microbiota. Inflammatory cell infiltration and gut permeability were further validated. Results: Obese rats had decreased intestinal NLRP6 levels, which could be restored by RYGB but not by calorie restriction. This regulation was dependent on the gut microbiota-related metabolites, taurine, and histamine. After RYGB, there were increased levels of taurine, which could positively affect NLRP6 expression. The pair-fed groups showed increased histamine, which had the opposite effects on NLRP6. Obese rats had greater intestinal permeability along with increased CD8+ T cell infiltration. However, RYGB but not calorie restriction could restore these changes in a manner, dependent on gut NLRP6 expression. Conclusions: In rat models, RYGB could efficiently restore abnormal gut permeability and reduce inflammation in the intestine, depending on reactivation of NLRP6. [ABSTRACT FROM AUTHOR]