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Inflammasomes are involved in gut homeostasis and inflammatory pathologies, but the role of NLRP3 inflammasome in these processes is not well understood. Cryopyrin-associated periodic syndrome (CAPS) patients with NLRP3 mutations have autoinflammation in skin, joints, and eyes, but not in the intestine. Here we show that the intestines of CAPS model mice carrying an Nlrp3 R258W mutation maintain homeostasis in the gut. Additionally, such mice are strongly resistant to experimental colitis and colorectal cancer; this is mainly through a remodelled gut microbiota with enhanced anti-inflammatory capacity due to increased induction of regulatory T cells (Tregs). Mechanistically, NLRP3R258W functions exclusively in the lamina propria mononuclear phagocytes to directly enhance IL-1β but not IL-18 secretion. Increased IL-1β boosts local antimicrobial peptides to facilitate microbiota remodelling. Our data show that NLRP3R258W-induced remodelling of the gut microbiota, induces local Tregs to maintain homeostasis and compensate for otherwise-detrimental intestinal inflammation., Inflammasomes are involved in gut homeostasis and inflammatory pathologies. The authors show that a hyperactive NLRP3 inflammasome maintains gut homeostasis through remodelling of the gut microbiota and induction of regulatory T cells.

Calorie restriction has been regarded as the only experimental regimen that can effectively lengthen lifespan in various animal models, but the actual mechanism remains controversial. The gut microbiota has been shown to have a pivotal role in host health, and its structure is mostly shaped by diet. Here we show that life-long calorie restriction on both high-fat or low-fat diet, but not voluntary exercise, significantly changes the overall structure of the gut microbiota of C57BL/6 J mice. Calorie restriction enriches phylotypes positively correlated with lifespan, for example, the genus Lactobacillus on low-fat diet, and reduces phylotypes negatively correlated with lifespan. These calorie restriction-induced changes in the gut microbiota are concomitant with significantly reduced serum levels of lipopolysaccharide-binding protein, suggesting that animals under calorie restriction can establish a structurally balanced architecture of gut microbiota that may exert a health benefit to the host via reduction of antigen load from the gut., Calorie restriction has been shown to extend lifespan in diverse model systems, however, the mechanisms underlying this effect remain unclear. Zhang et al. show that calorie restriction changes the structure of the gut microbiota in mice, enriching for phylotypes positively correlated with lifespan.