Summary Dysfunction in host immune responses and pathologic alterations in the gut microbiota, referred to as dysbiosis, can both contribute to the development of inflammatory bowel disease (IBD). However, it remains unclear how specific changes in host immunity or the microbiota cause disease. We previously demonstrated that the loss of the innate immune receptor NLRP6 in mice resulted in impaired production of IL18 and increased susceptibility to epithelial-induced injury. Here, we show that NLRP6 is important for suppressing the development of spontaneous colitis in the IL10−/− mice model of IBD and that NLRP6-deficiency results in the enrichment of Akkermansia muciniphila. A. muciniphila was sufficient for promoting intestinal inflammation in both specific-pathogen free and germfree IL10−/− mice. Our results demonstrate that A. muciniphila can act as a pathobiont to promote colitis in a genetically-susceptible host and that NLRP6 is a key regulator of its abundance.

NLRP6 is a member of the Nod like receptor family, whose members are involved in the recognition of microbes and/or tissue injury. NLRP6 was previously demonstrated to regulate the production of IL-18 and is important for protecting mice against chemically-induced intestinal injury and colitis-associated colon cancer. However, the cellular mechanisms by which NLRP6 reduces susceptibility to colonic inflammation remain unclear. Here, we determined that NLRP6 expression is specifically upregulated in Ly6Chi inflammatory monocytes that infiltrate into the colon during dextran sulfate sodium (DSS)-induced inflammation. Adoptive transfer of WT Ly6Chi inflammatory monocytes into Nlrp6−/− mice was sufficient to protect them from mortality, significantly reducing intestinal permeability and damage. NLRP6-deficient inflammatory monocytes were defective in TNFα production, which was important for reducing DSS-induced mortality and was dependent on autocrine IL-18 signaling by inflammatory monocytes. Our data reveal a previously unappreciated role for NLRP6 in inflammatory monocytes, which are recruited after DSS-induced intestinal injury to promote barrier function and limit bacteria-driven inflammation. This study highlights the importance of early cytokine responses, particularly NLRP6-dependent and IL-18-dependent TNFα production, in preventing chronic dysregulated inflammation.

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Non-alcoholic steatohepatitis (NASH) is a chronic and progressive form of non-alcoholic fatty liver disease. Its global incidence is increasing and makes NASH an epidemic and a public health threat. Non-alcoholic fatty liver disease is associated with major morbidity and mortality, with a heavy burden on quality of life and liver transplant requirements. Due to repeated insults to the liver, patients are at risk for developing hepatocellular carcinoma. The progression of NASH was initially defined according to a two-hit model involving an initial development of steatosis, followed by a process of lipid peroxidation and inflammation. In contrast, current evidence proposes a “multi-hit” or “multi-parallel hit” model that includes multiple pathways promoting progressive fibrosis and oncogenesis. This model includes multiple cellular, genetic, immunological, metabolic, and endocrine pathways leading to hepatocellular carcinoma development, underscoring the complexity of this disease.

NLRP6 is a member of the Nod-like receptor (NLR) family, whose members are involved in the recognition of microbes and/or tissue injury. NLRP6 was previously shown to regulate IL-18 secretion and is important for protecting mice against chemically-induced colitis and colitis-associated colon cancer. However, the cellular mechanisms by which NLRP6 reduces susceptibility to colonic inflammation remain unclear. Here, we determined that NLRP6 expression is specifically upregulated in Ly6Chi inflammatory monocytes that infiltrate into the colon during dextran sulfate sodium (DSS)-induced inflammation. Adoptive transfer of WT Ly6Chi inflammatory monocytes into Nlrp6−/− mice was sufficient to protect them from mortality, significantly reducing intestinal permeability and damage. NLRP6-deficient inflammatory monocytes were specifically defective in TNFα production, which was important for reducing DSS-induced mortality and dependent on autocrine IL-18 signaling by inflammatory monocytes. Our data reveal a previously unappreciated role for NLRP6 in inflammatory monocytes, which are recruited during colitis to promote barrier function and limit bacteria-driven inflammation. This study also highlights the importance of early cytokine responses, particularly NLRP6-dependent and IL-18-dependent TNFα production, in preventing chronic dysregulated inflammation that occurs in patients with inflammatory bowel disease.