Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and the leading cause of chronic liver disease in the Western world. Twenty percent of NAFLD individuals develop chronic hepatic inflammation (non-alcoholic steatohepatitis, NASH) associated with cirrhosis, portal hypertension and hepatocellular carcinoma, yet causes of progression from NAFLD to NASH remain obscure. Here, we show that the NLRP6 and NLRP3 inflammasomes and the effector protein IL-18 negatively regulate NAFLD/NASH progression, as well as multiple aspects of metabolic syndrome via modulation of the gut microbiota. Different animal models reveal that inflammasome deficiency-associated changes in the configuration of the gut microbiota are associated with exacerbated hepatic steatosis and inflammation through influx of TLR4 and TLR9 agonists into the portal circulation, leading to enhanced hepatic TNF-α expression that drives NASH progression. Furthermore, co-housing of inflammasome-deficient animals to wild type mice results in exacerbation of hepatic steatosis, glucose intolerance, and obesity. Thus, altered interactions between the gut microbiota and the host, produced by defective NLRP3 and NLRP6 inflammasome sensing, may govern the rate of progression of multiple metabolic syndrome-associated abnormalities, highlighting the central role of the microbiota in the pathogenesis of heretofore seemingly unrelated systemic auto-inflammatory and metabolic disorders.

Significance The mammalian intestines contain an enormous number of microorganisms within the lumen. Given the constant exposure to these microbes, the intestinal immune system has the difficult task of maintaining tolerance to commensal bacteria while remaining responsive to potential pathogens. The mechanisms by which this balance is achieved are relatively unknown. Here, we identify a bacterial metabolite, n-butyrate, that exerts immunomodulatory effects on intestinal macrophages and renders them hyporesponsive to commensals that reside in the colon. Our studies elucidate a possible mechanism that contributes to immune homeostasis in the intestines.

SUMMARY Specific members of the intestinal microbiota dramatically affect inflammatory bowel disease (IBD) in mice. In humans, however, identifying bacteria that preferentially affect disease susceptibility and severity remains a major challenge. Here, we used flow cytometry-based bacterial cell sorting and 16S sequencing to characterize taxa-specific coating of the intestinal microbiota with immunoglobulin A (IgA−SEQ) and show that high IgA−coating uniquely identifies colitogenic intestinal bacteria in a mouse model of microbiota-driven colitis. We then used IgA−SEQ and extensive anaerobic culturing of fecal bacteria from IBD patients to create personalized disease-associated gut microbiota culture collections with pre-defined levels of IgA coating. Using these collections, we found that intestinal bacteria selected on the basis of high coating with IgA conferred dramatic susceptibility to colitis in germ-free mice. Thus, our studies suggest that IgA−coating identifies inflammatory commensals that preferentially drive intestinal disease. Targeted elimination of such bacteria may reduce, reverse, or even prevent disease development.

Inflammatory bowel disease (IBD) is thought to result from a dysregulated interaction between the host immune system and its commensal microflora. Heterogeneity of disease susceptibility in humans and rodents suggest that multiple mechanisms are responsible for the etiology of IBD. In particular, deficiencies in anti-inflammatory and immune-suppressive mechanisms play an important role in the development of IBD. However, it is unknown how the indigenous microflora stimulates the immune system and how this response is regulated. To address these questions, we investigated the role of Toll-like receptor (TLR) signaling in the development of spontaneous, commensal-dependent colitis in interleukin (IL)-2- and IL-10-deficient mice. We report that colitis was dependent on TLR signaling in Il10(-/-) mice. In contrast, Il2(-/-) mice developed intestinal inflammation in the absence of TLR signaling pathways. These results demonstrate a differential role of innate immune recognition by TLRs in the development of commensal-dependent colitis.

The microbiota is pivotal in the pathogenesis of inflammatory bowel disease (IBD)-associated inflammation-induced colorectal cancer (CRC), yet mechanisms for these effects remain poorly characterized. Here, we demonstrate that aberrant inflammasome-induced microbiota plays a critical role in CRC development, where mice deficient in the NOD-like receptor family pyrin domain containing 6 (NLRP6) inflammasome feature enhanced inflammation-induced CRC formation. Intriguingly, WT mice cohoused either with inflammasome-deficient mice or with mice lacking IL-18 feature exacerbated inflammation-induced CRC compared with singly housed WT mice. Enhanced tumorigenesis is dependent on microbiota-induced chemokine (C-C motif) ligand 5 (CCL5)-driven inflammation, which in turn promotes epithelial cell proliferation through local activation of the IL-6 pathway, leading to cancer formation. Altogether, our results mechanistically link the altered microbiota with the pathogenesis of inflammation-induced CRC and suggest that in some conditions, microbiota components may transfer CRC susceptibility between individuals.