NLRP6 inflammasome modulates disease progression in a chronic-plus-binge mouse model of alcoholic liver disease.

Alcoholic liver disease (ALD) develops in individuals with excessive alcohol intake and affects a significant percentage of the population. It is characterized by inflammatory signals from within the liver and from other organs such as intestine. One of the central inflammatory mediators is the NLR family pyrin domain containing 6 (NLRP6) inflammasome complex. The aim of this study was to evaluate a novel mouse model for ALD characterized by 8-week chronic-plus-binge ethanol administration and to investigate the role of NLRP6 inflammasome for intestinal homeostasis and ALD progression using Nlrp6-/- mice. We show that chronic-plus-binge ethanol administration triggers hepatic steatosis, injury, and neutrophil infiltration. Furthermore, we observed marked disturbances of intestinal microbial communities, included increased relative abundances of bacteria within the phyla Bacteroidota and Campilobacterota, and reduced occurrence of Firmicutes phylum. Abrogation of NLRP6 signaling in this ALD model did not impact liver steatosis or injury, and mildly affected intestinal homeostasis by altering intestinal epithelium function and gut microbiota. Intriguingly, Nlrp6 deficiency led to substantial reduction of hepatic immune cell infiltration. Thus, our novel mouse model encompasses many characteristics of human ALD including intestinal dysbiosis. Interference with NLRP6 inflammasome function alleviated hepatic immune cell recruitment indicating a disease-aggravating role of NLRP6 during ALD.