Gut microbiota–NLRP3 inflammasome crosstalk in metabolic dysfunction-associated steatotic liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease associated with metabolic dysfunction, ranging from hepatic steatosis with or without mild inflammation to nonalcoholic steatohepatitis, which can rapidly progress to liver fibrosis and even liver cancer. In 2023, after several rounds of Delphi surveys, a new consensus recommended renaming NAFLD as metabolic dysfunction-associated steatotic liver disease (MASLD). Ninety-nine percent of NAFLD patients meet the new MASLD criteria related to metabolic cardiovascular risk factors under the "multiple parallel hits" of lipotoxicity, insulin resistance (IR), a proinflammatory diet, and an intestinal microbiota disorder, and previous research on NAFLD remains valid. The NLRP3 inflammasome, a well-known member of the pattern recognition receptor (PRR) family, can be activated by danger signals transmitted by pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), as well as cytokines involved in immune and inflammatory responses. The activation of the NLRP3 inflammasome pathway by MASLD triggers the production of the inflammatory cytokines IL-1β and IL-18. In MASLD, while changes in the composition and metabolites of the intestinal microbiota occur, the disrupted intestinal microbiota can also generate the inflammatory cytokines IL-1β and IL-18 by damaging the intestinal barrier, negatively regulating the liver on the gut–liver axis, and further aggravating MASLD. Therefore, modulating the gut–microbiota–liver axis through the NLRP3 inflammasome may emerge as a novel therapeutic approach for MASLD patients. In this article, we review the evidence regarding the functions of the NLRP3 inflammasome and the intestinal microbiota in MASLD, as well as their interactions in this disease.