Intestinal NLRP3 Deficiency Exacerbates MASLD in Male Mice via Reduced Butyrate Production

Area of Science:

• Gastroenterology and Hepatology
• Immunology
• Microbiology

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health concern with complex underlying mechanisms.
• The gut-liver axis, particularly the role of intestinal inflammation, is increasingly recognized as crucial in MASLD pathogenesis.

Purpose of the Study:

• To investigate the role of the intestinal NOD-, LRR-, and pyrin-domain-containing protein 3 (NLRP3) inflammasome in MASLD.
• To identify potential therapeutic targets within the gut-liver axis for MASLD treatment.

Main Methods:

• Utilized a methionine-choline-deficient (MCD) diet model in mice to induce MASLD and fibrosis.
• Employed Villin-Cre;Nlrp3-floxed mice (Vil1^creNlrp3^f/f) to assess intestinal epithelial cell-specific NLRP3 deletion.
• Evaluated the impact of gut microbiota via co-housing and the therapeutic potential of butyrate administration.

Main Results:

• Intestinal NLRP3 deletion worsened MASLD and impaired gut barrier integrity.
• Co-housing with wild-type mice or butyrate treatment ameliorated hepatic steatosis and fibrosis.
• Mechanistically, intestinal NLRP3 loss reduced PPARα activation and increased AP-1 signaling, which were reversed by butyrate or co-housing.

Conclusions:

• Intestinal NLRP3 plays a protective role in MASLD by influencing butyrate production and gut barrier function.
• Dysregulation of PPARα and AP-1 signaling pathways is linked to intestinal NLRP3 deficiency in MASLD.
• Targeting intestinal NLRP3 or enhancing butyrate levels may offer therapeutic strategies for MASLD.