Gut microbiota modulates nonalcoholic fatty liver disease (NAFLD) progression via regulation of gluconeogenesis: mechanisms and translational research

Pharmacol Res. 2026 Sep 16:108444. doi: 10.1016/j.phrs.2026.108444. Online ahead of print.

ABSTRACT

The terminology of fatty liver disease has evolved from non-alcoholic fatty liver disease (NAFLD) to alternative metabolically oriented frameworks, including metabolic dysfunction-associated fatty liver disease (MAFLD) and, more recently, metabolic dysfunction-associated steatotic liver disease (MASLD). Its complex pathogenesis and the lack of targeted therapeutic agents highlight the urgent need for new research perspectives. This review first systematically proposes a novel model: the “gut microbiota-gluconeogenesis-NAFLD axis”. Under insulin-resistant conditions, impaired suppression of hepatic gluconeogenesis may coexist with increased de novo lipogenesis, thereby contributing to hyperglycemia and hepatic lipid accumulation. In contrast, intestinal gluconeogenesis (IGN) acts as a key “anticipatory signal” that actively inhibits hepatic glucose output and improves systemic insulin sensitivity via the gut-brain-liver neural circuit. More importantly, gut microbiota and its metabolites (e.g., short-chain fatty acids, bile acids) bidirectionally regulate IGN activation and GNG remodeling through pathways such as cAMP, FFAR3, and FXR/TGR5, suggesting a potential new mechanism of microbiota-host metabolic interaction. This model expands the traditional “liver-centered” perspective to “gut-liver crosstalk” and provides an integrated framework for understanding the metabolic imbalance in NAFLD. It also points towards precision intervention strategies aimed at enhancing IGN and restoring glucose homeostasis (e.g., prebiotics, traditional Chinese medicine polysaccharides, FMT), which are of considerable translational and scientific importance.

PMID:42749095 | DOI:10.1016/j.phrs.2026.108444