Metabolic switching in MASLD: therapeutic roles of ketogenic diet, intermittent fasting, and the gut-liver axis

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is common and clinically heterogeneous, with fibrosis stage serving as a major determinant of long-term liver-related risk. This focused narrative review evaluates ketogenic dietary interventions and intermittent fasting as metabolic-switching strategies while explicitly distinguishing conventional or eucaloric ketogenic diets, very-low-energy ketogenic therapy, non-ketogenic low-carbohydrate diets, and distinct fasting protocols. Both approaches can reduce body weight, improve insulin sensitivity, and decrease hepatic steatosis in selected patients, but much of the human evidence is short-term and protocol-dependent. Mechanistic effects attributed to beta-hydroxybutyrate, including inflammasome inhibition, histone modification, and mitochondrial signaling, are supported predominantly by cell and animal studies and have not been directly confirmed in patients with MASLD. The gut-liver axis provides a biologically plausible link through intestinal permeability, microbial metabolites, bile acid signaling, and hepatic innate immunity; however, direct human evidence that ketogenic diets or intermittent fasting restore gut-barrier function remains limited. No trial has directly compared a well-defined ketogenic intervention with documented nutritional ketosis against intermittent fasting. Therefore, relative efficacy, durability, adherence, and weight-loss-independent effects remain uncertain. Clinical use should prioritize fibrosis risk stratification, nutritional adequacy, comorbidity-specific safety, and integration with evidence-based lifestyle and pharmacologic care.