Lean NAFLD: A Distinct Entity Shaped by Differential Metabolic Adaptation

Background and Aims Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the adult population. A significant subset of patients are lean, but their underlying pathophysiology is not well understood. Approach and Results We investigated the role of bile acids (BAs) and the gut microbiome in the pathogenesis of lean NAFLD. BA and fibroblast growth factor (FGF) 19 levels (a surrogate for intestinal farnesoid X receptor [FXR] activity), patatin‐like phospholipase domain containing 3 (PNPLA3), and transmembrane 6 superfamily member 2 (TM6SF2) variants, and gut microbiota profiles in lean and nonlean NAFLD were investigated in a cohort of Caucasian patients with biopsy‐proven NAFLD (n = 538), lean healthy controls (n = 30), and experimental murine models. Patients with lean NAFLD had a more favorable metabolic and histological profile compared with those with nonlean NAFLD (P