Gut Microbiota and Genetic Polymorphisms Appear to Drive Disease Expression of Nonalcoholic Fatty Liver Disease in Lean Individuals

Abstract

Background/Objectives: There are very few comparative studies worldwide between ‘lean’ and ‘nonlean/obese nonalcoholic fatty liver disease (NAFLD)’ patients analyzing the differences in gut microbiome, genotype, and serum bile acids. Our aim was to compare the genotype, gut microbiome, bile acid profile, and metabolic patterns of lean NAFLD and obese NAFLD patients with special reference to hepatic fibrosis. Methods: Both lean and obese NAFLD patients diagnosed by ultrasonography along with matched controls were included. Genotyping, fecal microbiome analysis and estimation of serum total bile acid levels were done for patients as well as controls. Results: Biochemical and metabolic patterns of lean and obese NAFLD patients were comparable. Lean NAFLD patients had lower fasting plasma glucose (FPG) and homoeostasis model assessment-insulin resistance (HOMA-IR), although the proportions of patients having elevated HOMA-IR and metabolic syndrome (MS) were comparable. Noninvasive scores of liver fibrosis were also comparable. A greater proportion of lean NAFLD patients had the PNPLA3 rs738409 (G/G) genotype. However, there was no association of genetic polymorphisms with steatosis or fibrosis. Nonlean and lean NAFLD patients had comparable serum total bile acid levels. On microbiome analysis, lean NAFLD patients were found to have distinct expression of bacterial species while beta diversity was found to be significantly different across all groups. Conclusion: Lean NAFLD patients were found to have the PNPLA3 rs738409 (G/G) genotype. Lean NAFLD patients were also found to have unique gut microbial signatures, while beta diversity significantly differed across all groups. Differential expression of gut microbiota and genetic polymorphisms could underlie the pathogenesis of lean NAFLD. © 2025 Indian National Association for Study of the Liver