Distinct signatures of gut microbiome and metabolites associated with significant fibrosis in non-obese NAFLD

TLDR

Non‑obese individuals can develop NAFLD, challenging the view that the disease is solely linked to obesity. The study profiled gut microbiomes of 171 Asian NAFLD patients and 31 controls using 16S rRNA sequencing, stratified subjects by fibrosis stage, and tested four fibrosis‑associated species in mouse models to assess their impact on liver injury. In non‑obese NAFLD patients, fibrosis severity correlates with reduced microbiome diversity, enrichment of Ruminococcaceae and Veillonellaceae, and higher stool bile acids and propionate, supporting a causal role of the microbiome in liver fibrosis.

Abstract

Abstract Nonalcoholic fatty liver disease (NAFLD) is associated with obesity but also found in non-obese individuals. Gut microbiome profiles of 171 Asians with biopsy-proven NAFLD and 31 non-NAFLD controls are analyzed using 16S rRNA sequencing; an independent Western cohort is used for external validation. Subjects are classified into three subgroups according to histological spectra of NAFLD or fibrosis severity. Significant alterations in microbiome diversity are observed according to fibrosis severity in non-obese, but not obese, subjects. Ruminococcaceae and Veillonellaceae are the main microbiota associated with fibrosis severity in non-obese subjects. Furthermore, stool bile acids and propionate are elevated, especially in non-obese subjects with significant fibrosis. Fibrosis-related Ruminococcaceae and Veillonellaceae species undergo metagenome sequencing, and four representative species are administered in three mouse NAFLD models to evaluate their effects on liver damage. This study provides the evidence for the role of the microbiome in the liver fibrosis pathogenesis, especially in non-obese subjects.