Beyond the Gut: Tracing the Microbiome–Liver–Brain Axis in Non-Alcoholic Fatty Liver Disease (NAFLD)

Azlan Seruji¹ , Nurul Izzati² , Faizal Prasetiyawan³ ,Shahrin Jamil⁴ , Mei Ling Tan⁵

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) is now the most prevalent liver condition globally, yet its systemic implications are underrecognised. Emerging evidence suggests that gut microbiota may influence liver inflammation and cognitive dysfunction through the gut–liver–brain axis. This study aimed to investigate the roles of microbial and neurological biomarkers in non-alcoholic fatty liver disease (NAFLD) patients in determining their impact on hepatic and cognitive outcomes.
Methods: A total of 324 biopsy-confirmed NAFLD patients from three academic hospitals in Malaysia were enrolled between 2021 and 2024. Faecal microbiota analysis (16S rRNA sequencing), serum inflammatory markers (IL-1β, TNF-α), liver elastography, and Montreal Cognitive Assessment (MoCA) tests were performed. A healthy control group (n = 120) was matched by age, sex, and BMI. Microbial diversity indices and pathway analysis were compared between groups. Multivariate linear regression was used to assess the associations between microbial patterns, cognitive scores, and liver stiffness.
Results: NAFLD patients had significantly reduced microbial diversity (Shannon index: 2.64 vs. 3.52; p < 0.001). Bacteroides and Ruminococcus gnavus abundance were linked with higher liver stiffness (β = 0.29, p = 0.004) and lower MoCA scores (β = –0.31, p = 0.002). Elevated IL-1β levels mediated the relationship between dysbiosis and cognitive impairment (p for mediation = 0.01). Patients in the lowest quartile of microbial diversity had a 2.7-fold increased risk of mild cognitive impairment (OR = 2.72; 95% CI: 1.58–4.69).
Conclusion: NAFLD is associated not only with hepatic dysfunction but also with microbial dysbiosis and cognitive impairment via systemic inflammation. The gut–liver–brain axis represents a promising target for early detection and integrative treatment strategies in NAFLD.