An age-independent MASLD-related liver fibrosis index reflecting gut dysbiosis and hepatic stellate cells reprogramming

Background The burden of metabolic dysfunction-associated steatotic liver disease (MASLD) is of immediate concern, as its prevalence is increasing worldwide. MASLD often progresses to liver fibrosis, posing significant health risks. Age-independent non-invasive tools to evaluate fibrosis are needed to improve diagnostic accuracy across all age groups. Methods. 84 inflammatory, hematological, and metabolic variables were quantified in the blood of n = 63 individuals with MASLD with different degrees of fibrosis and n = 22 age-matched controls. Linear regression models were employed to identify markers strongly correlated with liver fibrosis but not influenced by age. Logistic regression models were used to evaluate the ability of various indexes to discriminate between no/mild and severe liver fibrosis. Results. Levels of glutamine and propionate were identified as strongly correlated to fibrosis but not age and combined to form the GP index. The GP index demonstrated superior predictive power for liver fibrosis compared to existing scores, like circulating creatinine. It showed higher discriminatory ability (AUC = 0.872) and better model fit, indicating its robustness and reliability across all age groups. Conclusions. The study introduces the GP index, an age-independent tool for diagnosing and monitoring liver fibrosis in MASLD patients. By excluding age-dependent markers, the GP index can potentially reduce false positives and improve diagnostic accuracy, particularly in older populations. The combination of glutamine and propionate in this index reflects a novel approach, capturing both intrinsic hepatic metabolic changes and extrinsic influences from gut microbiota, offering a simple yet effective solution for liver fibrosis staging.