Targeting gut dysbiosis: a new frontier in MASLD management

Abstract

Globally, Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prominent leading cause of CLD, which is intricately linked with obesity, T2D, and metabolic syndrome. Recent insights in pathophysiologically of MASLD have shifted from the traditional “two-hit” model to a “multiple-hit” paradigm, demonstrating the importance of understanding the gut-liver axis and gut dysbiosis as central drivers of disease progression. Hence, this narrative review explores the mechanistic pathways through which an altered gut microbiome contributes to MASLD, by specifically emphasizing intestinal barrier disruption, endotoxemia, altered bile acid metabolism, and SCFA imbalance. These dysregulations trigger oxidative stress, leading to systemic inflammation and insulin resistance, propelling simple steatosis toward steatohepatitis and fibrosis at last. Furthermore, we also highlighted the diagnostic utility of microbial signatures and multi-omics approaches in identifying disease-specific microbial shifts, such as the depletion of beneficial SCFA-producing bacteria like Faecalibacterium and Akkermansia. Eventually, to address the growing hepatic-associated health burden, microbiome-targeted therapeutics can emerge as one of the promising contributors. In this review, we synthesise and demonstrate the current and prospective interventions, including dietary modifications, biotics (probiotics, prebiotics, synbiotics), and FMT. Additionally, we also show the transition of care toward precision microbiome therapies utilizing engineered bacteria, bacteriophages, and AI-guided patient stratification. While current microbiome-centric treatments demonstrate promise in modulating hepatic inflammation and restoring mucosal integrity, their clinical translation remains hindered by patient heterogeneity and a lack of standardized protocols. Ultimately, managing MASLD effectively will require moving beyond broad ecosystem resets toward highly tailored, multi-omics-driven precision medicine to accurately target individualized microbial deficits.