Harnessing Gut Microbiome–Brain–Liver Crosstalk: Novel Therapeutic Strategies for Metabolic Dysfunction‐Associated Steatotic Liver Disease

ABSTRACT Metabolic dysfunction‐associated steatosis liver disease (MASLD) is the most common chronic liver disease, having a profound impact on the stability, functionality, and diversity of the microbial community. Our review systematically elucidates the core pathogenic mechanisms by which gut bacteria, and their metabolites regulate liver metabolic disorders and immune‐inflammatory imbalances through the “brain‐gut‐liver” axis. Unlike conventional antibiotics that disrupt the entire gut microbiota, phages offer a “microbiome‐editing” tool to specifically neutralize pathogenic strains. Subsequently, this review emphasizes how phages modulate bacterial communities and metabolic functions to impact brain energy perception (e.g., psychological stress), intestinal microenvironment (e.g., intestinal barrier permeability), and liver metabolism (e.g., glucose, lipid, and BAs metabolism) in MASLD and its related adverse outcomes. Ultimately, by bridging precision microbiome editing with systemic metabolic regulation, this review summarizes four pertinent phage‐related strategies for MASLD and related metabolic disorders, including (1) the integration phage with probiotics, (2) the application of the CRISPR‐Cas system to phage display technique (PDT), (3) the utilization of phage derivatives, and (4) engineered phage strategies. These strategies provide a novel framework for comprehending the role of host‐microbial interactions in MASLD, warranting further investigation for clinical application.