Gut Microbial Metabolites Mediated Immune Reprogramming in MASLD Spectrum: Mechanisms and Therapeutic Interventions

ABSTRACT Metabolic dysfunction‐associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease driven by a complex interplay among microbes, metabolism, and inflammation. Emerging evidence positions the gut‐immune axis as a critical upstream driver of disease progression. Dysbiosis releases a mixture of injurious and protective metabolites, and the balance struck between them appears to determine whether immunity drives disease or restrains it. Acting on this balance, gut‐derived signals activate circulating and tissue‐resident immune cells, may impose trained immunity‐like states on myeloid progenitors, and can bias T and B cell differentiation toward pro‐inflammatory phenotypes. Chemokine‐driven recruitment then delivers these primed leukocytes to the steatotic liver, where we propose, as a hypothesis, that they act upon and amplify the responses of liver‐resident immune cells. Recent single‐cell, cohort, and genetic studies in patients are consistent with such an outside‐in sequence, although the number of studies is limited and they do not yet establish its direction. Therapeutically, microbiome‐based strategies aim to restore immune tolerance rather than suppress inflammation broadly. Targeting commensal‐derived short‐chain fatty acids, bile acid derivatives, tryptophan metabolites, and aryl hydrocarbon receptor ligands can reinforce regulatory networks by promoting regulatory T cells, IL‐10‐producing B cells, and tolerogenic myeloid states. We also outline emerging tools, including engineered microbes, targeted postbiotics, and microbial immune checkpoint modulation, which may offer opportunities to intercept MASLD at early and potentially reversible stages.