Decoding the Gut-Liver Crosstalk: Microbial Metabolite- Driven AhR Signalling Networks in MASLD Pathogenesis

Metabolic-dysfunction-associated steatotic liver disease (MASLD), one of the most common liver diseases worldwide, has become an important public health issue, particularly with the increasing prevalence of obesity and diabetes. The gut microbiota is critical to the overall health of the human body, and accumulating evidence indicates that gut microbial alterations and their derived metabolites not only contribute to the development of MASLD but also represent potentially modifiable therapeutic targets. This review proposes that microbiota-derived metabolic signals regulate the aryl hydrocarbon receptor (AhR) to form a "gut microbiota-metabolite-AhR-MASLD" axis, which serves as a central hub linking intestinal microbial dysbiosis to hepatic metabolic reprogramming. Microbial tryptophan metabolites and short-chain fatty acids act as endogenous AhR ligands and exert hepatoprotective effects by modulating lipid metabolism, inflammatory responses, and immune homeostasis, including suppression of lipogenic signalling pathways, induction of anti-inflammatory regulators, and activation of Interleukin-22 (IL-22)-related hepatoprotective pathways. In addition, AhR exerts regulatory functions in non-parenchymal liver cells, including hepatic stellate cells, Kupffer cells, and liver sinusoidal endothelial cells, contributing to anti-inflammatory responses, barrier protection, and anti-fibrotic effects. From a translational perspective, targeting this regulatory axis-such as modulating AhR ligand-producing microbiota or employing natural products to restore AhR signaling homeostasis-may provide a multi-target therapeutic strategy for MASLD. Overall, this review systematically integrates gut microbial metabolic signaling with host AhR pathways, highlighting AhR as a key mediator of gut-liver metabolic communication and underscoring its therapeutic potential for precision intervention in MASLD.