Interplay between circadian rhythms, gut microbiota, and MASLD: from mechanistic foundations to therapeutic opportunities

Metabolic dysfunction-associated fatty liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), has become the most common chronic liver disease worldwide. Although excessive lipid accumulation, insulin resistance, and chronic low-grade inflammation are recognized as the main pathophysiological drivers, an increasing body of research indicates that the relationship between circadian rhythms, gut microbiota, and liver metabolism is far more complex than previously imagined, forming a systemic regulatory network. Disruption of circadian rhythms can affect the temporal coordination of metabolic pathways in the liver and other surrounding tissues. At the same time, the gut microbiota itself also exhibits circadian rhythm variations. The dysregulation of these rhythms, leading to microbial imbalance, intestinal permeability defects, and imbalances in microbial metabolites, can exacerbate lipid deposition and inflammatory responses in the liver. Research shows that important microorganisms can produce short-chain fatty acids, regulate bile acid balance, and enhance intestinal barrier function, creating a synergistic effect with the host's circadian rhythms. Conversely, during circadian disruption, the proliferation of harmful symbionts can exacerbate the entry of lipopolysaccharides into the bloodstream, oxidative stress, and the development of steatohepatitis. This relationship among the three establishes the ' circadian rhythm-gut microbiota-liver axis' as a new model for understanding the mechanisms underlying MASLD and for developing temporal therapies and microbiome interventions. This review systematically explores how circadian rhythms regulate the relationship between the gut microbial ecology and liver metabolism, focusing on the microbial species closely related to the interaction between circadian rhythms and MASLD. It also introduces emerging therapeutic strategies, including time-restricted feeding, circadian probiotics, postbiotics supplementation, and circadian rhythm drugs. These findings collectively suggest that targeting the temporal dimension of the interactions between the host and microbiota holds clinical potential for the prevention and treatment of MASLD.