Distinct Gut–Liver Adaptations to Dihydromyricetin and Silybin in Middle-aged Mice with Alcohol-associated Liver Injury

<title>Abstract</title> <p> Alcohol-associated liver disease (ALD) is increasingly recognized as an age-related systemic disorder shaped by gut–liver axis dysfunction, yet how ageing influences disease susceptibility and intervention responses remains poorly understood. By integrating GBD and NHANES data, we identified middle age as a critical window of heightened alcohol-associated hepatic vulnerability and modeled this context in 11–12-month-old male mice. We compared Dihydromyricetin (DHM) and Silybin to determine whether these bioactive interventions elicit distinct gut–liver axis adaptations under middle-aged alcohol exposure. Both interventions partially attenuated alcohol-associated mortality and hepatic steatosis, whereas conventional serum biochemical responses were modest and endpoint-dependent. Multi-omics profiling revealed this overlapping phenotypic protection arose from divergent adaptive trajectories. DHM was associated with adaptive energy metabolism, detoxification-associated remodeling, jejunal epithelial renewal, and host-state-dependent microbial remodeling, including context-dependent regulation of <italic>Akkermansia.</italic> In contrast, Silybin aligned with proteostatic stress buffering, inflammatory lipid regulation, and immune-associated ecological rebalancing. These findings demonstrate that the host's physiological state critically shapes intervention outcomes. By defining distinct metabolic–epithelial–microbial adaptation patterns in middle-aged ALD, this study provides a rationale for age-stratified intervention strategies in aging-associated liver injury. </p>