Distinct gut–liver adaptations to dihydromyricetin and Silybin in middle-aged mice with alcohol-associated liver injury

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. Population-level GBD and NHANES analyses showed that alcohol-related cirrhosis burden and higher liver stiffness were concentrated in mature and older adults, particularly men, providing a translational context for the use of 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 produced partial and endpoint-dependent phenotypic effects, with Silybin showing more consistent improvements in survival and hepatic lipid accumulation. Multi-omics profiling further identified divergent intervention-associated molecular, metabolic, and ecological signatures. DHM was associated with adaptive energy metabolism, detoxification-associated remodeling, jejunal epithelial-renewal-associated transcriptional programs, and host-state-dependent microbial relative-abundance patterns, including context-dependent shifts in the relative abundance of Akkermansia . In contrast, Silybin was associated with transcriptional programs related to proteostasis and ER stress, inflammatory lipid-associated metabolic changes, and distinct immune-associated microbial patterns. These findings define distinct intervention-associated adaptive responses within a middle-aged physiological context and support further age-stratified evaluation in alcohol-associated liver injury.