Multi-omic analysis reveals transkingdom gut dysbiosis in metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common condition linked to obesity and the metabolic syndrome, yet its transkingdom connections have been under-investigated. We performed high-resolution multi-omic profiling-including stool metagenomes, metatranscriptomes and metabolomes-in 211 MASLD cases and 502 controls from a cohort of female nurses. Here we show that MASLD is associated with shifts in 66 gut bacterial species, including widespread enrichment of oral-typical microbes, and transkingdom dysbiosis involving not only bacterial but also viral taxa. Streptococcus spp. are more abundant in non-lean versus lean MASLD, the latter being a paradoxical subtype of a disease typically associated with increased adiposity. These microbial changes correspond with shifts in transcripts and metabolites, including increases in polyamines and acylcarnitines and reductions in secondary bile acids. We highlight gut viral perturbations in MASLD, showing that expansions of bacteriophage targeting oral-typical bacteria correspond to expansions of their bacterial hosts in the gut. We provide a comprehensive resource for understanding MASLD and highlight transkingdom multi-omic microbial shifts as potential contributors to its aetiopathogenesis.