Gut phageome in Mexican Americans: a population at high risk for metabolic dysfunction-associated steatotic liver disease and diabetes.

Mexican Americans are disproportionally affected by metabolic dysfunction-associated steatotic liver disease (MASLD), which often co-occurs with diabetes. Despite extensive evidence on the causative role of the gut microbiome in MASLD, studies determining the involvement of the gut phageome are scarce. In this cross-sectional study, we characterized the gut phageome in Mexican Americans of South Texas by stool shotgun metagenomic sequencing of 340 subjects, concurrently screened for liver steatosis by transient elastography. Inter-individual variations in the phageome were associated with gender, country of birth, diabetes, and liver steatosis. The phage signatures for diabetes and liver steatosis were subsequently determined. Enrichment of was associated with both diabetes and liver steatosis. Diabetes was further associated with the enrichment of predominantly temperate phages, some of which possessed virulence factors. Liver steatosis was associated with the depletion of phages r1t and BK5-T, and enrichment of the globally prevalent phages, including members of genus cluster IX (, ) and VI (). The phages showed strong correlations and co-occurrence with , while the phages, , , and UAG-readthrough crAss clade correlated and co-occurred with . In conclusion, we identified the gut phageome signatures for two closely linked metabolic diseases with significant global burden. These phage signatures may have utility in risk modeling and disease prevention in this high-risk population, and identification of potential bacterial targets for phage therapy.IMPORTANCEPhages influence human health and disease by shaping the gut bacterial community. Using stool samples from a high-risk Mexican American population, we provide insights into the gut phageome changes associated with diabetes and liver steatosis, two closely linked metabolic diseases with significant global burden. Common to both diseases was an enrichment of , a group of phages that infect bacterial hosts chronically without lysis, allowing them to significantly influence bacterial growth, virulence, motility, biofilm formation, and horizontal gene transfer. Diabetes was additionally associated with the enrichment of -infecting phages, some of which contained virulence factors. Liver steatosis was additionally associated with the depletion of -infecting phages, and enrichment of phages, a group of virulent phages with high global prevalence and persistence across generations. These phageome signatures may have utility in risk modeling, as well as identify potential bacterial targets for phage therapy.