Abstract
Metabolic dysfunction Associated Steatotic Liver Disease (MASLD), formerly known as NAFLD, is a major health concern and is the most common liver disease worldwide. The link between gut microbiota and liver is bidirectional, however, it is not yet fully understood, particularly in relation to the development of liver disease. Existing studies have reported the association between members of the human gut microbiome and MASLD development, however these studies did not dissect the effect of Type-2 diabetes (T2D), which is a major MASLD comorbidity, from the MASLD effect on the microbiome. Therefore, we conducted an observational case-control study on a sub-cohort from the Cooperative Health Research in South Tyrol (CHRIS) cohort, aiming to disentangle the microbiota association with MASLD from T2D. In total, 111 participants of T2D- and MASLD-, 56 participants of T2D+ and MASLD-, 68 participants of T2D- and MASLD+; and 115 participants of T2D+ and MASLD+ were surveyed via shotgun metagenomic sequencing, plasma metabolomics, complete blood counts, and dietary questionnaires. As results, we identified 17 and 10 species-level, and 155 and 240 metabolic pathways-level associations with MASLD and T2D, respectively (FDR 0.2). A machine learning classifier trained on joint taxonomic, functional, and plasma metabolomics profiles was able to stratify the participants according to the disease status at AUC ~ 0.8. The results presented here open a door on the microbiome potential for Type-2 diabetes independent MASLD screening technologies.