Understanding pathophysiology of gallstone disease: a multi-omic analysis focused on women with obesity

Background Gallstone disease has a complex, multifactorial pathophysiology. Both the gut microbiome and the liver have been implicated as potential contributors. Because obesity is associated with alterations in gut microbial composition and is itself a risk factor for gallstone formation, we investigated the relative roles of the gut microbiome, the liver, and adipose tissue in gallstone disease in female patients with obesity. Methods From the BARIA cohort, 108 consecutive female patients with obesity were included, of whom at baseline 39 had ultrasound proven gallstones (cases) whereas 69 did not have gallstones (controls). Fecal shotgun metagenomics, untargeted fasting plasma metabolomic analysis and bulkRNAseq transcriptome analyses of liver, visceral (VAT) and subcutaneous (SAT) biopsies (taken during surgery) were analyzed. Results Especially VAT showed differences in expression of 57 genes, whereas liver gene expression revealed differences only after secondary analysis. In contrast to other publications, in liver “classic” ABC transporter gallstone genes were not identified in this cohort. Instead, the cholesterol transporter ABCG1 popped up, and was decreased in patients with gallstone disease. Plasma metabolome showed increase of primary and secondary bile acids in patients with gallstone disease, possibly a consequence of decreased bile acid secretion in the bile. Conclusions The results of our study suggest VAT instead of the liver as a potential driver for gallstone formation.