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

backgroundGallstone 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.

methodsFrom 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.

resultsEspecially 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 emerged, and expression was decreased in patients with gallstone disease. Plasma metabolomic profiling demonstrated increased levels of primary and secondary bile acids in the gallstone group. In contrast, gut microbiome differences between groups were limited.

conclusionsThis integrated multi-omics analysis suggests that visceral adipose tissue may play a more prominent role in gallstone disease pathophysiology in women with obesity than previously appreciated. The observed selective molecular alterations and persistent bile acid differences highlight the complex metabolic interplay underlying gallstone formation and provide insight into tissue-specific mechanisms associated with obesity-related gallstone disease.