Journal Pre-proof and associated with after

Several risk factors are associated with gallstone disease after bariatric surgery, but the underlying pathophysiological mechanisms of gallstone formation are unclear. We hypothesize that gallstone formation after bariatric surgery is induced by different pathways compared to gallstone formation in the general population, since postoperative formation occurs rapidly in patients who did not develop gallstones in preceding years. To identify both pathophysiological and potentially protective mechanisms against postoperative gallstone formation, we compared the preoperative fasting metabolome, fecal microbiome, and liver and adipose tissue transcriptome obtained before or during bariatric surgery of obese patients with and without postoperative gallstones. In total, 88 patients were selected from the BARIA longitudinal cohort study. Within this group, 32 patients had postoperative gallstones within two years. Gut microbiota metagenomic analyses showed group differences in abundance of 41 bacterial species, particularly abundance of Lactobacillaceae and Enterobacteriaceae in patients without gallstones. Subcutaneous adipose tissue transcriptomic analyses revealed four genes that were suppressed in gallstone patients compared to patients without gallstones. These baseline gene expression and gut microbiota composition differences might relate to protective mechanisms against gallstone formation after bariatric surgery. Moreover, baseline fasting blood samples of patients with postoperative gallstones showed increased levels of several bile acids. Overall, we revealed different genes and bacteria associated with gallstones than those previously reported in the general population, supporting the hypothesis that gallstone formation after bariatric surgery follows a different trajectory. Further research is necessary to confirm the involvement of the bile acids, adipose tissue activity, and microbial species observed here. significantly lower in bariatric gallstone patients (16). It seems that the formation of gallstones in bariatric patients follows a different trajectory than in patients without previous bariatric surgery. This is likely based on the changed gastrointestinal anatomy after bariatric surgery and the following rapid weight loss that is accompanied by a decrease of adipose tissue mass and pronounced alterations of glucose, lipid, and bile acid metabolism. Bariatric surgery also leads to changes in composition of gut microbiota and derived metabolites. Nevertheless, most obese patients undergoing bariatric surgery do not develop gallstones despite having several risk factors. We hypothesized that apart from risk factors, other mechanisms might exist that protect against gallstone formation after bariatric surgery. Investigating patients just before and after bariatric surgery might reveal new and possibly protecting pathways or metabolic processes against gallstone disease in this patient population. The aim of the present study was to compare preoperative plasma metabolites, gut microbiome composition, and genetic expression in liver and adipose tissue of patients without gallstones after bariatric surgery to patients with gallstones after bariatric surgery. The findings can potentially increase the predictability of gallstone formation in bariatric patients and can be used in future studies to further unravel the pathological mechanisms involved in gallstone formation and/or prevention after bariatric surgery.