Background/Objectives: Bariatric-metabolic surgery (BMS) improves obesity through neuroendocrine mechanisms involving bile acids (BAs) and nutrient-stimulated gastrointestinal hormones. However, the underlying pathophysiology involved remains poorly understood. BAs are essential for the digestion and absorption of dietary fat and fat-soluble vitamins and act as nutrient-responsive signaling molecules, so their handling after malabsorptive procedures is relevant both to metabolic outcomes and to nutritional status. Methods: We prospectively compared Roux-en-Y gastric bypass (RYGB) and single-anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) in a single-center case-control study including 37 RYGB and 31 SADI-S patients with severe obesity and 19 non-obese controls. Before and one year after surgery, participants underwent a standardized mixed-meal test (nutrient challenge) with measurement of 14 individual BA fractions, insulin, GLP-1, ghrelin, FGF19, leptin, and adiponectin; bile acid malabsorption was assessed one year after surgery with the 75Se-SeHCAT test, and weight was followed for up to 5 years. Results: Fasting total BAs increased after both techniques, with no significant between-technique difference in total BA exposure (primary outcome). The techniques were associated with distinct BA profiles: fasting concentrations of conjugated BAs (GCA, GCDCA, and TDCA) were higher after SADI-S than after RYGB (FDR-adjusted q < 0.05), with a similar but more variable pattern in postprandial AUCs, whereas RYGB was characterized by a greater postprandial rise in the unconjugated secondary BA DCA. After surgery, FGF19 increased progressively during the mixed-meal test, peaking at 90 min, and its increase correlated with the rise in conjugated BAs, particularly in SADI-S. The postprandial insulin peak shifted earlier in both techniques, with a lower insulin AUC in SADI-S; GLP-1 responses were supraphysiological, and ghrelin increased post RYGB but was suppressed after SADI-S. Leptin decreased markedly, and in an exploratory analysis, its decrease was associated with weight-loss success at 3 years. Weight loss was greater with SADI-S at 1 year, but not significantly different at 3 and 5 years; in an exploratory analysis, the increase in conjugated BAs correlated negatively with recurrence weight gain from nadir at 5 years. The SeHCAT test showed no bile acid malabsorption in SADI-S and normal retention in 90.6% of RYGB patients. Despite routine supplementation, total protein, zinc, copper, and the vitamin A/RBP and vitamin E/cholesterol ratios decreased after both techniques. Conclusions: In conclusion, RYGB and SADI-S are associated with differentiated BA and hormonal profiles. The predominance of conjugated BAs after SADI-S, which we hypothesize may be related to its longer biliopancreatic limb, emerges as a potential candidate mechanism for weight maintenance that requires confirmation and was not accompanied by clinically relevant bile acid malabsorption; however, the decreases observed in several micronutrients support careful nutritional follow-up after both techniques. Clinical trial registration: ISRCTN81954082.
