Inulin-Bentonite Hybrid Microparticles Enhance Orlistat Efficacy While Mitigating Gut Microbiota Disruption in a High-Fat Diet Rat Model

Abstract Orlistat is an established pharmacotherapy for metabolic syndrome (MetS); however, its clinical utility is constrained by gastrointestinal adverse effects and gut microbiota disruption. This study evaluates hybrid inulin (INU)-bentonite (BEN) microparticles (InuClay) as a microbiota-protective adjunct to orlistat therapy. In vitro lipolysis under biorelevant fasted-state conditions demonstrated that InuClay significantly reduced free fatty acid liberation relative to untreated controls and INU alone (p < 0.01). In a 21-day high-fat diet rat model of MetS, InuClay and orlistat monotherapies reduced cumulative weight gain by 4.5% and 5.7%, respectively. Co-administration achieved a 7.7% reduction that was significantly greater than either monotherapy alone. Combination therapy also produced the greatest reduction in fasting blood glucose (27%) exceeding both InuClay monotherapy (12%) and orlistat monotherapy (16%). At the microbiota level InuClay co-administration prevented orlistat-induced Proteobacteria expansion (2.5-fold reduction versus orlistat alone) while selectively enriching butyrate-producing taxa including Lachnospiraceae (1.42-fold) and Blautia (11.8-fold) without significantly altering alpha diversity. Circulating markers of cellular injury were substantially lower with combination therapy, with lactate dehydrogenase decreased by 63% and aspartate aminotransferase by 23% versus controls. These reductions were absent with orlistat monotherapy. Collectively these findings establish InuClay as a dual-action adjunct that enhances orlistat efficacy while attenuating dysbiotic shifts and systemic markers of tissue stress. This approach represents a promising strategy for improving translational outcomes in lipase inhibitor-based MetS management.