Saccharomyces boulardii reduces food intake and attenuates weight gain in diet-induced obese mice: links to gut microbial, metabolic, and immune remodeling

Introduction The gut microbiome is a key regulator of metabolic homeostasis and contributes to obesity progression through effects on immune signaling, gut barrier integrity, and systemic inflammation. Microbiome-targeted strategies are therefore being explored as complementary approaches to conventional weight-loss therapies. Here, we investigated whether the probiotic yeast Saccharomyces boulardii modulates the gut–immune–metabolic axis in diet-induced obesity (DIO). Methods Male C57BL/6JRj mice maintained on a 60% kcal high-fat diet (HFD) for eight weeks were randomized by body weight (n = 9 per group) and received daily oral gavage of S. boulardii or vehicle for seven weeks, with HFD continued throughout. Body weight and food intake were recorded by a caretaker blinded to treatment assignment. Endpoint analyses combined metabolic phenotyping, gut microbiome profiling, untargeted cecal metabolomics, colonic transcriptomics, and portal vein cytokine profiling. Results S. boulardii reduced food intake and attenuated weight gain without major changes in circulating metabolic hormone levels. Microbial diversity remained largely preserved, but Bacteroidales lineages, including Muribaculaceae, were selectively enriched alongside functional remodeling of microbial pathways. Cecal metabolomics revealed increased B vitamins, betaine, and GABA, with reduced stress-associated metabolites. Colonic transcriptomics showed attenuation of TNF-α/NF-κB signaling and enrichment of interferon and epithelial programs, while portal cytokine profiling revealed a significant treatment-associated shift in the overall cytokine profile, with trends toward lower inflammatory chemokines and increased IL-17A and IL-22. Integrated multi-omics analysis identified coordinated host–microbe interactions across metabolic, transcriptional, and immune layers. Discussion These exploratory findings show that S. boulardii modulates the gut–immune–metabolic axis in obesity, coupling reduced energy intake with microbial, metabolic, and mucosal immune remodeling. The design does not establish causal ordering between the omics layers, and mechanistic follow-up is required. Collectively, the results support microbiome-based interventions as potential adjunct strategies targeting metabolic inflammation.