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An advanced microbiome therapeutic consisting of genetically engineered probiotic yeast *Saccharomyces boulardii* that produces and secretes Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, directly in the gastrointestinal tract. The engineered yeast delivers the therapeutic peptide *in situ*, where it activates GLP-1 receptors in the gastrointestinal tract and intestinal sensory neurons to suppress appetite and promote weight loss. The mechanism involves interaction with the enteric nervous system (ENS) and vagus nerve. When tested in mice with diet-induced obesity and combined with cold exposure (8°C), this therapeutic suppressed appetite by 25% and promoted 4-fold higher weight loss compared to controls. The Exendin-4 produced by the engineered yeast demonstrated biological activity by inducing insulin secretion from pancreatic islets. The therapeutic is designed for oral administration, with the yeast producing Exendin-4 locally in the gut, avoiding the need for systemic circulation and frequent injections required by conventional GLP-1 receptor agonist therapies.
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