Plain Language Summary
Reviews the gut-obesity-depression triad, examining how gut microbiota dysbiosis links metabolic and neuropsychiatric pathology, with GLP-1 RAs including semaglutide positioned as treatments with dual metabolic and microbiome-modifying effects. Covers semaglutide's effects on gut microbiota composition and their downstream neuropsychiatric implications. Provides a biological framework connecting GLP-1 RA therapy to mood regulation through the gut-brain axis—supporting emerging clinical observations of semaglutide's antidepressant and anti-addiction effects.
Abstract
The global rise in obesity and depression, two highly prevalent and often comorbid disorders has intensified interest in the gut–brain axis as a shared biological link. Mounting evidence indicates that the gut microbiota profoundly influences both metabolic and neuropsychiatric regulation, positioning it as a promising therapeutic target for these interconnected conditions. This review explores the complex interactions among microbial dysbiosis, host metabolism, and mood regulation, emphasizing pharmacological strategies that harness this triad for treatment. Gut-derived hormones such as glucagon-like peptide-1 (GLP-1) and microbiome-produced metabolites, including short-chain fatty acids (SCFAs) and bile acids, have demonstrated potential to modulate appetite, insulin sensitivity, inflammation, and brain function. GLP-1 receptor agonists like semaglutide originally developed for diabetes and obesity also exhibit antidepressant properties, highlighting their dual therapeutic promise. Emerging microbiome-based interventions, such as precision probiotics, engineered psychobiotics, and fecal microbiota transplantation (FMT), are being investigated to restore microbial balance and improve both metabolic and mood outcomes. Furthermore, combination therapies pairing microbiota-targeted agents with conventional antidepressants or anti-obesity drugs may offer synergistic benefits, enhance efficacy while minimize adverse effects. Despite this promise, significant challenges remain, including ensuring safety, understanding long-term impacts, navigating regulatory hurdles for live biotherapeutics, and addressing ethical concerns about altering the human microbiome. A deeper understanding of the gut–microbiome–brain axis may ultimately enable personalized, microbiota-guided therapies that treat both the physiological and psychological dimensions of obesity and depression, marking a major step toward holistic and precision medicine.