Microbes, mood, and metabolism/obesity: Pharmacological insights into the gut-obesity-depression triad

Mar 3, 2026Cellular and molecular life sciences : CMLS

How gut microbes and drugs relate to mood and metabolism in obesity and depression

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Abstract

The gut microbiota may influence both metabolic and neuropsychiatric regulation.

Microbial is linked to obesity and depression, suggesting a shared biological pathway.
Gut-derived hormones and microbiome-produced metabolites could modulate appetite, insulin sensitivity, inflammation, and brain function.
GLP-1 receptor agonists, such as semaglutide, may have both anti-obesity and antidepressant effects.
Emerging interventions like precision probiotics and fecal microbiota transplantation are being studied for their potential to restore microbial balance.
Combination therapies that include microbiota-targeted agents alongside traditional treatments may enhance effectiveness and reduce side effects.
Challenges remain regarding the safety and long-term effects of microbiota manipulation, as well as regulatory and ethical considerations.

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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 , 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.

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Microbes, mood, and metabolism/obesity: Pharmacological insights into the gut-obesity-depression triad

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