Mika Matera-Vatnick

GLP-1 receptor agonists are highly effective treatments for obesity and type 2 diabetes, but about one-third of patients do not lose a meaningful amount of weight, and common clinical factors like age, sex, and starting weight explain only a small portion of this variability. By analyzing the gut microbiome in stool samples collected before treatment, we found that people who later lost more weight had greater microbial diversity and distinct microbiome patterns, suggesting the gut microbiome may help predict who will respond best to these medications.

GLP-1 receptor agonists (GLP-1RAs) have transformed the treatment of obesity and type 2 diabetes, however, approximately one-third of patients do not achieve clinically meaningful weight loss. Baseline clinical variables, including age, BMI, and sex, explain only 19.2% of the variance in 6-month weight loss following GLP-1RA initiation. We therefore hypothesized that baseline gut microbiome features may account for a portion of the unexplained interindividual variability in treatment response. To test this hypothesis, we performed metagenomic sequencing on baseline stool samples from a cohort of patients with obesity initiating GLP-1RAs. We found that baseline microbial alpha diversity, was significantly higher in responders compared to non-responders. In addition, overall baseline microbial community composition was associated with the magnitude of weight loss over six months. These findings suggest that the baseline gut microbiome may serve as a predictive biomarker of GLP-1RA-induced weight loss and a potential target to enhance drug efficacy in nonresponders.