Letter to the Editor: The Gut Microbiome-Endocrine Axis in Obesity: Mechanisms and Therapeutics.

Obesity therapeutics is rapidly evolving, and mechanistic frameworks linking the gut microbiome to systemic metabolism are essential for clinical translation. In this letter, I commend the invited review by Mao et al., which elegantly integrates mechanistic insights across the gut-brain, gut-adipose, and gut-pancreas axes, and we propose three extensions to strengthen its clinical relevance. First, I highlight the bidirectional interplay between GLP-1 receptor agonists (GLP-1 RAs)-now first-line obesity pharmacotherapy-and the gut microbiome: GLP-1 RAs enrich Akkermansia muciniphila and short-chain-fatty-acid-producing taxa, while baseline microbiome composition modulates individual drug responsiveness. Second, I argue for greater attention to upper gastrointestinal microbial niches and synthetic biology approaches, including engineered Clostridium butyricum strains that secrete GLP-1 locally within the intestinal lumen. Third, I emphasize the circadian dimension of the gut-endocrine axis-time-restricted feeding restores microbial diurnal oscillations-and its integration with phenotype-guided precision medicine (e.g., "hungry gut," "hungry brain," and "emotional hunger" subtypes). Incorporating these perspectives would transform the review into a practical roadmap for personalized obesity intervention.