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The constipation pathway: Predominant GLP-1 receptor expression in the colon Slowed peristalsis exceeds the gut's ability to adapt Increased water absorption Hard, infrequent stools The diarrhea pathway: Predominant GLP-1 receptor expression in the small intestine Slowed small bowel transit allows bacterial overgrowth or malabsorption Osmotic load in the colon from unabsorbed nutrients Loose, frequent stools The mixed pathway (most common): Early diarrhea (weeks 1-4) from acute gastric retention and bile acid malabsorption Transition to constipation (weeks 4-12) as colonic adaptation lags behind gastric adaptation Resolution to normal or near-normal bowel habits after 12-16 weeks A 2024 paper in Gut (Acosta et al.) measured GLP-1 receptor density in colonic biopsies from 86 patients starting semaglutide