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Gastroenterology ; 161(2): 608-622.e7, 2021 08.
Article in English | MEDLINE | ID: mdl-33895170

ABSTRACT

BACKGROUND & AIMS: Constipation is commonly associated with diabetes. Serotonin (5-HT), produced predominantly by enterochromaffin (EC) cells via tryptophan hydroxylase 1 (TPH1), is a key modulator of gastrointestinal (GI) motility. However, the role of serotonergic signaling in constipation associated with diabetes is unknown. METHODS: We generated EC cell reporter Tph1-tdTom, EC cell-depleted Tph1-DTA, combined Tph1-tdTom-DTA, and interstitial cell of Cajal (ICC)-specific Kit-GCaMP6 mice. Male mice and surgically ovariectomized female mice were fed a high-fat high-sucrose diet to induce diabetes. The effect of serotonergic signaling on GI motility was studied by examining 5-HT receptor expression in the colon and in vivo GI transit, colonic migrating motor complexes (CMMCs), and calcium imaging in mice treated with either a 5-HT2B receptor (HTR2B) antagonist or agonist. RESULTS: Colonic transit was delayed in males with diabetes, although colonic Tph1+ cell density and 5-HT levels were increased. Colonic transit was not further reduced in diabetic mice by EC cell depletion. The HTR2B protein, predominantly expressed by colonic ICCs, was markedly decreased in the colonic muscles of males and ovariectomized females with diabetes. Ca2+ activity in colonic ICCs was decreased in diabetic males. Treatment with an HTR2B antagonist impaired CMMCs and colonic motility in healthy males, whereas treatment with an HTR2B agonist improved CMMCs and colonic motility in males with diabetes. Colonic transit in ovariectomized females with diabetes was also improved significantly by the HTR2B agonist treatment. CONCLUSIONS: Impaired colonic motility in mice with diabetes was improved by enhancing HTR2B signaling. The HTR2B agonist may provide therapeutic benefits for constipation associated with diabetes.


Subject(s)
Colon/drug effects , Constipation/prevention & control , Diabetes Complications/prevention & control , Gastrointestinal Motility/drug effects , Indoles/pharmacology , Interstitial Cells of Cajal/drug effects , Myoelectric Complex, Migrating/drug effects , Receptor, Serotonin, 5-HT2B/drug effects , Serotonin 5-HT2 Receptor Agonists/pharmacology , Thiophenes/pharmacology , Animals , Calcium Signaling , Colon/metabolism , Colon/physiopathology , Constipation/etiology , Constipation/metabolism , Constipation/physiopathology , Diabetes Complications/metabolism , Diabetes Complications/physiopathology , Disease Models, Animal , Female , Genes, Reporter , Interstitial Cells of Cajal/metabolism , Male , Mice, Inbred C57BL , Mice, Transgenic , Ovariectomy , Proto-Oncogene Proteins c-kit/genetics , Proto-Oncogene Proteins c-kit/metabolism , Receptor, Serotonin, 5-HT2B/metabolism , Serotonin/metabolism , Tryptophan Hydroxylase/genetics , Tryptophan Hydroxylase/metabolism
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