Effects of Short Chain Fatty Acids on Colonic Motility

短链脂肪酸对结肠蠕动的影响

• 批准号: 7690279
• 负责人: Toku Takahashi
• 金额: $ 21.6万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7690279
• 关键词: Acceleration; Aerobic Bacteria; Atropine; Capsaicin; Carbohydrates; Conscious; Corticotropin-Releasing Hormone; Diarrhea; Diet; Dose; Enterochromaffin Cells; Fatty Acids; Fiber; Hypersensitivity; Incidence; Injection of therapeutic agent; Irritable Bowel Syndrome; Large Intestine; Maize; Mucous Membrane; Pathogenesis; Pathway interactions; Potato; Production; Rattus; Reflex action; Serotonin; Serotonin Receptors 5-HT-3; Starch; Vagotomy; Volatile Fatty Acids; Zea mays; acid stress; cell motility; density; response; restraint stress; toe corn

DESCRIPTION (provided by applicant): Short chain fatty acids (SCFAs) are breakdown products of undigested carbohydrates in the large bowel by aerobic bacteria. We have recently showed that intraluminal administration of SCFA (30-200 mM) significantly accelerated colonic transit and stimulated colonic motility in a dose dependent manner in conscious rats. The stimulatory effects of SCFAs were abolished by perivagal capsaicin treatment, atropine, vagotomy and the intraluminal treatment with 5-HT3 receptor antagonists. We also demonstrated that luminal administration of SCFAs significantly increased 5-HT release into the colonic lumen. Therefore, we postulate that 5-HT is released from enterochromaffin (EC) cells in response to SCFAs which in turn stimulates colonic motility via mucosal 5-HT3 receptors and a vago-vagal reflex. We have also found that rats given a low SCFAs-production diet (corn starch) had significantly increased density of 5-HT3 receptor immunoreactive fibers in the colonic mucosa when compared to rats receiving a high SCFAs-production diet (potato starch). In addition, it is known that restraint stress in the rat accelerates colonic transit via corticotropin releasing factor (CRF) and vagal pathways. Our preliminary studies demonstrated that restraint stress-induced acceleration of colonic transit was abolished by perivagal capsaicin treatment, intraluminal 5-HT3 antagonists, vagotomy, atropine and intracisternal (ic) injection of CRF antagonists. This suggests that central CRF-induced by restraint stress primarily stimulates 5-HT release from EC cells which results in an acceleration of colonic transit via 5-HT3 receptors and a vago-vagal reflex. Accelerated colonic transit and the incidence of diarrhea in response to restraint stress were much greater in rats receiving a low SCFAs-diet than that in rats given a high SCFAs-diet. In this proposal, we hypothesize that hypersensitivity of 5-HT3 receptors develops when luminal concentration of SCFAs is lowered. These results may provide a rational explanation as to how low concentrations of luminal SCFAs and stress contributes to the pathogenesis of diarrhea-predominant irritable bowel syndrome (IBS).

描述（由申请人提供）：短链脂肪酸（SCFA）是大肠中未消化的碳水化合物被需氧细菌分解的产物。我们最近发现，在清醒大鼠中，腔内给予 SCFA (30-200 mM) 显着加速结肠转运并以剂量依赖性方式刺激结肠运动。迷走神经周围辣椒素治疗、阿托品、迷走神经切断术和 5-HT3 受体拮抗剂腔内治疗消除了 SCFA 的刺激作用。我们还证明，SCFA 的腔内给药显着增加了结肠腔中 5-HT 的释放。因此，我们假设肠嗜铬 (EC) 细胞响应 SCFA 释放 5-HT，进而通过粘膜 5-HT3 受体和迷走神经反射刺激结肠运动。我们还发现，与接受高 SCFA 产生饮食（马铃薯淀粉）的大鼠相比，给予低 SCFA 产生饮食（玉米淀粉）的大鼠结肠粘膜中 5-HT3 受体免疫反应纤维的密度显着增加。此外，众所周知，大鼠的束缚应激通过促肾上腺皮质激素释放因子（CRF）和迷走神经途径加速结肠转运。我们的初步研究表明，通过迷走神经周围辣椒素治疗、腔内 5-HT3 拮抗剂、迷走神经切断术、阿托品和脑池内 (ic) 注射 CRF 拮抗剂，可以消除束缚应激诱导的结肠转运加速。这表明，束缚应激诱导的中枢 CRF 主要刺激 EC 细胞释放 5-HT，从而通过 5-HT3 受体和迷走神经反射加速结肠转运。接受低 SCFAs 饮食的大鼠的结肠运输加速和因束缚应激而发生的腹泻发生率比给予高 SCFAs 饮食的大鼠要高得多。在此提议中，我们假设当 SCFA 的管腔浓度降低时，5-HT3 受体会发生超敏反应。这些结果可能为低浓度的管腔 SCFA 和应激如何导致腹泻型肠易激综合征 (IBS) 的发病机制提供合理的解释。