Effects of Short Chain Fatty Acids on Colonic Motility

描述（由申请方提供）：短链脂肪酸（SCFA）是大肠中需氧菌未消化碳水化合物的分解产物。我们最近发现，在清醒大鼠中，SCFA（30-200 mM）的腔内给药以剂量依赖性方式显著加速结肠运输并刺激结肠运动。辣椒素、阿托品、迷走神经切断术和5-HT 3受体拮抗剂的腔内处理均能阻断SCFAs的兴奋作用。我们还证明了SCFA的管腔给药显著增加了5-HT释放到结肠腔中。因此，我们推测，5-HT释放肠嗜铬细胞（EC）响应SCFA，这反过来又刺激结肠运动通过粘膜5-HT 3受体和迷走神经-迷走神经反射。我们还发现，与接受高SCFAs生产饮食（马铃薯淀粉）的大鼠相比，给予低SCFAs生产饮食（玉米淀粉）的大鼠结肠粘膜中5-HT 3受体免疫反应性纤维的密度显著增加。此外，已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运输。我们的初步研究表明，束缚应激诱导的结肠运输加速被取消的周围迷走辣椒素治疗，腔内5-HT 3拮抗剂，迷走神经切断术，阿托品和脑池内（IC）注射CRF拮抗剂。这表明束缚应激诱导的中枢CRF主要刺激EC细胞释放5-HT，通过5-HT 3受体和迷走-迷走反射加速结肠运输。接受低SCFAs饮食的大鼠对束缚应激的结肠运输加速和腹泻发生率远高于接受高SCFAs饮食的大鼠。在这个提议中，我们假设当SCFAs的管腔浓度降低时，5-HT 3受体的超敏性发展。这些结果可能提供了一个合理的解释，如何低浓度的管腔SCFAs和应激有助于肠道易激综合征（IBS）的发病机制，以大肠杆菌为主。

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).