Effects of Short Chain Fatty Acids on Colonic Motility

说明(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，SCFA(30-200 mM)腔内给药显著促进清醒大鼠的结肠运输，并以剂量依赖的方式刺激结肠运动。迷走神经周围应用辣椒素、阿托品、切断迷走神经和腔内注射5-HT3受体拮抗剂均可阻断SCFAs的兴奋作用。我们还证明，腔内给予SCFAs显著增加了5-羟色胺在结肠腔内的释放。因此，我们推测肠嗜铬细胞(EC)释放5-羟色胺(5-HT)作为对SCFAs的反应，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，与高SCFAs饮食(马铃薯淀粉)相比，给予低SCFAs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著增加。此外，已知束缚应激通过促肾上腺皮质激素释放因子(CRF)和迷走神经通路加速大鼠的结肠运输。我们的初步研究表明，迷走神经周围辣椒素治疗、5-HT3拮抗剂腔内注射、迷走神经切断术、阿托品和脑池内注射CRF拮抗剂可消除束缚应激引起的结肠传输加速。这表明束缚应激诱导的中枢性CRF主要刺激EC细胞释放5-羟色胺，从而通过5-HT3受体和迷走神经反射加速结肠运输。在接受低SCFAs饮食的大鼠中，结肠运输加速和因束缚应激而引起的腹泻的发生率比接受高SCFAs饮食的大鼠要高得多。在这一建议中，我们假设5-HT3受体的超敏反应是当SCFAs的管腔浓度降低时发生的。这些结果可能为低浓度的腔内单链脂肪酸和应激在腹泻型肠易激综合征(IBS)发病机制中的作用提供合理的解释。

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).