Effects of Short Chain Fatty Acids on Colonic Motility

描述（由申请人提供）：短链脂肪酸（SCFAs）是需氧细菌在大肠中未消化的碳水化合物的分解产物。我们最近的研究表明，在有意识的大鼠中，腹腔内给药SCFA （30-200 mM）显著加速结肠运输并以剂量依赖的方式刺激结肠运动。迷走神经周围辣椒素、阿托品、迷走神经切开术和5-HT3受体拮抗剂均可消除scfa的刺激作用。我们还证明，腹腔给药SCFAs显著增加5-HT释放到结肠腔。因此，我们假设5-羟色胺是肠染色质（EC）细胞对scfa的反应而释放的，scfa通过粘膜5-HT3受体和迷走反射刺激结肠运动。我们还发现，与接受高scfa饮食（马铃薯淀粉）的大鼠相比，给予低scfa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，已知大鼠的约束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结肠转运。我们的初步研究表明，迷走神经周围辣椒素治疗、腔内5-HT3拮抗剂、迷走神经切开术、阿托品和腹腔内注射CRF拮抗剂可以消除抑制应激诱导的结肠运输加速。这表明，约束应激诱导的中枢性crf主要刺激EC细胞释放5-HT，从而通过5-HT3受体和迷走反射加速结肠转运。与高scfas饮食的大鼠相比，低scfas饮食的大鼠在约束压力下加速结肠运输和腹泻的发生率要高得多。在这个提议中，我们假设当SCFAs的管腔浓度降低时，5-HT3受体会产生超敏反应。这些结果可能为低浓度的腔内SCFAs和应激如何导致腹泻型肠易激综合征（IBS）的发病提供了合理的解释。

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).