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: 7691279
• 负责人: Toku Takahashi
• 金额: $ 21.12万
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7691279
• 关键词: Acceleration; Acetates; Aerobic Bacteria; Amylases; Atropine; Butyrates; Capsaicin; Carbohydrates; Cholinergic Fibers; Colon; Complex; Conscious; Corn starch preparation; Corticotropin-Releasing Hormone; Diarrhea; Diet; Digestion; Dorsal; Dose; Enterochromaffin Cells; Fermentation; Fiber; Genus Cola; Human; Hypersensitivity; Immunohistochemistry; Incidence; Injection of therapeutic agent; Intake; Intestinal Mucosa; Irritable Bowel Syndrome; Large Intestine; Mediating; Mediation; Mucous Membrane; Pathogenesis; Pathway interactions; Patients; Peripheral; Physiological; Potato; Production; Propionates; Rattus; Reflex action; Research Personnel; Resistance; Role; Serotonin; Serotonin Receptors 5-HT-3; Small Intestines; Sodium; Starch; Testing; Vagotomy; Volatile Fatty Acids; Water; absorption; acid stress; base; cell motility; cholinergic; density; motility disorder; programs; response; restraint stress

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）是有氧细菌大肠中未消化的碳水化合物的分解产物。我们最近表明，在有意识的大鼠中，SCFA（30-200 mM）的腔内给药显着加速了结肠传输，并以剂量​​依赖性的剂量刺激了结肠运动。通过5-HT3受体拮抗剂，通过周围的辣椒素治疗，阿托品，迷走神经术和腔内治疗来消除SCFA的刺激作用。我们还证明，SCFA的管腔给药可显着增加5-HT释放到结肠内腔。因此，我们假设5-HT是从肠球毒蛋白（EC）细胞中释放出来的，响应SCFA，进而通过粘膜5-HT3受体和Vago-Vagal反射刺激了结肠运动。我们还发现，与接受高SCFAS产生饮食（马铃薯淀粉）的大鼠相比，在结肠粘膜中，低SCFAS产生饮食（玉米淀粉）的5-HT3受体免疫反应性纤维的密度显着增加。此外，众所周知，大鼠的约束应力通过皮质激素释放因子（CRF）和迷走神经途径加速了结肠转运。我们的初步研究表明，通过圆锥形辣椒素治疗，腔内5-HT3拮抗剂，迷走神经切开术，阿托品和内部（IC）注射CRF拮抗剂，消除了约束应激诱导的结肠传输加速度。这表明，通过约束应力引起的中央CRF主要刺激了EC细胞的5-HT释放，这导致通过5-HT3受体和Vago-vagal反射加速结肠传输。在低于SCFA的大鼠的大鼠中，加速的结肠传输和腹泻的发生率要比在较高的SCFAS-DIET的大鼠中大得多。在此提案中，我们假设5-HT3受体的高敏性在降低SCFA的腔内浓度时会形成。这些结果可能提供了一个合理的解释，即对腔内SCFA的浓度低和应力有助于腹泻促炎的肠易激综合征（IBS）的发病机理。

项目成果

Luminally released serotonin stimulates colonic motility and accelerates colonic transit in rats.

腔内释放的血清素刺激结肠运动并加速大鼠的结肠转运。

• DOI: 10.1152/ajpregu.00856.2006
• 发表时间: 2007
• 期刊: American journal of physiology. Regulatory, integrative and comparative physiology
• 作者: Tsukamoto,Kiyoshi;Ariga,Hajime;Mantyh,Chris;Pappas,TheodoreN;Yanagi,Hidenori;Yamamura,Takehira;Takahashi,Toku
• 通讯作者: Takahashi,Toku

Hypothalamic oxytocin mediates adaptation mechanism against chronic stress in rats.

• DOI: 10.1152/ajpgi.00483.2009
• 发表时间: 2010-10
• 期刊: American journal of physiology. Gastrointestinal and liver physiology
• 作者: Jun Zheng;R. Babygirija;M. Bülbül;Diana Cerjak;K. Ludwig;Toku Takahashi

Effects of autonomic nerve stimulation on colorectal motility in rats.

• DOI: 10.1111/j.1365-2982.2009.01461.x
• 发表时间: 2010-06
• 期刊: Neurogastroenterology and motility
• 影响因子: 3.5
• 作者: Tong WD;Ridolfi TJ;Kosinski L;Ludwig K;Takahashi T
• 通讯作者: Takahashi T

The role of 5-HT3 and 5-HT4 receptors in the adaptive mechanism of colonic transit following the parasympathetic denervation in rats.

• DOI: 10.1016/j.jss.2010.05.002
• 发表时间: 2011-12
• 期刊: The Journal of surgical research
• 作者: Tong W;Kamiyama Y;Ridolfi TJ;Zietlow A;Zheng J;Kosinski L;Ludwig K;Takahashi T
• 通讯作者: Takahashi T