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).

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK062768-06
Application #
7691279
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
Carrington, Jill L
Project Start
2005-09-01
Project End
2011-08-31
Budget Start
2009-09-01
Budget End
2011-08-31
Support Year
6
Fiscal Year
2009
Total Cost
$211,173
Indirect Cost
Name
Medical College of Wisconsin
Department
Surgery
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
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Babygirija, Reji; Zheng, Jun; Bülbül, Mehmet et al. (2010) Beneficial effects of social attachment to overcome daily stress. Brain Res 1352:43-9
Zheng, Jun; Babygirija, Reji; Bulbul, Mehmet et al. (2010) Hypothalamic oxytocin mediates adaptation mechanism against chronic stress in rats. Am J Physiol Gastrointest Liver Physiol 299:G946-53
Tong, W D; Ridolfi, T J; Kosinski, L et al. (2010) Effects of autonomic nerve stimulation on colorectal motility in rats. Neurogastroenterol Motil 22:688-93
Babygirija, Reji; Zheng, Jun; Ludwig, Kirk et al. (2010) Central oxytocin is involved in restoring impaired gastric motility following chronic repeated stress in mice. Am J Physiol Regul Integr Comp Physiol 298:R157-65
Nakade, Yukiomi; Pappas, Theodore N; Takahashi, Toku (2008) Peripheral plasma corticotropin-releasing factor concentration does not correlate with augmented colonic motility in response to restraint stress in rats. Clin Exp Pharmacol Physiol 35:934-7
Takahashi, Toku; Nakade, Yukiomi; Fukuda, Hiroyuki et al. (2008) Daily intake of high dietary fiber slows accelerated colonic transit induced by restrain stress in rats. Dig Dis Sci 53:1271-7
Nakade, Yukiomi; Tsukamoto, Kiyoshi; Iwa, Masahiro et al. (2007) Glucagon like peptide-1 accelerates colonic transit via central CRF and peripheral vagal pathways in conscious rats. Auton Neurosci 131:50-6
Nakade, Yukiomi; Fukuda, Hiroyuki; Iwa, Masahiro et al. (2007) Restraint stress stimulates colonic motility via central corticotropin-releasing factor and peripheral 5-HT3 receptors in conscious rats. Am J Physiol Gastrointest Liver Physiol 292:G1037-44
Nakade, Yukiomi; Mantyh, Christopher; Pappas, Theodore N et al. (2007) Fecal pellet output does not always correlate with colonic transit in response to restraint stress and corticotropin-releasing factor in rats. J Gastroenterol 42:279-82

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