Irritable bowel syndrome (IBS) is a gastrointestinal motility and visceral sensation disorder that affects 30 million people in the United States. IBS is twice as common in women as men and IBS symptom severity is related to fluctuations in circulating female sex hormones and to episodes of stress. In addition, drugs which act at some 5-hydroxytryptamine (5- HT serotonin) receptors relieve IBS symptoms, including visceral pain, in some patients. Finally, many IBS patients have a polymorphism in the promoter region of the gene that encodes the serotonin transporter (SERT). This polymorphism leads to low SERT expression. These data indicate that there is an interaction between serotonin and female sex hormone signaling that leads to IBS symptoms especially visceral pain. The underlying pathophysiology of visceral pain is unclear and this is partly due to a lack of animal models where mechanistic and interventional studies can be conducted. We will use This hypothesis will be tested using male and female serotonin transporter (SERT) knockout (KO) rats, which we propose is an animal model of sex specific visceral hypersensitivity. This project will test th hypothesis that 5-hydroxytryptamine (5-HT, serotonin) corticotropin releasing hormone (CRH) and estrogen signaling interact to increase neurotransmission of primary afferent neurons supplying the colon to second order spinal sensory neurons and that probiotic bacteria L. reuteri (Lactobacillus reuteri 6475) can be used as a safe and effective treatment for visceral pain in IBS. The overall hypothesis will be tested in 3 specific aims.
Specific aim 1 will tes the hypothesis that 5-HT3 and CRH1 antagonists can reduce visceral hypersensitivity as measured by the visceromotor response (VMR) to colorectal balloon distention (CRD).
Specific aim 2 will test the hypothesis that the probiotic bacteria L. retueri can reduce visceral hypersensitivity in female SERT KO rats and this this probiotic may be a safe and effective treatment for visceral pain in IBS.
Specific aim 3 will test the hypothesis that serotonin, 17-beta estradiol and CRH interaction to alter the excitability of colon projecting sensory neurons and that colon projecting neurons from female SERT KO rats will show reduced excitability. The data would indicate that the SERT KO rat is a model for studying changes in the sensory nerve supply of the gut that leads to visceral hypersensitivity.

Public Health Relevance

Irritable bowel syndrome (IBS) is a very common gastrointestinal motility and pain disorder that is more common in women than men. The causes of IBS are not entirely clear and this is partly due to lack of an animal model for studies of physiology and pharmacology. The proposed studies will use a novel animal model of IBS to identify the factors that cause gastrointestinal pain and also to test potential new drug treatments for IBS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK103759-04
Application #
9399658
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Hamilton, Frank A
Project Start
2014-12-01
Project End
2018-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Michigan State University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
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