Intestinal Microecology in Chronic Constipation

NCT ID: NCT00934479

Last Updated: 2013-07-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 21 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-04-30
• Study Completion Date: 2012-02-29

Brief Summary

The purpose of this study is to determine whether the bacteria normally present in the bowels are different in people with constipation and to see what effect the treatment with the Food and Drug Administration (FDA) - approved drug, lubiprostone, has on these bacteria.

Detailed Description

Chronic constipation is a common condition with a heterogeneous pathophysiology and resulting clinical manifestations. Recent evidence in the literature and collected in our laboratory confirm that there are differences in the gut microbiota between healthy individuals and those with a variety of disorders (e.g., inflammatory bowel disease, irritable bowel syndrome and obesity) suggesting that the development of certain disorders may be determined by the composition of the gut microbiota. Existing evidence warrants further investigation of the role of the microbial ecology of the human gut in constipation and an exploration of modification of the gut microbiota as a means to treat constipation by its actions on the colonic metabolism of nutrient substrates to alter colonic transit and fluid fluxes.

The proposed research will exploit our proven capability to use high-throughput molecular genomic techniques to define the intestinal microbiome in order to help define the role of the gut microbiota in chronic constipation and will explore the potential value of altering the microbiota as a management strategy in constipation. The linkage of high-throughput genomic analyses with cause-and-effect understanding of how the gut microbiota affects bowel function may lead to a reliable means to manage the gut microbiota with the intent to prevent and/or treat constipation. The immediate goals of this project are to expand on existing information about the microbial ecology in the human intestines focusing on its relationship with constipation using molecular microbiological techniques and to assess the effects on the gut microorganisms resulting from the use of the FDA-approved medication, lubiprostone. Lubiprostone is a member of a novel therapeutic class called prostones and is an orally active, bicyclic fatty acid that selectively acts on type 2 chloride channels to stimulate chloride secretion which induces a net increase in luminal fluid secretion. Unlike antibiotic, probiotic and prebiotic agents, it has no known direct effects on the gut microbiota. It is FDA-approved for the treatment of chronic constipation in men and women and for women with constipation-predominant IBS (C-IBS). The rationale for using lubiprostone to modify the gut microbiota stems from the use of similar strategies for controlling recalcitrant small intestinal bacterial overgrowth (i.e., altering fluid fluxes in the gut lumen).

We believe that this research will greatly improve our understanding of the role that the gut microbiota play in the development of constipation and potentially lead to new strategies with which to combat this common problem.

Conditions

Other Constipation; Irritable Bowel Syndrome

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Healthy Subjects

Healthy subjects completed a baseline 1-week diary of stool and defecatory characteristics, fasting breath for hydrogen and methane and a stool sample for pyrosequencing. Otherwise, the healthy subjects received no intervention.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Constipated Subjects

Subjects with constipation included those with chronic constipation (CC) and those with constipation predominant irritable bowel syndrome (C-IBS). They completed a baseline 1-week diary of stool and defecatory characteristics, fasting breath for hydrogen and methane and a stool sample for pyrosequencing.

Following baseline test and because of differences in the FDA-approved dosing for the 2 subtypes of chronic constipation, the CC subjects received open-label lubiprostone 24 mcg orally twice daily for 4 weeks; while the C-IBS subjects received open-label lubiprostone 8 mcg orally twice daily for 4 weeks.

Following the 4-weeks treatment with lubiprostone, they completed another stool diary, fasting breath test, and stool sample for pyrosequencing.

Group Type: EXPERIMENTAL

Lubiprostone

Intervention Type: DRUG

Following the initial stool and breath collections and because of differences in the FDA-approved dosing for the 2 subtypes of chronic constipation, (that is, chronic constipation (CC) versus constipation due to irritable bowel syndrome (C-IBS), the CC subjects received open-label lubiprostone 24 mcg orally twice daily for 4 weeks; while the C-IBS subjects received open-label lubiprostone 8 mcg orally twice daily for 4 weeks.

Interventions

Lubiprostone

Following the initial stool and breath collections and because of differences in the FDA-approved dosing for the 2 subtypes of chronic constipation, (that is, chronic constipation (CC) versus constipation due to irritable bowel syndrome (C-IBS), the CC subjects received open-label lubiprostone 24 mcg orally twice daily for 4 weeks; while the C-IBS subjects received open-label lubiprostone 8 mcg orally twice daily for 4 weeks.

Intervention Type: DRUG

Other Intervention Names

Amitiza

Eligibility Criteria

Inclusion Criteria

1. Fewer than 3 bowel movements/day and more than 3 bowel movements/week without the need for significant straining with defecation or frequent sensation of incomplete evacuation after defecation

2. Absence of current or chronic gastrointestinal symptoms

1. Meet Rome III criteria for chronic functional constipation

2. Colonoscopy within the previous 10 years for subjects ≥ 50 years of age

1. Meet Rome III criteria for C-IBS

2. Colonoscopy within the previous 10 years for subjects ≥ 50 years of age

Exclusion Criteria

1. Prior gastrointestinal surgery that altered the anatomy of the esophagus, stomach, or small/large intestine (exceptions include appendectomy and cholecystectomy)

2. Gastrointestinal, cardiovascular, endocrine, renal, or other chronic disease likely to affect gastrointestinal motility (e.g., uncontrolled diabetes mellitus)

3. Females of childbearing age who are not practicing birth control and/or are pregnant or lactating (a urine pregnancy test will be performed on female subjects prior to lubiprostone use)

4. Significant untreated psychiatric disease

5. History of hypersensitivity reaction or intolerance to lubiprostone

6. Inability to stop antibiotics, probiotics, and fiber supplements 1 month prior to stool sample collection

7. Inability to stop proton pump inhibitors, histamine 2 receptor antagonists, prokinetic agents, narcotic analgesic agents, laxatives, and anticholinergic agents 2 weeks prior to stool sample collection

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Arizona State University

OTHER

Sponsor Role: collaborator

Takeda Pharmaceuticals North America, Inc.

INDUSTRY

Sponsor Role: collaborator

Mayo Clinic

OTHER

Sponsor Role: lead

Responsible Party

John K. DiBaise

MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

John K. DiBaise, M.D.

Role: PRINCIPAL_INVESTIGATOR

Mayo Clinic

Locations

Mayo Clinic Arizona

Scottsdale, Arizona, United States

Countries

United States

References

Kang DW, DiBaise JK, Ilhan ZE, Crowell MD, Rideout JR, Caporaso JG, Rittmann BE, Krajmalnik-Brown R. Gut microbial and short-chain fatty acid profiles in adults with chronic constipation before and after treatment with lubiprostone. Anaerobe. 2015 Jun;33:33-41. doi: 10.1016/j.anaerobe.2015.01.005. Epub 2015 Jan 21.

Reference Type: DERIVED

PMID: 25617726 (View on PubMed)

Other Identifiers

09-001281

Identifier Type: -

Identifier Source: org_study_id