Effects of Gastric Acid on Colonic Microbiome

The colonic microbiome is essential in human health and disease. Clostridium difficile-associated diarrhea (CDAD), a highly morbid form of infectious diarrhea, is caused by antibiotics which perturb the microbiome and allow C. difficile to proliferate. Proton pump inhibitors (PPIs) are powerful suppressors of gastric acid and among the most common medicines in the United States. Dozens of observational studies show that longterm PPI use is associated with CDAD. However, the mechanism by which PPIs cause CDAD is unknown. We believe that PPIs cause CDAD by inducing alterations in the human colonic microbiome. We will confirm or refute the hypothesized mechanism for the association between PPIs and CDAD using an unblinded, single-armed study design. We will use pyrosequencing of the hypervariable V4 region of the bacterial 16S ribosomal subunit gene in human fecal samples to describe the colonic flora. We will collect fecal samples from volunteers before and after PPIs given for different durations and test the microbiome to determine 1) whether PPIs diminish overall diversity, 2) whether PPIs diminish relative abundance of Bacteroidetes, 3) whether increased duration of PPIs affects diversity, and 4) whether there is recovery of diversity after completing a defined course of PPIs. We believe that PPIs will cause a pattern of diminished overall microbiome diversity and reduced anaerobes - the same pattern seen after use of antibiotics. Furthermore, we believe that increased PPI duration will further diminish diversity and that the microbiome will return to pre-PPI levels of diversity after PPIs are stopped. These results will facilitate biologically-based clinical interventions to reduce rates of CDAD among patients who require acid suppression.

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Key information

Conditions

Clostridium Difficile

Age range

18 year and older

Sex eligibility

Male

Study type

Interventional

Phase

Phase 4

Primary location

Columbia University

New York, 10032, United States

About this study

Study Design We will recruit 12 adult volunteers for a crossover study with a total duration of 12 weeks. Subjects will be observed off of PPIs for 4 weeks and then will be placed on PPIs for 4 weeks. Subsequently, subjects will be randomized to receive an additional 4 weeks of PPIs or no therapy. Stool samples will be collected at 4 separate time points.

Study Outcomes and Statistical Analyses The primary outcome will be change in overall diversity of fecal flora after 4 weeks of PPIs compared to 4 weeks of no acid suppression. Additional outcomes to be assessed include the effect of PPIs on the relative abundance of Bacteroidetes at week 4 and change in the diversity of fecal flora at week 8.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

18 or more years old
Able to give informed consent

Exclusion criteria

Use of systemic antibiotics within the past year
Use of acid suppression medications (PPIs or H2-receptor antagonists) within the past year (antacids permitted if more than one month from date of enrollment)
History of chronic gastrointestinal mucosal disease (e.g. inflammatory bowel disease, celiac disease, microscopic colitis)
Any clinically significant or uncontrolled major morbidity, including but not limited to serious cardiac or respiratory disease or uncontrolled HIV
Abnormal bowel frequency (minimum once every 2 days, maximum 3 times per day)
Use of clopidogrel or medications with potential significant interaction with PPIs
Osteoperosis or history of non-traumatic bone fracture
History of adverse reactions to PPIs
Initiation of any new medication within the month prior to enrollment
Pregnancy
Inability to give informed consent

Treatment and study plan

Omeprazole 40 mg bid

Drug

As above.

Other names: Brand name: Prilosec

Primary outcomes

Shannon Diversity Index Measuring Change in Microbiome Diversity

Time frame: Baseline (Week 0), Week 4, Week 8
In order to assess the diversity of the colonic microbiome, the Shannon diversity index will be calculated for each subject:
- After four weeks of no acid suppression (Week 0 vs. Week 4)
- After four weeks of twice daily PPI (Week 4 vs. Week 8)
The Shannon diversity index is a mathematical measure of species diversity in a given community. The Shannon index is calculated as: -∑[(pi)×ln(pi)] where H is the Shannon diversity index, and pi is the proportion of individuals of i-th species in a whole community. The minimum value of the Shannon diversity index is 0, which indicates there's no diversity - only one species is found in that habitat. There is no upper limit to the Shannon index. The higher the value of H, the higher the diversity of species in a particular community.

Sponsors and collaborators

Lead sponsor

Daniel Freedberg, MD

Other

Registry information

Official study title

The Effects of Gastric Acid Suppression on the Colonic Microbiome

Important dates

Study start: 2013
Primary completion: 2015
Study completion: 2015
First posted: Jul 17, 2013
Registry last updated: Aug 15, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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