PPI and Microbiome in Healthy Volunteers and Functional Dyspepsia

Effect of Proton Pump Inhibitors on the Duodenal Microbiome in Healthy Volunteers and Functional Dyspepsia Patients

Prospective interventional study of the effect of PPI on the duodenal microbiome in healthy volunteers and functional dyspepsia patients

Study Overview

• Status: Completed
• Conditions: Dysbiosis
• Intervention / Treatment: Drug: Pantoprazole 40mg; Other: PPI withdrawal

Detailed Description

PPIs are the first-line therapy in functional dyspepsia (FD) but frequently (over-)prescribed with potential adverse events, especially in the long term. As C. difficile and CAP are important causes of morbidity, mortality and healthcare costs, it is important to study the underlying mechanisms of PPI-induced dysbiosis.

In this prospective interventional study, study procedures will be performed at inclusion (1), after a baseline period of 4 weeks (2) and after treatment with Pantoprazole (Pantomed®) 40mg once daily during 4 weeks (3) in healthy volunteers and FD patients. In addition, study procedures will be performed at inclusion (1) and after PPI-withdrawal for 8 weeks in refractory FD patients.

The investigators aim to assess alterations of the duodenal (mucosa-associated and luminal) microbiome with PPI therapy and to correlate changes in the duodenal microbiota with oral and fecal microbiota, bile acids, intestinal permeability and histology and biochemical variables.

The results from this study will help to unravel the onset and extent of dysbiosis and provide additional arguments not to prescribe or continue PPI without clear clinical indications, especially in cases where alternative regimens may be available or the benefits of PPI are uncertain.

• Study Type: Interventional
• Enrollment (Actual): 79
• Phase: Phase 4

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • UZ Leuven

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 64 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects aged between 18 and 64 years inclusive
• Male or female (not pregnant or lactating and using contraception or postmenopausal)
• Normal bowel habits (defecation once every 3 days up to 3 times a day)
• Witnessed written informed consent
• Access to home freezer (-18 to -20°C)
• Capable to understand and comply with the study requirements

Exclusion Criteria:

• Active psychiatric symptoms (stable dose of single antidepressant allowed)
• Use of acid suppressive drugs (before starting Pantomed), immunosuppressants or antibiotics <3 months before sampling
• Use of drugs influencing stool consistency, NSAIDs, anti-allergy drugs, bile acid sequestrants or ursodeoxycholic acid <2 weeks before sampling
• Use of prokinetics <2 weeks before sampling (unless if ≤3/week)
• History of major abdominal surgery, including cholecystectomy but not appendectomy or splenectomy
• Personal or family (first-degree relative) history of diabetes mellitus type 1, celiac disease, inflammatory bowel disease, psoriasis, rheumatic or other auto-immune diseases (including therapy)
• Allergy or atopy (eczema, asthma and/or allergic rhinoconjunctivitis) (including therapy)
• Kidney, liver or coagulation disorders
• Active coronary or peripheral artery disease
• Diabetes mellitus type 2 (including therapy)
• Active malignancy (including therapy)
• Known HIV, HBV or HCV infection (including therapy)
• Magnetizable objects (e.g. cochlear implants, neural stimulator, pacemaker, metal fragments or implants) or claustrophobia (MRI safety criteria with additional consent form, other procedures can still take place)
• Significant alcohol use (>10 units/weeks)
• Any use of alcohol or smoking ≤2 days before sampling
• Females who are pregnant or lactating, who are not using contraception and premenopausal

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Pantoprazole 40mg in healthy volunteers; Peroral Pantoprazole 40mg once daily for 4 weeks	Drug: Pantoprazole 40mg; Peroral Pantoprazole 40mg once daily during 28 days; Other Names: Pantomed
Other: Pantoprazole 40mg in functional dyspepsia; Peroral Pantoprazole 40mg once daily for 4 weeks	Drug: Pantoprazole 40mg; Peroral Pantoprazole 40mg once daily during 28 days; Other Names: Pantomed
Other: PPI-withdrawal in functional dyspepsia; no PPI for 8 weeks	Other: PPI withdrawal; PPI withdrawal for 8 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in microbiota composition	Change in microbiota composition in the duodenum (lumen and mucosa) and feces	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in mucosal inflammation	Change in mucosal inflammation (using immunohistochemistry) of the duodenum	4 weeks
Change in mucosal permeability	Change in mucosal permeability (using ussing chambers) of the duodenum	4 weeks
Change in bile acid composition	Change in bile acid composition in the duodenum	4 weeks

Collaborators and Investigators

• Sponsor: Universitaire Ziekenhuizen KU Leuven
• Investigators: Principal Investigator: Tim Vanuytsel, MD PhD, UZ Leuven

Publications and helpful links

General Publications

• Wauters L, Ceulemans M, Frings D, Lambaerts M, Accarie A, Toth J, Mols R, Augustijns P, De Hertogh G, Van Oudenhove L, Tack J, Vanuytsel T. Proton Pump Inhibitors Reduce Duodenal Eosinophilia, Mast Cells, and Permeability in Patients With Functional Dyspepsia. Gastroenterology. 2021 Apr;160(5):1521-1531.e9. doi: 10.1053/j.gastro.2020.12.016. Epub 2020 Dec 18.

Study record dates

Study Major Dates

• Study Start (Actual): April 23, 2018
• Primary Completion (Actual): March 8, 2020
• Study Completion (Actual): September 22, 2020

Study Registration Dates

• First Submitted: April 24, 2018
• First Submitted That Met QC Criteria: May 22, 2018
• First Posted (Actual): June 4, 2018

Study Record Updates

• Last Update Posted (Actual): September 28, 2020
• Last Update Submitted That Met QC Criteria: September 23, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: proton pump inhibitor; microbiome; duodenum
• Additional Relevant MeSH Terms: Pathologic Processes; Signs and Symptoms, Digestive; Dyspepsia; Dysbiosis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gastrointestinal Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Pantoprazole
• Other Study ID Numbers: S60984/60953

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No