Effects of H.Pylori Eradication on Microbiome

Study Overview
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Brief Summary
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The aim of this Project is, within the scope of industrial research, to evaluate the long term effects of H.pylori eradication on microbiome (gut microbiome, upper respiratory tract microbiome) and lasting adverse events. In addition, the project aims to evaluate its effects on abundance and prevalence of extended-spectrum beta-lactamases coding genes and develop cost effective ESBL screening test prototype.

Detailed Description
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The current international guidelines and expert working groups are encouraging search-and-treat strategy for H.pylori to prevent gastric cancer1, 2. The highest yield of this approach is expected in countries with high incidence of gastric cancer and high prevalence of H.pylori infection. This approach will be further supported by the Maastricht V European guidelines (manuscript in preparation). The rationale for this approach is that 1-2% of the infected individuals are developing gastric cancer; the International Agency for Research on Cancer has classified H.pylori infection as Class I carcinogen3, 4. A study in Matsu island with high gastric cancer risk has suggested that gastric cancer incidence can be decreased by 25% by such strategy5; the limitations, however, include lack of the control group. Three recent meta-analysis have confirmed the cost-effectiveness of such approach6-8; of course, those are based on the limited currently available data on potential risks caused by population-based strategy application. In the countries which are expected to benefit from the strategy most this would mean offering eradication treatment to the majority of population, e.g. in Latvia this would require antibiotic treatment to 79% of population9, and would change the current status of low antibiotic consumption country to an average consumption country. This could potentially result in adverse consequences unrelated to H.pylori. In a country with low H.pylori resistance to clarithromycin (such as Latvia), the recommended H.pylori 1st-line standard eradication regimen would consist of clarithromycin in combination to either amoxicillin or metronidazole, and a proton-pump inhibitor; the duration would be at least 10 days10. Areas with higher H.pylori resistance to clarithromycin would require more aggressive treatment modalities, e.g. by including levofloxacin to the regimen. The potential adverse events caused by such therapies to microbiome are insufficiently studied; the expert opinion that are developing guidelines is generally limited to the consideration that 1-2 week single-time antibiotic treatment would be a minor and fully reversible intervention upon microbiome since according to the available statistic in many countries the average antibiotic intake rates one or several treatments per year in a subject. However, from the limited data available, there is a clear message that even one-week treatment with macrolides (clarithromycin, azithromycin) is increasing the resistance of macrolide-resistant S.pneumoniae in pharynx in healthy volunteers; this difference was statistically significant within a period of 180 days11. Thus the aim of this project proposal is to evaluate the long term effects of H.pylori eradication on Gastro intestinal tract (GIT) microbiome, evaluate its effects on abundance and prevalence of extended-spectrum beta-lactamases (ESBL) coding genes and develop cost effective ESBL screening test prototype. To reach this goal during within the scope of this project fecal samples will be collected of patients that are undergoing the eradication therapy at two time points: before the start eradication and one year after the final treatment. In order to decrease the number of feces samples that patients shall have to acquire and standardize the sampling procedure, participants should explore the possibility to employ fecal occult blood test containers. Since there are no conclusively positive reports on employment of these devices in such analyses within the scope of this research participants shall also develop an appropriate DNA extraction methodology. Further, employing Next generation sequencing based analyses participants shall determine the microbial community composition within each sample and through comparison of data from each time point participants should be able to estimate the long term effects of eradication therapy. Following this analysis participants should perform the identification of ESBL repertoire within each sample and also evaluation their abundances abundance. Similarly as in the case of community analysis the comparison of both time points shall allow to estimate the effects of eradication therapy. Following the acquisition of the data participants shall outsource the creation of ESBL screening test prototype, which shall be based on employment micro-bead technology.

Official Title
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Long Term Effects of H.Pylori Eradication on Microbiome and Adverse Events

Conditions
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Human Microbiome

Intervention / Treatment
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* Other: Microbiome Diversity detection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals with established H.pylori infection Individuals in whom H.pylori eradication therapy is indicated according to the international or national recommendations Individuals who agree to undergo H.pylori eradication therapy Exclusion Criteria: Severely sick patients Individuals in whom H.pylori eradication therapy is contra-indicated due to any reasons Individuals unable or unwilling to provide a sample for microbiome testing

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Comparison between intervention groups and the group without intervention will be made
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: H.pylori Eradication index<br>Microbiome diversity detection in Participants Positive for H.pylori and undergoing Eradication therapy with Clarythromycin-containing eradication therapy | Other: Microbiome Diversity detection<br>* detection of microbiome composition and detection of specific mutations in genes conferring resistance to antibiotics<br>|
| No Intervention: Control<br>Microbiome diversity detection in Participants Without H.pylori Eradication therapy | |
| Active Comparator: H.pylori Eradication comparative<br>Microbiome diversity detection in Participants Positive for H.pylori and undergoing Eradication therapy with high dose Amoxicillin and bismuth containing eradication therapy | Other: Microbiome Diversity detection<br>* detection of microbiome composition and detection of specific mutations in genes conferring resistance to antibiotics<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effects of various H.pylori eradication regimens upon the gut microbiome | Gut microbiome | 6-36 months between the initial and the follow-up sample | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effects of various H.pylori eradication regimens upon adverse events in short term | Telephone interview following eradication | 21-28 days following the expected starting data of the treatmennt | 
| Effectiveness of various H.pylori eradication regimens | Effectiveness of H.pylori eradication will be evaluated by 13C urea breath test (UBT). Initially, 14 day clarythromycin-containing triple therapy will be compared to 14-day amoxicillin and bismuth containing therapy | 1-12 months following eradication therapy | 
| Effects of various H.pylori eradication regimens upon the pharyngeal microbiome | Pharyngeal microbiome before and after H.pylori eradication will be compared | 6-36 months between the initial and the follow-up sample | 
| Effects of various H.pylori eradication regimens upon long-lasting adverse events | Adverse evens like symptoms of gastro-esophageal reflux disease, obesity, functional bowel disease will be addressed | 6 months - 10 years following eradication | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GIT, Helicobacter pylori, Eradication, Microbiome, ESBL