Effect of Aspirin on Gut Microbiome

Study Overview
=================
Brief Summary
-----------------
Regular use of aspirin may reduce the incidence of colorectal cancer (CRC). However, it is unclear through which mechanism aspirin exerts its effect, in whom it decreases CRC risk and in whom it causes side effects. Recently, the imbalanced gut microbiome was linked to inflammation and CRC risk. The main hypothesis for this study is that aspirin may decrease CRC risk via targeting the gut microbiome. The study will be a randomized placebo-controlled double-blinded design, recruiting 50 healthy subjects, 50-75 years old, from the PRospective Evaluation of SEPTin 9 (PRESEPT) cohort living in the greater Twin Cities area, who will receive either aspirin or placebo for 6 weeks.

Detailed Description
-----------------
The pilot study will evaluate the feasibility of conducting a large randomized trial and estimate the effects of aspirin on the gut microbiome. The study will recruit 50 healthy subjects, 50-75 years old, from the PRospective Evaluation of SEPTin 9 (PRESEPT) cohort living in the greater Twin Cities area. The Primary Aim is to estimate the impact of a 3- and 6-week intake of once daily 325 mg aspirin on the composition of the gut microbiome using a randomized placebo-controlled double-blinded design, i.e. examine the change of microbiome over time within and between the subjects. The hypothesis for this aim is that in the aspirin arm versus the placebo arm, gut microbiome composition will shift towards a lower proportion of pro-inflammatory, CRC-predisposing bacteria (e.g. Fusobacteria) and higher proportion of anti-inflammatory, CRC-protective bacteria (e.g. butyrate-producing bacteria). The Secondary Aims are to examine the correlation between the aspirin-related changes in microbiome profile with the levels of circulating inflammatory biomarkers in urine and plasma. Within-individual and between-arm differences in microbiome composition will be compared after 3 and 6 weeks of aspirin intake. Also, the microbiome composition will be compared after 3-week and 6-week wash-out periods to test whether these periods are sufficient to restore gut microbiome composition to a pre-treatment level. This study will inform future crossover randomized studies focusing on CRC preventive interventions that will enable clinicians to identify optimal candidates for aspirin therapy for the purposes of CRC prevention using this accessible and cheap drug.

Official Title
-----------------
Pilot Trial to Examine the Effect of Aspirin on the Gut Microbiome

Conditions
-----------------
Healthy

Intervention / Treatment
-----------------
* Drug: Aspirin
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy adults aged 50-75 years who reside within the greater Twin Cities area Capable and willing to comply with the entire study protocol Able to give voluntary written informed consent. Exclusion Criteria: Use of any aspirin-containing products or other non-steroidal anti-inflammatory drugs (NSAIDs) (≥ 2 days per week on a regular basis) Known hypersensitivity to NSAIDs Any active cancer, history of gastrointestinal cancer, or chronic disease such as peptic ulcer, irritable bowel syndrome, inflammatory bowel disease, intestinal malabsorption syndrome or other gastrointestinal disorder History of any coagulation, bleeding, or blood disorders (e.g. Anemia) History of stroke/ Transient Ischemic Attack Acute heart disease or history of heart attack, atrial fibrillation, or angina Diagnosis of dementia Use of antibiotics, antiplatelets (e.g. clopidogrel), or anticoagulants (e.g. warfarin) within the last 3 months. A complete list of contraindicated medications will be provided (Appendix A) Regular use of laxatives (e.g. Ex-lax, Dulcolax, Miralax) that may affect the microbiome ≥2 days a week (Appendix B) Body mass index (BMI) greater than or equal to 40 or less than or equal to 17 kg/m2 at screening visit Unexplained change in weight (>4.5 kg) within the past 6 months Major changes in eating habits within the past 3 months

Ages Eligible for Study
-----------------
Minimum Age: 50 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Aspirin<br>The subjects will receive 325 mg of aspirin once a day for 6 weeks followed by a 6-week washout. | Drug: Aspirin<br>* 325mg aspirin per day<br>* Other names: Acetylsalicylic acid (ASA);|
| Placebo Comparator: Placebo<br>The subjects will receive placebo once a day for 6 weeks followed by a 6-week washout. | Drug: Placebo<br>* placebo in matching capsules<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composition of the gut microbiome | Fecal microbial diversity and the prevalence of specific taxa associated with colorectal cancer (e.g. Fusobacteria, butyrate producing bacteria) will be estimated at each time point. The aspirin-related changes in the prevalence of each taxon will be assessed individually and also combined into a microbiome index (the abundance of protective taxa will be included as a negative value). | 5 times within 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urinary and blood inflammatory biomarkers | Each inflammatory biomarker (e.g. urinary metabolite of Prostaglandin E2 (PGE2)) will be measured before and after treatment with aspirin. Changes in inflammatory markers will be correlated to changes in the microbial diversity and the microbiome index. | 2 times within 6 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
aspirin, gut microbiome, inflammation, placebo, circulating biomarker