Metabolic and Metagenomic Effects of Intestinal Microbiome Repopulation in Unexplained Atherosclerosis

Study Overview
=================
Brief Summary
-----------------
Patients with unexplained atherosclerosis (severe atherosclerosis not explained by traditional risk factors) will receive fecal microbial transplants (FMT) from patients with a Protected phenotype (patients who have high levels of risk factors but little or no carotid atherosclerosis). The objective is to determine what changes in the intestinal microbiome are associated with a decline in plasma levels of toxic metabolites of the itnestinal microbiome such as trimethylamine N-oxide (TMAO) and p-cresylsulfate. The intention is to develop an ecosystem therapeutic of cultured bacteria to treat atherosclerosis.

Detailed Description
-----------------
100 patients with Unexplained Atherosclerosis, and 5 donors with the protected phenotype will be recruited; there will be extensive microbial, viral and parasitic screening of the donors. Recipients will be randomized to receive capsules of stool from the donors, or cellulose placebo. Recipients will take cloxacillin 500 mg 4 times daily for 5 days before the FMT, and will undergo purging with an electrolyte solution, (PegLyte) the day before the FMT. Metagenomic analysis of the recipient stool will be performed before FMT, 6 weeks later and after 12 months.Plasma levels of toxic intestinal metabolites will be measured before FMT, at 6 weeks and 12 months after FMT; the levels to be measured will be TMAO, P-cresylsulfate, Hippuric acid. Indoxyl sulfate, P-cresyl glucuronide. Phenyl acetyl glutamine, and Phenyl sulfate. The investigators will analyze the metagenomic changes in the intestinal microbiome of recipients that are associated with decline in the plasma levels of the metabolic products of the intestinal microbiome to identify candidate bacteria for an ecosystem therapeutic for atherosclerosis. Based on previous experience of designing such a therapeutic for clostridium difficile, it is anticipated that   40 bacterial species would be needed.

Official Title
-----------------
Metabolic and Metagenomic Effects of Repopulation of the Intestinal Microbiome in Patients With Severe Unexplained Atherosclerosis

Conditions
-----------------
Atherosclerosis, Intestinal Microbiome

Intervention / Treatment
-----------------
* Biological: Fecal microbial transplant


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Severe atherosclerosis, with total plaque area in the top quartile (>119 mm2), not explained by traditional risk factors in linear regression (residual score >= 2) Exclusion Criteria: Excluded will be patients unwilling/unable to provide informed consent, unwilling to ingest the stool capsules at baseline, patients with moderate to severe renal failure (eGFR<50), immunosuppressed patients, and patients with cancer, unstable angina, planned carotid revascularization or other conditions that might be expected to reduce their survival to < 1 year (including age >80).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

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

Accepts Healthy Volunteers
-----------------
No

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

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized controlled trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Cellulose capsules, cloxacillin, electrolyte purgative (Peglyte) | Biological: Fecal microbial transplant<br>* Fecal microbial transplant<br>|
| Active Comparator: Active<br>Capsules of stool from Protected donors, cloxacillin, electrolyte purgative (Peglyte) | Biological: Fecal microbial transplant<br>* Fecal microbial transplant<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in plasma levels of metabolites of the intestinal microbiome | The primary outcome is changes in plasma levels of trimethylamine N-oxide and p-cresylsulfate | 6 weeks and 12 months | 
| Metagenomic changes of the intestinal microbiome | Metagenomic changes in the stool of transplant recipients will be analyzed to determine what changes in the intestinal bacteria are associated with changes in the plasma levels of the intestinal metabolites. | 6 weeks and 12 months |