Metabolic and Metagenomic Effects of Intestinal Microbiome Repopulation in Unexplained Atherosclerosis

Official title

Metabolic and Metagenomic Effects of Repopulation of the Intestinal Microbiome in Patients with Severe Unexplained Atherosclerosis

Overview

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.

Interventions

• Biological Fecal microbial transplant
  Fecal microbial transplant

Primary outcome measures

• Changes in plasma levels of metabolites of the intestinal microbiome [Time frame: 6 weeks and 12 months]
• Metagenomic changes of the intestinal microbiome [Time frame: 6 weeks and 12 months]

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).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Prevention

Study locations

Canada · 1 center

• Stroke Prevention & Atherosclerosis Research Centre, Robarts Research Institute — London

Publications

• Bogiatzi C, Gloor G, Allen-Vercoe E, Reid G, Wong RG, Urquhart BL, Dinculescu V, Ruetz KN, Velenosi TJ, Pignanelli M, Spence JD. Metabolic products of the intestinal microbiome and extremes of atherosclerosis. Atherosclerosis. 2018 Jun;273:91-97. doi: 10.1016/j.atherosclerosis.2018.04.015. Epub 2018 Apr 17. PMID 29702430

Identifiers

NCT: NCT04410003 · 115450

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗