Effect of Gut Microbiome Intervention on Aging Via Oral FMT

Official title

Effect of Fecal Microbiota Transplantation on Aging and the Underlying Mechanism of Gut Microbiome Restoration: a Randomized Clinical Trial

Overview

A severe public health issue facing global population is aging. Increasing preclinical and clinical data indicate the contribution of gut microbiome on aging and aging-related diseases such as cardiovascular disease, Alzheimer Disease, and diabetes. Interventions on microbiota are developed including prebiotics, probiotics, and fecal microbial transplantation (FMT). FMT via oral capsules also advances in recent with limited safety concerns compared with invasive routes. A hypothesis is thus raised that gut microbiome intervention via oral FMT can be a potential safe approach to encourage healthy aging, with multiple aspects evaluated for clinical phenotype of frailty, anthropometric measurement, cognitive function, cardiovascular aging, physical function, living activity, hippocampal volume, telomere length, cognitive biomarkers, inflammatory biomarkers, altered microbial composition and metabolites.

Detailed description

Objective: To explore the effect, safety and underlying mechanisms of gut microbiome intervention via FMT on aging. Study Design: A multi-center, randomized, blinded, placebo-controlled pilot study. Data quality control and statistical analysis: The investigators have invited professional statistic analysts to assist analyzing data and a third party to supervise data quality. Ethics: The Ethics Committee of Fuwai Hospital approved this study. Informed consents before patient enrollment are required.

Interventions

• Biological FMT capsules
  FMT capsules containing extensively screened donor stool.
• Other Placebo capsules
  Placebo capsules that do not contain donor stool or any active drug.

Primary outcome measures

• Proportion of participants with reduced frailty score at week 96 follow-up [Time frame: week 96]

Secondary outcome measures (12)

• Proportion of participants with reduced frailty score at week 12 follow-up [Time frame: week 12]
• Proportion of participants with reduced frailty score at week 24 follow-up [Time frame: week 24]
• Proportion of participants with reduced frailty score at week 48 follow-up [Time frame: week 48]
• Proportion of participants with reduced frailty score at week 72 follow-up [Time frame: week 72]
• Change from baseline in Frailty score [Time frame: week 12, week 24, week 48, week 72, week 96, compared with baseline]
• Change from baseline in telomere length [Time frame: week 48, week 96]
• Change from baseline in Cognitive assessment via Mini Mental State Examination(MMSE) [Time frame: week 24, week 48, week 72, week 96, compared with baseline]
• Change from baseline in Cognitive assessment via Montreal Cognitive Assessment(MoCA) [Time frame: week 24, week 48, week 72, week 96, compared with baseline]
• Change from baseline in Hippocampal volumes [Time frame: week 48, week 96]
• Change from baseline in cognitive biomarkers [Time frame: week 12, week 24, week 48, week 72, week 96]
• Change from baseline in inflammatory biomarkers [Time frame: week 12, week 24, week 48, week 72, week 96]
• Change from baseline in Intestinal Microbiota Composition Pre- and Post-intervention via Metagenomic Analysis [Time frame: week 12, week 24, week 48, week 72, week 96]

Eligibility criteria

Inclusion criteria

• Age 70-85 years.
• Patients with informed consent after thorough explanation.

Exclusion criteria

• Participants of other clinical trials;
• Antibiotics or probiotics usage within last 4 weeks;
• Severe hepatic or renal diseases ((ALT >3 times the upper limit of normal value, or end stage renal disease on dialysis or eGFR <30 mL/min/1.73 m2, or serum creatinine >2.5 mg/dl \[>221 μmol/L\]);
• History of large atherosclerotic cerebral infarction or hemorrhagic stroke (not including lacunar infarction and transient ischemic attack \[TIA\]);
• Hospitalization for myocardial infarction within last 6 months; Coronary revascularization (PCI or CABG) within last 12 months; Planned for PCI or CABG in the next 6 months;
• NYHA class III-IV heart failure; Hospitalization for chronic heart failure exacerbation within last 6 months;
• Severe valvular diseases; Potential for surgery or percutaneous valve replacement within the study period;
• Dilated cardiomyopathy; Hypertrophic cardiomyopathy; Rheumatic heart disease; Congenital heart disease;
• History of dementia, Parkinson's disease, intracranial infection, intracranial tumor, schizophrenia, anxiety, depression;
• History of neurosurgical operation;
• History of gastrointestinal tumor, gastrointestinal surgery, inflammatory bowel disease; Hospitalization for peptic ulcer disease exacerbation within last 6 months or anticipated hospitalization for peptic ulcer disease the next 6 months;
• Hypertension with uncontrolled blood pressure ≥180/110mmHg;
• Diabetes Mellitus with uncontrolled fasting glucose level ≥200mg/dl (11.1mmol/L), or HbA1C>8%;
• Addicted to alcohol; Use of medication influencing cognitive function(i.e., antihistamine, antipsychotic);
• General anesthesia within last 3 months;
• Other severe diseases influencing the entry or survival of participants, such as malignant tumor or acquired immune deficiency syndrome, life expectancy <1 year;
• Impaired verbal communication who are incapable of providing their own informed consent, or incapable of self-care;
• Special diet influencing microbiota (i.e. vegetarian);
• Other conditions inappropriate for recruitment according to the investigators.

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

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

China · 6 centers

• Beijing Chao-yang Hospital, Capital Medical University — Beijing
• Beijing Hospital — Beijing
• Chinese People's Liberation Army (PLA) General Hospital — Beijing
• Xuanwu Hospital, Capital Medical University — Beijing
• Huadong Hospital Affiliated to Fudan University — Shanghai
• Zhejiang Hospital — Hangzhou

Publications

• Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, Seeman T, Tracy R, Kop WJ, Burke G, McBurnie MA; Cardiovascular Health Study Collaborative Research Group. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001 Mar;56(3):M146-56. doi: 10.1093/gerona/56.3.m146. PMID 11253156
• Ghosh TS, Rampelli S, Jeffery IB, Santoro A, Neto M, Capri M, Giampieri E, Jennings A, Candela M, Turroni S, Zoetendal EG, Hermes GDA, Elodie C, Meunier N, Brugere CM, Pujos-Guillot E, Berendsen AM, De Groot LCPGM, Feskins EJM, Kaluza J, Pietruszka B, Bielak MJ, Comte B, Maijo-Ferre M, Nicoletti C, De Vos WM, Fairweather-Tait S, Cassidy A, Brigidi P, Franceschi C, O'Toole PW. Mediterranean diet in PMID 32066625
• Ng TP, Feng L, Nyunt MS, Feng L, Niti M, Tan BY, Chan G, Khoo SA, Chan SM, Yap P, Yap KB. Nutritional, Physical, Cognitive, and Combination Interventions and Frailty Reversal Among Older Adults: A Randomized Controlled Trial. Am J Med. 2015 Nov;128(11):1225-1236.e1. doi: 10.1016/j.amjmed.2015.06.017. Epub 2015 Jul 6. PMID 26159634
• Mullish BH, Quraishi MN, Segal JP, McCune VL, Baxter M, Marsden GL, Moore DJ, Colville A, Bhala N, Iqbal TH, Settle C, Kontkowski G, Hart AL, Hawkey PM, Goldenberg SD, Williams HRT. The use of faecal microbiota transplant as treatment for recurrent or refractory Clostridium difficile infection and other potential indications: joint British Society of Gastroenterology (BSG) and Healthcare Infection PMID 30154172
• Kundu P, Lee HU, Garcia-Perez I, Tay EXY, Kim H, Faylon LE, Martin KA, Purbojati R, Drautz-Moses DI, Ghosh S, Nicholson JK, Schuster S, Holmes E, Pettersson S. Neurogenesis and prolongevity signaling in young germ-free mice transplanted with the gut microbiota of old mice. Sci Transl Med. 2019 Nov 13;11(518):eaau4760. doi: 10.1126/scitranslmed.aau4760. PMID 31723038

Identifiers

NCT: NCT05598112 · 2022-1784

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗