Aging
Conditions
Keywords
Fecal Microbiome Transplant, Aging, Young-donor FMT, Microbiome Rejuvenating Diet, Inflammaging, Gut Microbiome, DunedinPACE
Brief summary
The purpose of this study is to test whether young-donor fecal microbiome transplantation (FMT) and a fermented, plant-rich high-fiber, microbiome rejuvenating diet (MRD) reduce inflammatory and biological aging markers. Participants (≥40 years) will be randomized (1:1:1:1) for 8 weeks with 4-week follow-up to: (A) diet alone, (B) FMT alone, (C) diet + FMT, or (D) Placebo FMT. We will use rigorously screened young and healthy FMT donors and encapsulated delivery. Outcomes include change from baseline to end of dietary intervention (week 8) in markers of aging and inflammation. Secondary outcomes include defining microbiome engraftment/diversity/function, key metabolites, diet adherence, and quality-of-life.
Detailed description
For this study, the research participant will receive a once daily oral dose of healthy young FMT and diet modification to increase fiber and fermented food consumption. Throughout the study's duration, the participant will provide stool, blood and urine samples as well as a series of health questionnaires to track the impact of the intervention. \*PROTOCOL OVERVIEW\* The study will begin with the selection of possible participants through the samples collected through the Stanford Microbiome Bank (IRB 85544), the participants identified will be contacted through the appropriate channels and asked to complete a short online questionnaire if interested in continuing with being a part of the protocol.After completing the questionnaire, those selected will be contacted via phone to schedule an in person appointment in the Clinical and Translational Research Unit (CTRU). During this appointment, the study team will obtain informed consent and one stool sample. Their initial stool sample will be sent outside Stanford for microbiome composition analysis which will determine if the participant is a good candidate for the protocol. After enrollment in the protocol, the participants will be randomized in a 1:1:1:1 ratio to one of four study arms: Placebo, placebo + diet, FMT no diet, or FMT + diet. Those randomized to one of the FMT groups will be instructed to take a single oral dose of young FMT (4 capsules) for two weeks, and those randomized to a diet arm will have an initial appointment with the study's dietitian to establish a microbiome rejuvenating diet (MRD) starting with a one week ramp up period and continued for a total of 8 weeks. The main factors incorporated into the MRD will be \ 3 servings/day fermented foods and ≥30-40 g/day or +20g fiber(plant-based whole food), 5g of resistant starch supplements and 5g of psyllium husk. Throughout their enrollment in the protocol, the participants will provide stool samples weekly for analysis and complete general health and lifestyle questionnaires to assess protocol adherence and any changes in their health status. On weeks 0, 2, 4, 8 & 12 participants will be asked to give a blood, urine and stool sample for further analysis and to complete a Nutrition Data System for Research (NDSR) questionnaire; stool is additionally collected at Week 6. All patient samples will be coded and stored in Stanford facilities for further processing.
Interventions
DRUGFecal Microbiota Transplant Capsules
Each dose (4 capsules) will be taken daily in the morning on an empty stomach. Clear liquids are allowed and regular breakfast can follow one hour later. If the dose is skipped, the missed dose should be skipped and the standard 4-capsule dose resumed the following morning; doses must not be doubled. There should be no solid food at the time of ingestion , solid food should be avoided at least 4 hours prior to ingestion of capsules, however, liquid diet is always allowed and a full glass of water should be taken after every dose ingestion. The treatment will be administered daily for 2 weeks.
BEHAVIORALMicrobiome Rejuvenating Diet
Fiber intake: participants will be instructed to increase their fiber intake to \>30/40g or +20g per day . There will be a 1 week ramp-up period in which participants will increase their intake progressively. Detailed instructions will be provided to include a variety of fiber sources (legumes, seeds, whole grains, nuts, vegetables, and fruits). Participants will also be instructed to include 5g of resistant starch supplements and 5g of psyllium husk in their diet. Fermented food intake: participants will be instructed to add at least 3 portions of fermented food into their daily diet. There will be a 1 week ramp-up period in which participants will increase their intake progressively and maintain a high level of consumption for the following 8 weeks. Detailed instructions will be provided to include a variety of fermented foods (fermented dairy products, fermented vegetables, fermented non-alcoholic drinks, etc.).
Participants will receive a once daily dose (4 pills) of inactive pills that are identical in size, shape, color, taste and feel to the active FMT pills
Sponsors
Stanford University
University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Caregiver)
Masking description
In addition to the parties designated in the structured masking fields, the study biostatistician and data analysts will remain masked to treatment allocation until database lock. Laboratory personnel processing and analyzing biological samples (e.g., stool, blood) will be masked to arm assignment.
Intervention model description
Study will consist of 4 arms Arm 1: FMT + Diet Arm 2: FMT Arm 3: Placebo + Diet Arm 4: Placebo
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Able and willing to provide written informed consent prior to completion of any study procedures. * Age ≥40 years at the time of consent. * In generally good health, as determined by medical history, medication review, and investigator assessment. * Willing and able to comply with all study procedures, assessments, and study-related restrictions for the duration of participation. * Willing to adhere to the study's lifestyle considerations for the duration of the study (maintain usual diet unless assigned to the diet arm; maintain usual physical activity; avoid non-essential systemic antibiotics; avoid probiotic/prebiotic/synbiotic supplements). * Willing and able to attend all required in-person study visits at Stanford University and complete remote assessments, if applicable.
Exclusion criteria
* Moderate or severe irritable bowel syndrome (IBS). * Current or prior diagnosis of inflammatory bowel disease (IBD), including ulcerative colitis, Crohn's disease, or indeterminate colitis. * Active gastrointestinal disease, including infectious gastroenteritis, colitis, gastritis, recurrent Clostridioides difficile infection, untreated Helicobacter pylori infection, or clinically significant malabsorption disorders (e.g., celiac disease). * Major gastrointestinal surgery within the past 5 years (excluding cholecystectomy and appendectomy), or history of major bowel resection at any time. * Body mass index (BMI) ≥40 kg/m². * Diabetes mellitus. * Hyperthyroidism or uncontrolled hypothyroidism. * Clinically significant renal disease. * Clinically significant hepatic disease or significant liver enzyme abnormalities. * Clinically significant cardiovascular disease. * Autoimmune or systemic inflammatory disease. * Current malignancy or history of malignancy within the past 5 years, excluding adequately treated non-melanoma skin cancer. * Current use of immunosuppressive medications, including systemic corticosteroids, thiopurines, methotrexate, calcineurin inhibitors, biologic agents, or other immunosuppressive therapies. * Receipt of fecal microbiota transplantation (FMT) within the previous 12 months. * Use of systemic antibiotic therapy within 30 days prior to enrollment or anticipated antibiotic use during the study period. * Use of probiotic supplements, prebiotic supplements, synbiotics, or live microbial therapeutics within 30 days prior to enrollment. * Current use or use within the previous 6 months of medications prescribed primarily for weight loss. * Current use of medications known to significantly affect body weight unless the medication and dose have remained stable for at least 6 months prior to enrollment. * Neurodevelopmental, psychiatric, neurological, or neuromuscular disorders that, in the opinion of the investigator, may impair the participant's ability to provide informed consent, comply with study procedures, or complete study assessments. * Current diagnosis of schizophrenia, bipolar disorder, or other severe psychiatric illness that may interfere with study participation. * Current substance use disorder. * Current smoking or nicotine use, including cigarettes, cigars, electronic cigarettes, vaping products, or nicotine replacement therapy. * History of anaphylaxis or severe allergic reaction to study-related dietary components. * Planned major dietary change, initiation of a structured weight-loss program, or initiation of a specialized therapeutic diet during the study period. * Concurrent participation in another interventional clinical trial. * Any other medical, psychiatric, or social condition that, in the opinion of the investigator, could compromise participant safety, study compliance, or interpretation of study outcomes. * Pregnancy or breastfeeding * Known immunodeficiency state, including HIV infection, primary immunodeficiency, active hematologic or solid-organ malignancy under treatment, or other clinically significant immunocompromise, independent of medication use. * Dysphagia or any condition impairing the ability to swallow oral capsules.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference in DunedinPACE | Baseline and 8 weeks | Difference in the 8-week change from baseline in DunedinPACE among the four randomized groups (FMT + MRD, FMT alone, MRD + placebo FMT, and placebo FMT), assessed by DNA methylation analysis of whole blood. DunedinPACE is a DNA methylation biomarker that quantifies the pace of biological aging, reported as a rate of biological aging per chronological year; higher values indicate a faster pace of aging and lower values indicate a slower pace. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Difference in Epigenetic Age | Baseline and 8 weeks | Difference in the 8-week change from baseline in epigenetic age among the four randomized groups (FMT + MRD, FMT alone, MRD + placebo FMT, and placebo FMT), assessed by epigenetic clocks (PC GrimAge, PC PhenoAge, and Horvath). |
| Difference in Telomere Length | Baseline and 8 weeks | Difference in the 8-week change from baseline in telomere length among the four randomized groups (FMT + MRD, FMT alone, MRD + placebo FMT, and placebo FMT), assessed by DNA methylation-based estimation. |
| Difference in Gut Microbial Alpha Diversity | Baseline and 8 weeks | Difference in the 8-week change from baseline in gut microbial alpha diversity among the four randomized groups (FMT + MRD, FMT alone, MRD + placebo FMT, and placebo FMT), assessed by the Shannon diversity index from shotgun metagenomic sequencing of stool. |
| Difference in Interleukin-6 (IL-6) | Baseline and 8 weeks | Difference in the 8-week change from baseline in Interleukin-6 (IL-6) among the four randomized groups (FMT + MRD, FMT alone, MRD + placebo FMT, and placebo FMT). |
| Difference in High-Sensitivity C-Reactive Protein (hsCRP) | Baseline and 8 weeks | Difference in the 8-week change from baseline in High-Sensitivity C-Reactive Protein (hsCRP) among the four randomized groups (FMT + MRD, FMT alone, MRD + placebo FMT, and placebo FMT). |
| Difference in Growth Differentiation Factor-15 (GDF-15) | Baseline and 8 weeks | Difference in the 8-week change from baseline in Growth Differentiation Factor-15 (GDF-15) among the four randomized groups (FMT + MRD, FMT alone, MRD + placebo FMT, and placebo FMT). |
| Difference in Cytokines and Inflammatory Proteins | Baseline and 8 weeks | Difference in the 8-week change from baseline in a panel of cytokines and inflammatory proteins, including CC- and CXC-motif chemokines (CCL and CXCL), among the four randomized groups (FMT + MRD, FMT alone, MRD + placebo FMT, and placebo FMT), assessed by the NUcleic acid Linked Immuno-Sandwich Assay (NULISA™) and Olink proximity extension assay. |
| Difference in Gut Microbiome Composition | Baseline and 8 weeks | Difference in the 8-week change from baseline in gut microbiome composition among the four randomized groups (FMT + MRD, FMT alone, MRD + placebo FMT, and placebo FMT), assessed by shotgun metagenomic sequencing of stool. |
| Difference in Gut Microbial Beta Diversity | Baseline and 8 weeks | Difference in the 8-week change from baseline in gut microbial beta diversity among the four randomized groups (FMT + MRD, FMT alone, MRD + placebo FMT, and placebo FMT), assessed by between-sample dissimilarity from shotgun metagenomic sequencing of stool. |
| Difference in Gut Microbiome Functional Capacity | Baseline and 8 weeks | Difference in the 8-week change from baseline in gut microbiome functional capacity among the four randomized groups (FMT + MRD, FMT alone, MRD + placebo FMT, and placebo FMT), assessed by functional pathway and gene content profiling from shotgun metagenomic sequencing of stool. |
| Engraftment of Donor-Derived Microbial Strains | Baseline, 8 weeks, and 12 weeks | Detection, relative abundance, and persistence of donor-derived microbial strains in recipient stool in the FMT-treated groups compared with the placebo FMT groups, assessed by shotgun metagenomic sequencing. |
| Difference in Metabolomic Profiles | Baseline and 8 weeks | Difference in the 8-week change from baseline in metabolomic profiles, including short-chain fatty acids, secondary bile acids, and aryllactates, among the four randomized groups (FMT + MRD, FMT alone, MRD + placebo FMT, and placebo FMT), assessed by targeted and untargeted metabolomics of stool and blood. |
| Difference in Grip Strength | Baseline and 8 weeks | Difference in the 8-week change from baseline in grip strength among the four randomized groups (FMT + MRD, FMT alone, MRD + placebo FMT, and placebo FMT), assessed by hand dynamometry and measured in kilograms. Higher values indicate greater muscle strength. |
| Difference in Timed Up and Go (TUG) | Baseline and 8 weeks | Difference in the 8-week change from baseline in the Timed Up and Go (TUG) test among the four randomized groups (FMT + MRD, FMT alone, MRD + placebo FMT, and placebo FMT), measured in seconds. Lower values indicate better mobility. |
| Difference in Cognitive Function, Mini-Mental State Examination (MMSE) | Baseline and 8 weeks | Difference in the 8-week change from baseline in cognitive function among the four randomized groups (FMT + MRD, FMT alone, MRD + placebo FMT, and placebo FMT), assessed by the Mini-Mental State Examination (MMSE). Scores range from 0 to 30; higher scores indicate better cognitive function. |
| Difference in Cognitive Function, Montreal Cognitive Assessment (MoCA) | Baseline and 8 weeks | Difference in the 8-week change from baseline in cognitive function among the four randomized groups (FMT + MRD, FMT alone, MRD + placebo FMT, and placebo FMT), assessed by the Montreal Cognitive Assessment (MoCA). Scores range from 0 to 30; higher scores indicate better cognitive function. |
| Difference in Physical Function | Baseline and 8 weeks | Difference in the 8-week change from baseline in self-reported physical function among the four randomized groups (FMT + MRD, FMT alone, MRD + placebo FMT, and placebo FMT), assessed by the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function short form. Scores are reported as T-scores standardized to a population mean of 50 and standard deviation of 10; higher scores indicate better physical function. |
| Difference in Fatigue | Baseline and 8 weeks | Difference in the 8-week change from baseline in self-reported fatigue among the four randomized groups (FMT + MRD, FMT alone, MRD + placebo FMT, and placebo FMT), assessed by the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue short form. Scores are reported as T-scores standardized to a population mean of 50 and standard deviation of 10; higher scores indicate greater fatigue. |
| Difference in Frailty | Baseline and 8 weeks | Difference in the 8-week change from baseline in frailty among the four randomized groups (FMT + MRD, FMT alone, MRD + placebo FMT, and placebo FMT), assessed by the FRAIL scale. Scores range from 0 to 5; higher scores indicate greater frailty. |
| Difference in Weight | Baseline and 8 weeks | Difference in the 8-week change from baseline in weight among the four randomized groups (FMT + MRD, FMT alone, MRD + placebo FMT, and placebo FMT), measured in kilograms. |
| Difference in Body Mass Index (BMI) | Baseline and 8 weeks | Difference in the 8-week change from baseline in Body Mass Index (BMI) among the four randomized groups (FMT + MRD, FMT alone, MRD + placebo FMT, and placebo FMT), measured in kilograms per square meter. |
| Difference in Systolic Blood Pressure | Baseline and 8 weeks | Difference in the 8-week change from baseline in systolic blood pressure among the four randomized groups (FMT + MRD, FMT alone, MRD + placebo FMT, and placebo FMT), measured in millimeters of mercury. |
| Difference in Diastolic Blood Pressure | Baseline and 8 weeks | Difference in the 8-week change from baseline in diastolic blood pressure among the four randomized groups (FMT + MRD, FMT alone, MRD + placebo FMT, and placebo FMT), measured in millimeters of mercury. |
| Difference in Dietary Fiber Intake | Baseline and 8 weeks | Difference in the 8-week change from baseline in total dietary fiber intake among the four randomized groups (FMT + MRD, FMT alone, MRD + placebo FMT, and placebo FMT), measured in grams per day and assessed by 24-hour dietary recalls using the Nutrition Data System for Research (NDSR). |
| Difference in Fermented Food Intake | Baseline and 8 weeks | Difference in the 8-week change from baseline in fermented food intake among the four randomized groups (FMT + MRD, FMT alone, MRD + placebo FMT, and placebo FMT), measured in servings per day and assessed by 24-hour dietary recalls using the Nutrition Data System for Research (NDSR). |
| Incidence of Treatment-Emergent Adverse Events | Informed consent through 12 weeks | Number of participants with treatment-emergent adverse events and serious adverse events among the four randomized groups (FMT + MRD, FMT alone, MRD + placebo FMT, and placebo FMT), with severity graded by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and relatedness assessed by the investigator. |
| Difference in Gastrointestinal and Systemic Tolerability Symptom Scores | Baseline and 8 weeks | Difference in the 8-week change from baseline in gastrointestinal and systemic tolerability symptom scores among the four randomized groups (FMT + MRD, FMT alone, MRD + placebo FMT, and placebo FMT), assessed by the weekly study tolerability questionnaire. |
Countries
United States
Contacts
CONTACTSean P Spencer, MD PhD
CONTACTRoujheen Sabetan, MPH
Outcome results
None listed