The RAMP Study - Rejuvenation of the Aging Microbiota With Prebiotics

Study Overview
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Brief Summary
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An individual's immune and metabolic status is coupled to consumed carbohydrates. Complex carbohydrates that are not digested by human enzymes may influence host biology by impacting microbiota composition and function, or act in a yet-unknown microbiota-independent manner. Prebiotics offer a promising safe route to influence host health, possibly via the microbiota. However, it remains largely unknown to what extent immune function and metabolism can be modulated by prebiotics.

Detailed Description
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The objective of this study is to define the impact of a prebiotic supplement on microbiome, immune system, and metabolic status in older adults. This study will determine the degree to which a prebiotic supplement can 1) regulate immune status and function including reducing chronic, systemic inflammation as assessed by high dimensional immune profiling, 2) alter microbiota composition and function, 3) impact the microbiota metabolites-potential normalizers of metabolic and immune dysfunction, and 4) alter metabolic markers.

Official Title
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Impact of a Prebiotic Supplement on Microbiome, Immune System, and Metabolic Status of Older Adults

Conditions
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Microbiome, Immune Function, Inflammation

Intervention / Treatment
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* Dietary Supplement: Placebo
* Dietary Supplement: Prebiotic supplement


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 60 years old and older Otherwise, healthy subjects willing and able to provide blood as well as stool specimens Must be able to provide signed and dated informed consent and be willing to follow protocol Exclusion Criteria: Body Mass Index >= 40 LDL-C > 190 mg/dL Systolic Blood Pressure >160 mmHg OR Diastolic Blood Pressure > 90 mmHg Use of any of the following drugs/supplements within the last 2 months: systemic antibiotics, antifungals, antivirals or antiparasitics (intravenous, intramuscular, or oral); corticosteroids (intravenous, intramuscular, oral, nasal or inhaled) cytokines methotrexate or immunosuppressive cytotoxic agents metformin proton pump inhibitors (PPIs) Regular use of any of the following medications: regular dose aspirin (>81mg/day) opiate pain medication Use of large doses of commercial probiotics consumed (greater than or equal to 10-8 cfu or organisms per day) - includes tablets, capsules, lozenges, chewing gum or powders in which probiotic is a primary component. Ordinary dietary components such as fermented beverages/milks, yogurts, foods do not apply. Acute disease at the time of enrollment. Acute disease is defined as the presence of a moderate or severe illness with or without fever. Examples include flu or gastroenteritis. Defer sampling until subject recover. Chronic, clinically significant, unstable (unresolved, requiring on-going changes to medical management or medication) pulmonary, cardiovascular, gastrointestinal, hepatic or renal functional abnormality, as determined by medical history. Type 2 diabetes, type 1 diabetes, and dialysis will be excluded. History of active uncontrolled gastrointestinal disorders or diseases including: inflammatory bowel disease (IBD) including ulcerative colitis (mild-moderate-severe), Crohn's disease (mild-moderate-severe), or indeterminate colitis; irritable bowel syndrome (IBS) (moderate-severe); persistent, infectious gastroenteritis, colitis or gastritis, persistent or chronic diarrhea of unknown etiology, Clostridium difficile infection (recurrent) or Helicobacter pylori infection (untreated). History of active cancer in the past 3 years except for squamous or basal cell carcinomas of the skin that have been medically managed by local excision. Unstable dietary history as defined by major changes in diet during the previous month, where the subject has eliminated or significantly increased a major food group in the diet. Recent history of chronic excessive alcohol consumption defined as more than five 1.5-ounce servings of 80 proof distilled spirits, five 12-ounce servings of beer or five 5-ounce servings of wine per day; or > 14 drinks/week. Positive test for HIV, HBV or HCV. Any confirmed or suspected condition/state of immunosuppression or immunodeficiency (primary or acquired) including HIV infection. Surgery of the GI tract, with the exception of cholecystectomy and appendectomy, in the past five years. Any major bowel resection at any time. Regular/frequent use of smoking or chewing tobacco, e-cigarettes, cigars or other nicotine-containing products. Any confirmed or suspected autoimmune disease. Examples include multiple sclerosis and Graves disease. Veganism. Dairy allergies.

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo group<br>Placebo product | Dietary Supplement: Placebo<br>* Placebo product<br>|
| Experimental: Prebiotic Supplement, low dose<br> | Dietary Supplement: Prebiotic supplement<br>* Prebiotic supplement<br>|
| Experimental: Prebiotic Supplement, high dose<br> | Dietary Supplement: Prebiotic supplement<br>* Prebiotic supplement<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune status and function | Change from baseline in Cytokine Response Score (CRS) at 6 weeks. The CRS is a single composite measure of cell-type specific activation of signaling pathways from ex vivo cytokine stimulation of blood samples. This provides a measure of immune response capacity which may be an indicator of immune fitness. The CRS will be calculated as described in Shen-Orr et al, Cell Systems, 2016. The CRS is the sum of 15 age-associated normalized cytokine responses identified in Shen-Orr et. al: In CD8+ T cells: IFNα pSTAT1, pSTAT3, pSTAT5; IL-6 pSTAT1, pSTAT3, pSTAT5; IFNγ pSTAT1; IL-21 pSTAT1; In CD4+ T cells: IFNα pSTAT5; IL-6 pSTAT5; In B cells: IFNα pSTAT1; in monocytes: IL-10 pSTAT3; IFNγ pSTAT3; IFNα pSTAT3; IL-6 pSTAT3. Each feature is calculated as the fold change of the protein in the stimulated condition relative to its level in the unstimulated condition. That value is then normalized to the feature's range: normalized = (x - xmin)/xmax. The 15 normalized values are summed for the CRS. | Baseline and 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Microbiota composition | Change from baseline in alpha diversity at 6 weeks. We will be using number of observed sequence variants (species) determined by standard 16S rRNA amplicon sequencing (V3-V5 region followed by DADA2 to define error-corrected sequence variants) as our primary metric of alpha diversity. Higher alpha diversity is better. The units are the # of sequence variants. | Baseline and 6 weeks | 
| Microbiota function | Change from baseline in composite of short-chain fatty acids (SCFA) concentration (ug/g stool: acetate + propionate + butyrate) at 6 weeks. | Baseline and 6 weeks | 
| Weight | Change from Baseline in weight at 6 weeks. | Baseline and 6 weeks | 
| Waist Circumference | Change from Baseline in waist circumference at 6 weeks. | Baseline and 6 weeks | 
| Blood pressure | Change from Baseline in blood pressure at 6 weeks. | Baseline and 6 weeks | 
| Total Cholesterol | Change from Baseline in total cholesterol at 6 weeks. | Baseline and 6 weeks | 
| Triglycerides | Change from Baseline in triglycerides at 6 weeks. | Baseline and 6 weeks | 
| HDL-cholesterol | Change from Baseline in HDL-cholesterol at 6 weeks. | Baseline and 6 weeks | 
| Fasting Glucose | Change from Baseline in fasting glucose at 6 weeks. | Baseline and 6 weeks | 
| Fasting Insulin | Change from Baseline in fasting insulin at 6 weeks. | Baseline and 6 weeks |