The RAMP Study - Rejuvenation of the Aging Microbiota With Prebiotics

Not Applicable

Completed

• Conditions: Inflammation; Immune Function; Microbiome
• Interventions: Dietary Supplement: Prebiotic supplement; Dietary Supplement: Placebo

• Registration Number: NCT03690999
• Lead Sponsor: Stanford University

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2018-09-17
• Study First Submitted QC: 2018-09-28
• Study First Posted: 2018-10-01
• Study Start: 2019-03-14
• Primary Completion: 2020-11-13
• Study Completion: 2020-12-14
• Status Verified: 2023-02
• Last Update Submitted: 2023-02-15
• Last Update Posted: 2023-02-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 98

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Prebiotic Supplement, low dose	Prebiotic supplement	-
Prebiotic Supplement, high dose	Prebiotic supplement	-
Placebo group	Placebo	Placebo product

Primary Outcome Measures

Name	Time	Method
Immune status and function	Baseline and 6 weeks	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.

Secondary Outcome Measures

Name	Time	Method
Fasting Insulin	Baseline and 6 weeks	Change from Baseline in fasting insulin at 6 weeks.
HDL-cholesterol	Baseline and 6 weeks	Change from Baseline in HDL-cholesterol at 6 weeks.
Microbiota composition	Baseline and 6 weeks	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.
Microbiota function	Baseline and 6 weeks	Change from baseline in composite of short-chain fatty acids (SCFA) concentration (ug/g stool: acetate + propionate + butyrate) at 6 weeks.
Waist Circumference	Baseline and 6 weeks	Change from Baseline in waist circumference at 6 weeks.
Fasting Glucose	Baseline and 6 weeks	Change from Baseline in fasting glucose at 6 weeks.
Weight	Baseline and 6 weeks	Change from Baseline in weight at 6 weeks.
Blood pressure	Baseline and 6 weeks	Change from Baseline in blood pressure at 6 weeks.
Total Cholesterol	Baseline and 6 weeks	Change from Baseline in total cholesterol at 6 weeks.
Triglycerides	Baseline and 6 weeks	Change from Baseline in triglycerides at 6 weeks.

Trial Locations

Locations (1)

Stanford University; 🇺🇸 Stanford, California, United States