WHNRC (Western Human Nutrition Research Center) Fiber Intervention Study

Early Phase 1CompletedNCT04543877

USDA, Western Human Nutrition Research Center60 enrolled

Overview

The purpose of this study is to determine if adding dietary fiber, such as inulin, to a diet that does not have enough fiber would raise the levels of potentially beneficial bacteria, such as Bifidobacterium, in the gut. There is evidence to suggest that these microbes can affect gut health and immune response, including to vaccines. The investigators will examine how inulin in the diet (compared to the maltodextrin control) (1) causes changes in the composition and function of the gut microbes, (2) reduces gut inflammation and gut leakiness caused by the vaccine, (3) increases immune response to vaccination, and (4) changes the expression of important adhesion molecules on the surface of white blood cells. Intestinal and whole-body responses will be measured in all participants.

Inulin, a dietary fiber supplement, is known to increase gut levels of potentially beneficial bacteria, including Bifidobacterium that are indigenous to gut microbiomes. Our underlying hypothesis is that the commensal microbiome, including Bifidobacterium, in the proximal colon or distal ileum affects the environment of draining lymph nodes and can thus modulate immune responses, including to vaccines. In the current study, participants will consume 12 grams/day inulin or maltodextrin (control) for 3 weeks before the administration of the Ty21a typhoid fever vaccine, 1 week during the vaccine, and 1 week after the vaccine. Vaccine response will be measured by counting T cells and immunoglobulin G (IgG) or immunoglobulin A (IgA)-secreting plasma cells specific for Ty21a. Gut permeability will be measured at baseline, and before and after the vaccine administration. Systemic inflammation and immune activation will be measured by analyzing blood for markers of inflammation.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

DOUBLE

Enrollment

Eligibility

Sex: ALLMin age: 18 YearsMax age: 59 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: 1. Body Mass Index (BMI) 18.5 - 30.9 kg/m2 2. inadequate total dietary fiber intake defined as: * Females 18 - 30 years old, less than 28 g/day * Females 31 - 50 years old, less than 25 g/day * Females 51+ year old, less than 22 g/day * Males 18 - 30 years old, less than 34 g/day * Males 31 - 50 years old, less than 31 g/day * Males 51+ years old, less than 28 g/day Exclusion Criteria: 1. blood pressure greater than or equal to 140/90 mmHg 2. has HIV/AIDS or another disease that affects the immune system 3. has any kind of cancer 4. inability to lift 30 pounds with assistance (for transporting refrigerated stool containers) 5. decline to take an HIV blood test 6. pregnant or lactating women 7. refusal to take a pregnancy test 8. female subjects: refusal to use a method of birth control 1 week prior to the administration of the vaccine, 1 week during the vaccine, and 1 week after the vaccine 9. allergy to vaccine components, i.e. thimerosal and enteric-coated capsules 10. allergy to oral typhoid vaccine 11. use of anti-inflammatory medications, i.e. nonsteroidal anti-inflammatory drugs (NSAID), aspirin, 3 or more times per month 12. use of sulfonamides or antibiotics 3 months prior to the receipt of Ty21a vaccine. 13. use of anti-hypertensive drugs, i.e. beta blockers, diuretics, calcium channel blockers 14. use of anti-malaria drugs, i.e. mefloquine, chloroquine, and proguanil 15. use of drugs that affects the immune system, i.e. immunosuppressants, immune-modifying drugs, corticosteroids, i.e. cortisone, prednisone, methylprednisolone, for 2 weeks or longer 16. use of biologics, i.e. Lantus, Remicade, Rituxan, Humira, Herceptin, Avastin, Lucentis, Enbrel for 2 weeks or longer 17. undergoing cancer treatment with radiation or drugs 18. greater than 10 years residence in a typhoid-endemic area 19. receipt of typhoid vaccine in the last 5 years 20. receipt of any vaccine two weeks prior to receipt of Ty21a vaccine 21. individuals at increased risk of developing complications from a live, bacterial vaccine 22. history of typhoid fever 23. history of primary immune deficiency or autoimmune disease 24. history of acute or chronic gastrointestinal (GI) disorder, i.e. Crohn's disease, irritable bowel syndrome, gastric ulcer 25. diarrheal illness (defined as passing 3 or more abnormally loose or watery stool in a 24 hour period) or persistent vomiting 2 weeks prior to the study 26. history of chronic illnesses, i.e. diabetes, cardiovascular disease, cancer, gastrointestinal malabsorption or inflammatory diseases, kidney disease, autoimmune disorders, HIV, liver disease, including hepatitis B and C 27. asthma if taking medication on a daily basis 28. recent surgery (within 3 months) 29. history of GI surgery 30. recent hospitalization (within 3 months) 31. fever (within 2 weeks) 32. unwillingness to discontinue probiotic, prebiotic, or other supplements (except Recommended Dietary Allowance-level vitamin and mineral supplements), fiber supplements, or food and beverage products containing inulin, chicory root fiber, or maltodextrin during the study 33. not having at least one arm vein suitable for blood drawing 34. unwilling or uncomfortable with blood draws and stool collections 35. regular blood or blood product donation and refusal to suspend donation 36. current participation in another research study 37. unable to fast for 12-16 hours 38. have fewer than 3 bowel movements per week 39. consuming one or more servings of added-inulin foods per day over the past month

Outcomes

Primary Outcomes

Change in vaccine-specific antibody-secreting cell response to oral Ty21a typhoid vaccination using the standard 4-dose regimen

Measurement of baseline level (Day 26; before first vaccine dose) and post-vaccine, antibody response, Immunoglobulin G (IgG), Immunoglobulin M (IgM) and IgA, 7 and 9 days after the first vaccine dose using the antibody-in-lymphocyte-supernatant (ALS) assay to identify antibody-secreting cells in blood. Two antigens will be used: Ty21a outer membrane protein and lipopolysaccharide from Salmonella Typhi.

Time frame: Day 26, 37, and 39

Secondary Outcomes

Change in vaccine-specific serum antibody response to typhoid vaccination

Measurement of baseline level (Day 26; before first vaccine dose) and post-vaccine (28 d after first vaccine dose) antibody levels (IgG, IgM, IgA)

Time frame: Day 26 and 58

Change in vaccine-specific fecal IgA antibody levels from typhoid vaccination

Measurement of baseline level (Day 26; before first vaccination dose) and change in fecal antibody levels

Time frame: Day 26, 39, and 58

Change in plasma cytokines as markers of systemic inflammation

Measurement of plasma cytokines, such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and IL-1beta

Time frame: Day 8, 26, 37, 39, and 58

Change in plasma acute phase proteins and adhesion molecules

Measurement of acute phase reactants, such as C-reactive protein (CRP) and serum amyloid-A (SAA), and intercellular adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial cell adhesion molecule-1 (VCAM-1)

Time frame: Day 8, 26, 37, 39, and 58

Change in a plasma marker of lipopolysaccharide (LPS) exposure

Measurement of plasma LPS-binding protein using an ELISA.

Time frame: Day 8, 26, 37, 39, and 58

Change in blood monocyte subsets

Monocyte subsets will be analyzed using flow cytometry.

Time frame: Day 8, 26, 37, 39, and 58

Change in plasma short chain fatty acids (SCFA)

Plasma SCFA will be measured using liquid chromatography-mass spectrometry (LC-MS).

Time frame: Day 8, 26, 37, 39, and 58

Change in urinary lactulose and D-mannitol

Measurement of lactulose to mannitol ratio, an indicator of intestinal permeability, in urine

Time frame: Day 8, 26, and 37

Change in fecal microbiome

Measurement of relative abundance of colonic bacteria using DNA isolated from stool.