WHNRC (Western Human Nutrition Research Center) Fiber Intervention Study

Early Phase 1

Recruiting

• Conditions: Vaccine; Intestinal Permeability; Inflammation; Typhoid Fever
• Interventions: Dietary Supplement: Inulin; Dietary Supplement: Maltodextrin; Biological: Ty21a Typhoid Fever Vaccine

• Registration Number: NCT04543877
• Lead Sponsor: USDA, Western Human Nutrition Research Center

Brief Summary

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.

Detailed Description

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 Timeline

• Study First Submitted: 2020-08-24
• Study First Submitted QC: 2020-09-02
• Study First Posted: 2020-09-10
• Study Start: 2022-09-27
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-05
• Last Update Posted: 2025-03-10
• Primary Completion: 2025-09-30
• Study Completion: 2025-09-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 60

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Inulin and Ty21a Vaccine	Inulin	Participants will consume 12 grams/day of inulin for 3 weeks before the administration of the Ty21a vaccine, 1 week during the vaccine, and 1 week after the vaccine for a total of 5 weeks.
Inulin and Ty21a Vaccine	Ty21a Typhoid Fever Vaccine	Participants will consume 12 grams/day of inulin for 3 weeks before the administration of the Ty21a vaccine, 1 week during the vaccine, and 1 week after the vaccine for a total of 5 weeks.
Maltodextrin and Ty21a Vaccine	Maltodextrin	Participants will consume 12 grams/day of maltodextrin (control) for 3 weeks before the administration of the Ty21a vaccine, 1 week during the vaccine, and 1 week after the vaccine for a total of 5 weeks.
Maltodextrin and Ty21a Vaccine	Ty21a Typhoid Fever Vaccine	Participants will consume 12 grams/day of maltodextrin (control) for 3 weeks before the administration of the Ty21a vaccine, 1 week during the vaccine, and 1 week after the vaccine for a total of 5 weeks.

Primary Outcome Measures

Name	Time	Method
Change in vaccine-specific antibody-secreting cell response to oral Ty21a typhoid vaccination using the standard 4-dose regimen	Day 26, 37, and 39	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.

Secondary Outcome Measures

Name	Time	Method
Change in a plasma marker of lipopolysaccharide (LPS) exposure	Day 8, 26, 37, 39, and 58	Measurement of plasma LPS-binding protein using an ELISA.
Change in fecal secretory total immunoglobulin A (sIgA)	Period 1: Days 1-7; Period 2: Days 16-25; Period 3: Days 26-36; Period 4: Days 37-43; Period 5: Days 58-65	Measurement of total fecal sIgA using ELISA.
Change in vaccine-specific fecal IgA antibody levels from typhoid vaccination	Day 26, 39, and 58	Measurement of baseline level (Day 26; before first vaccination dose) and change in fecal antibody levels
Change in GI symptoms	Period 1: Days 1-7; Period 2: Days 16-25; Period 3: Days 26-36; Period 4: Days 37-43; Period 5: Days 58-65	Measurement of GI symptoms using a 10-symptom health questionnaire with degree of discomfort ranked in one of four categories (0 absent, 1 mild, 2 moderate, or 3 severe; PMID: 9301412)
Change in blood monocyte subsets	Day 8, 26, 37, 39, and 58	Monocyte subsets will be analyzed using flow cytometry.
Change in urinary lactulose and D-mannitol	Day 8, 26, and 37	Measurement of lactulose to mannitol ratio, an indicator of intestinal permeability, in urine
Change in fecal mRNA	Period 1: Days 1-7; Period 2: Days 16-25; Period 3: Days 26-36; Period 4: Days 37-43; Period 5: Days 58-65	Total RNA, and specifically, messenger ribonucleic acid (mRNA), will be analyzed from preserved stools.
Change in plasma acute phase proteins and adhesion molecules	Day 8, 26, 37, 39, and 58	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)
Change in fecal pH	Period 1: Days 1-7; Period 2: Days 16-25; Period 3: Days 26-36; Period 4: Days 37-43; Period 5: Days 58-65	Measurement of fecal pH using a standard pH meter.
Change in vaccine-specific serum antibody response to typhoid vaccination	Day 26 and 58	Measurement of baseline level (Day 26; before first vaccine dose) and post-vaccine (28 d after first vaccine dose) antibody levels (IgG, IgM, IgA)
Change in plasma cytokines as markers of systemic inflammation	Day 8, 26, 37, 39, and 58	Measurement of plasma cytokines, such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and IL-1beta
Change in fecal microbiome	Period 1: Days 1-7; Period 2: Days 16-25; Period 3: Days 26-36; Period 4: Days 37-43; Period 5: Days 58-65	Measurement of relative abundance of colonic bacteria using DNA isolated from stool.
Change in stool consistency and frequency	Period 1: Days 1-7; Period 2: Days 16-25; Period 3: Days 26-36; Period 4: Days 37-43; Period 5: Days 58-65	Measurement of stool consistency using the Bristol stool scale, a medical tool used to classify stool forms into 7 categories, and frequency via self-report in diaries.
Change in fecal SCFA	Period 1: Days 1-7; Period 2: Days 16-25; Period 3: Days 26-36; Period 4: Days 37-43; Period 5: Days 58-65	Measurement of SCFA will be done by gas chromatography-mass spectrometry (GC-MS.)
Change in plasma short chain fatty acids (SCFA)	Day 8, 26, 37, 39, and 58	Plasma SCFA will be measured using liquid chromatography-mass spectrometry (LC-MS).
Change in fecal calprotectin	Period 1: Days 1-7; Period 2: Days 16-25; Period 3: Days 26-36; Period 4: Days 37-43; Period 5: Days 58-65	Measurement of calprotectin will be done by ELISA
Change in fecal metabolites	Period 1: Days 1-7; Period 2: Days 16-25; Period 3: Days 26-36; Period 4: Days 37-43; Period 5: Days 58-65	Measurement of bile acids and other metabolites will be measured

Trial Locations

Locations (1)

USDA, ARS, Western Human Nutrition Research Center; 🇺🇸 Davis, California, United States