WHNRC (Western Human Nutrition Research Center) Fiber Intervention Study

Study Overview
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Brief Summary
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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
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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.

Official Title
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WHNRC (Western Human Nutrition Research Center) Fiber Intervention Study

Conditions
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Inflammation, Vaccine, Intestinal Permeability, Typhoid Fever

Intervention / Treatment
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* Dietary Supplement: Inulin
* Dietary Supplement: Maltodextrin
* Biological: Ty21a Typhoid Fever Vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body Mass Index (BMI) 18.5 - 30.9 kg/m2 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 Males 18 - 30 years old, less than 34 g/day Males 31 - 50 years old, less than 31 g/day Exclusion Criteria: blood pressure greater than or equal to 140/90 mmHg has HIV/AIDS or another disease that affects the immune system has any kind of cancer inability to lift 30 pounds with assistance (for transporting refrigerated stool containers) decline to take an HIV blood test pregnant or lactating women refusal to take a pregnancy test 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 allergy to vaccine components, i.e. thimerosal and enteric-coated capsules allergy to oral typhoid vaccine use of anti-inflammatory medications, i.e. nonsteroidal anti-inflammatory drugs (NSAID), aspirin, 3 or more times per month use of sulfonamides or antibiotics 3 months prior to the receipt of Ty21a vaccine. use of anti-hypertensive drugs, i.e. beta blockers, diuretics, calcium channel blockers use of anti-malaria drugs, i.e. mefloquine, chloroquine, and proguanil 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 use of biologics, i.e. Lantus, Remicade, Rituxan, Humira, Herceptin, Avastin, Lucentis, Enbrel for 2 weeks or longer undergoing cancer treatment with radiation or drugs greater than 10 years residence in a typhoid-endemic area receipt of typhoid vaccine in the last 5 years receipt of any vaccine two weeks prior to receipt of Ty21a vaccine individuals at increased risk of developing complications from a live, bacterial vaccine history of typhoid fever history of primary immune deficiency or autoimmune disease history of acute or chronic gastrointestinal (GI) disorder, i.e. Crohn's disease, irritable bowel syndrome, gastric ulcer 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 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 asthma if taking medication on a daily basis recent surgery (within 3 months) history of GI surgery recent hospitalization (within 3 months) fever (within 2 weeks) 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 not having at least one arm vein suitable for blood drawing unwilling or uncomfortable with blood draws and stool collections regular blood or blood product donation and refusal to suspend donation current participation in another research study unable to fast for 12-16 hours have fewer than 3 bowel movements per week consuming one or more servings of added-inulin foods per day over the past month

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inulin and Ty21a Vaccine<br>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. | Dietary Supplement: Inulin<br>* Consume 12 grams/day of inulin for 5 weeks (Day 9 - 43).<br>* Other names: Orafti GR;Biological: Ty21a Typhoid Fever Vaccine<br>* All participants will receive the vaccine. One capsule is swallowed on alternate days, e.g. days 30, 32, 34, and 36 for a total of 4 capsules.<br>* Other names: Vivotif;|
| Placebo Comparator: Maltodextrin and Ty21a Vaccine<br>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. | Dietary Supplement: Maltodextrin<br>* Consume 12 grams/day of maltodextrin for 5 weeks (Day 9 - 43).<br>* Other names: Maltrin M100;Biological: Ty21a Typhoid Fever Vaccine<br>* All participants will receive the vaccine. One capsule is swallowed on alternate days, e.g. days 30, 32, 34, and 36 for a total of 4 capsules.<br>* Other names: Vivotif;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Day 26, 37, and 39 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 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 | 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 | 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) | 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. | Day 8, 26, 37, 39, and 58 | 
| Change in blood monocyte subsets | Monocyte subsets will be analyzed using flow cytometry. | 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). | 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 | Day 8, 26, and 37 | 
| Change in fecal microbiome | Measurement of relative abundance of colonic bacteria using DNA isolated from stool. | 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 | 
| Change in fecal mRNA | Total RNA, and specifically, messenger ribonucleic acid (mRNA), will be analyzed from preserved stools. | 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 | 
| Change in stool consistency and frequency | 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. | 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 | 
| Change in GI symptoms | 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) | 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 | 
| Change in fecal pH | Measurement of fecal pH using a standard pH meter. | 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 | 
| Change in fecal calprotectin | Measurement of calprotectin will be done by ELISA | 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 | 
| Change in fecal SCFA | Measurement of SCFA will be done by gas chromatography-mass spectrometry (GC-MS.) | 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 | 
| Change in fecal metabolites | Measurement of bile acids and other metabolites will be measured | 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 | 
| Change in fecal secretory total immunoglobulin A (sIgA) | Measurement of total fecal sIgA using ELISA. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gastrointestinal Health, Intestinal Permeability, Vaccine Response, Inflammation, Ty21a Typhoid Vaccine, Typhoid Fever, Microbiome, Bifidobacterium