WHNRC (Western Human Nutrition Research Center) Fiber Intervention Study

• ClinicalTrials.gov Identifier: NCT04543877
• Recruitment Status: Not yet recruiting
• First Posted: September 10, 2020
• Last Update Posted: March 2, 2022
• Sponsor: USDA, Western Human Nutrition Research Center
• Collaborator: University of Minnesota
• Information provided by (Responsible Party): USDA, Western Human Nutrition Research Center

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Inflammation; Vaccine; Intestinal Permeability; Typhoid Fever	Dietary Supplement: Inulin; Dietary Supplement: Maltodextrin; Biological: Ty21a Typhoid Fever Vaccine	Early Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Basic Science
• Official Title: WHNRC (Western Human Nutrition Research Center) Fiber Intervention Study
• Estimated Study Start Date: June 1, 2022
• Estimated Primary Completion Date: September 30, 2024
• Estimated Study Completion Date: September 30, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Inulin and Ty21a 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.	Dietary Supplement: Inulin; Consume 12 grams/day of inulin for 5 weeks (Day 9 - 43).; Other Name: Orafti GR; Biological: Ty21a Typhoid Fever Vaccine; 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.; Other Name: Vivotif
Placebo Comparator: Maltodextrin and Ty21a 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.	Dietary Supplement: Maltodextrin; Consume 12 grams/day of maltodextrin for 5 weeks (Day 9 - 43).; Other Name: Maltrin M100; Biological: Ty21a Typhoid Fever Vaccine; 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.; Other Name: Vivotif

Outcome Measures

Primary Outcome Measures :

1. Change in whole blood antibody response to typhoid vaccination [ Time Frame: Day 26, 37, and 39 ]
   Measurement of baseline level (Day 26; before first vaccine dose) and change of vaccine-specific antibody response using the antibody-in-lymphocyte-supernatant (ALS) assay to identify nascent antibody-secreting cells in blood.
2. Change in plasma antibody response to typhoid vaccination [ Time Frame: Day 26 and 58 ]
   Measurement of baseline level (Day 26; before first vaccine dose) and change in plasma antibody levels
3. Change in fecal antibody levels from typhoid vaccination [ Time Frame: Day 26, 39, and 58 ]
   Measurement of baseline level (Day 26; before first vaccine dose) and change in fecal antibody levels

Secondary Outcome Measures :

1. Change in plasma cytokines as markers of systemic inflammation [ Time Frame: Day 8, 26, 37, 39, and 58 ]
   Measurement of plasma cytokines interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), IL-1beta using an enzyme-linked immunoassay (ELISA)
2. Change in plasma chemokines [ Time Frame: Day 8, 26, 37, 39, and 58 ]
   Measurement of plasma chemokines including IL-8, Interferon-inducible protein 10 (IP-10) and Granulocyte-macrophage colony stimulating factor (GM-CSF) will be measured by ELISA.
3. Change in plasma acute phase proteins [ Time Frame: Day 8, 26, 37, 39, and 58 ]
   Measurement of acute phase reactants C reactive protein (CRP) and serum amyloid-A (SAA) measured by ELISA.
4. Change in plasma adhesion molecules [ Time Frame: Day 8, 26, 37, 39, and 58 ]
   Measurement of plasma intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial cell adhesion molecule-1 (VCAM-1) measured by ELISA.
5. Change in plasma myeloperoxidase [ Time Frame: Day 8, 26, 37, 39, and 58 ]
   Measurement of myeloperoxidase in plasma using an ELISA.
6. Change in plasma neopterin [ Time Frame: Day 8, 26, 37, 39, and 58 ]
   Measurement of neopterin in plasma using an ELISA.
7. Change in a plasma marker of lipopolysaccharide (LPS) exposure [ Time Frame: Day 8, 26, 37, 39, and 58 ]
   Measurement of plasma LPS-binding protein using an ELISA.
8. Change in blood monocyte subsets [ Time Frame: Day 8, 26, 37, 39, and 58 ]
   Monocyte subsets will be analyzed using flow cytometry.
9. Change in plasma short chain fatty acids (SCFA) [ Time Frame: Day 8, 26, 37, 39, and 58 ]
   Blood SCFA will be measured using GC-MS.
10. Change in urinary lactulose [ Time Frame: Day 8, 26, and 37 ]
    Measurement of lactulose, a synthetic sugar and an indicator of intestinal permeability, in urine by gas chromatography mass-spectrometry (GC-MS).
11. Change in urinary D-mannitol [ Time Frame: Day 8, 26, and 37 ]
    Measurement of D-mannitol, a sugar alcohol and an indicator of intestinal permeability, in urine by GC-MS.
12. Changes in dietary intake [ Time Frame: Period 1: Days 1-7; Period 2: Days 16-25; Period 3: Days 58-65 ]
    Three non-consecutive 24-hour dietary recalls will be collected per period. A 3-day average of nutrient intake will be calculated per period.
13. Change in fecal microbiome identity [ Time Frame: 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 polymerase chain reaction (PCR) amplification and sequencing of the 16S ribosomal ribonucleic acid (RNA) will be performed using DNA isolated from stool. Stools will be collected 3 times per period.
14. Change in fecal microbiome function [ Time Frame: 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, mucin-2 messenger ribonucleic acid (mRNA), will be analyzed from preserved stools. Stools will be collected 3 times per period.
15. Change in stool consistency [ Time Frame: 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. Stools will be collected 3 times per period.
16. Change in fecal pH [ Time Frame: 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. Stools will be collected 3 times per period.
17. Change in fecal calprotectin [ Time Frame: 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. Stools will be collected 3 times per period.
18. Change in fecal secretory immunoglobulin A (sIgA) [ Time Frame: 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 sIgA using ELISA. Stools will be collected 3 times per period.
19. Change in fecal SCFA [ Time Frame: 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 GC-MS. Stools will be collected 3 times per period.
20. Change in fecal bile acids [ Time Frame: 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 will be done by GC-MS. Stools will be collected 3 times per period.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 50 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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
   • Males 18 - 30 years old, less than 34 g/day
   • Males 31 - 50 years old, less than 31 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

Contacts and Locations

Contacts

Contact: Ellen Bonnel, PhD; 530-752-4184; ellen.bonnel@usda.gov

Contact: Yuriko Adkins, PhD; 530-752-9469; yuriko.adkins@usda.gov

Locations

United States, California

USDA, ARS, Western Human Nutrition Research Center

Davis, California, United States, 95616

Contact: Ellen Bonnel, PhD 530-752-4184 ellen.bonnel@usda.gov

Contact: Yuriko Adkins, PhD 530-752-9469 yuriko.adkins@usda.gov

Sponsors and Collaborators

USDA, Western Human Nutrition Research Center

University of Minnesota

Investigators

• Principal Investigator: Danielle Lemay, PhD; USDA, ARS, Western Human Nutrition Research Center
• Principal Investigator: Charles Stephensen, PhD; USDA, ARS, Western Human Nutrition Research Center
• Principal Investigator: Mary Kable, PhD; USDA, ARS, Western Human Nutrition Research Center

More Information

Publications:

Meyer D, Stasse-Wolthuis M. The bifidogenic effect of inulin and oligofructose and its consequences for gut health. Eur J Clin Nutr. 2009 Nov;63(11):1277-89. doi: 10.1038/ejcn.2009.64. Epub 2009 Aug 19. Review.

Costabile A, Kolida S, Klinder A, Gietl E, Bäuerlein M, Frohberg C, Landschütze V, Gibson GR. A double-blind, placebo-controlled, cross-over study to establish the bifidogenic effect of a very-long-chain inulin extracted from globe artichoke (Cynara scolymus) in healthy human subjects. Br J Nutr. 2010 Oct;104(7):1007-17. doi: 10.1017/S0007114510001571. Epub 2010 Jul 1.

Dewulf EM, Cani PD, Claus SP, Fuentes S, Puylaert PG, Neyrinck AM, Bindels LB, de Vos WM, Gibson GR, Thissen JP, Delzenne NM. Insight into the prebiotic concept: lessons from an exploratory, double blind intervention study with inulin-type fructans in obese women. Gut. 2013 Aug;62(8):1112-21. doi: 10.1136/gutjnl-2012-303304. Epub 2012 Nov 7.

Holscher HD, Bauer LL, Gourineni V, Pelkman CL, Fahey GC Jr, Swanson KS. Agave Inulin Supplementation Affects the Fecal Microbiota of Healthy Adults Participating in a Randomized, Double-Blind, Placebo-Controlled, Crossover Trial. J Nutr. 2015 Sep;145(9):2025-32. doi: 10.3945/jn.115.217331. Epub 2015 Jul 22.

Kolida S, Meyer D, Gibson GR. A double-blind placebo-controlled study to establish the bifidogenic dose of inulin in healthy humans. Eur J Clin Nutr. 2007 Oct;61(10):1189-95. Epub 2007 Jan 31.

Menne E, Guggenbuhl N, Roberfroid M. Fn-type chicory inulin hydrolysate has a prebiotic effect in humans. J Nutr. 2000 May;130(5):1197-9.

Micka A, Siepelmeyer A, Holz A, Theis S, Schön C. Effect of consumption of chicory inulin on bowel function in healthy subjects with constipation: a randomized, double-blind, placebo-controlled trial. Int J Food Sci Nutr. 2017 Feb;68(1):82-89. doi: 10.1080/09637486.2016.1212819. Epub 2016 Aug 5.

Petry N, Egli I, Chassard C, Lacroix C, Hurrell R. Inulin modifies the bifidobacteria population, fecal lactate concentration, and fecal pH but does not influence iron absorption in women with low iron status. Am J Clin Nutr. 2012 Aug;96(2):325-31. doi: 10.3945/ajcn.112.035717. Epub 2012 Jun 27.

Huda MN, Lewis Z, Kalanetra KM, Rashid M, Ahmad SM, Raqib R, Qadri F, Underwood MA, Mills DA, Stephensen CB. Stool microbiota and vaccine responses of infants. Pediatrics. 2014 Aug;134(2):e362-72. doi: 10.1542/peds.2013-3937. Epub 2014 Jul 7.

Huda MN, Ahmad SM, Alam MJ, Khanam A, Kalanetra KM, Taft DH, Raqib R, Underwood MA, Mills DA, Stephensen CB. Bifidobacterium Abundance in Early Infancy and Vaccine Response at 2 Years of Age. Pediatrics. 2019 Feb;143(2). pii: e20181489. doi: 10.1542/peds.2018-1489.

Zuckerman JN, Hatz C, Kantele A. Review of current typhoid fever vaccines, cross-protection against paratyphoid fever, and the European guidelines. Expert Rev Vaccines. 2017 Oct;16(10):1029-1043. doi: 10.1080/14760584.2017.1374861. Review.

Fiorentino M, Lammers KM, Levine MM, Sztein MB, Fasano A. In vitro Intestinal Mucosal Epithelial Responses to Wild-Type Salmonella Typhi and Attenuated Typhoid Vaccines. Front Immunol. 2013 Feb 12;4:17. doi: 10.3389/fimmu.2013.00017. eCollection 2013.

Salerno-Gonçalves R, Galen JE, Levine MM, Fasano A, Sztein MB. Manipulation of Salmonella Typhi Gene Expression Impacts Innate Cell Responses in the Human Intestinal Mucosa. Front Immunol. 2018 Nov 1;9:2543. doi: 10.3389/fimmu.2018.02543. eCollection 2018.

• Responsible Party: USDA, Western Human Nutrition Research Center
• ClinicalTrials.gov Identifier: NCT04543877
• Other Study ID Numbers: FL113
• First Posted: September 10, 2020
• Last Update Posted: March 2, 2022
• Last Verified: February 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by USDA, Western Human Nutrition Research Center:

Gastrointestinal Health; Intestinal Permeability; Vaccine Response; Inflammation; Ty21a Typhoid Vaccine; Typhoid Fever; Microbiome; Bifidobacterium

Additional relevant MeSH terms:

Typhoid Fever; Inflammation; Pathologic Processes; Salmonella Infections; Enterobacteriaceae Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections