WHNRC (Western Human Nutrition Research Center) Fiber Intervention Study

Inflammation Clinical Trial

Official title:

WHNRC (Western Human Nutrition Research Center) Fiber Intervention Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04543877
• Other study ID #: FL113
• Status: Recruiting
• Phase: Early Phase 1
• Start date: September 27, 2022
• Est. completion date: September 30, 2025

Study information

• Verified date: June 2024
• Source: USDA, Western Human Nutrition Research Center
• Contact: Ellen Bonnel, PhD
• Phone: 530-752-4184
• Email: ellen.bonnel[@]usda.gov
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: September 30, 2025
• Est. primary completion date: September 30, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 50 Years

Eligibility

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

Related Conditions & MeSH terms

• Inflammation
• Intestinal Permeability
• Typhoid Fever
• Vaccine

Intervention

Dietary Supplement:
• Inulin
Consume 12 grams/day of inulin for 5 weeks (Day 9 - 43).
• Maltodextrin
Consume 12 grams/day of maltodextrin for 5 weeks (Day 9 - 43).

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.

Locations

Country	Name	City	State
United States	USDA, ARS, Western Human Nutrition Research Center	Davis	California

Sponsors (2)

Lead Sponsor	Collaborator
USDA, Western Human Nutrition Research Center	University of Minnesota

Country where clinical trial is conducted

United States, 

References & Publications (13)

Costabile A, Kolida S, Klinder A, Gietl E, Bauerlein M, Frohberg C, Landschutze 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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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):e20181489. doi: 10.1542/peds.2018-1489. — View Citation

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. — View Citation

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. doi: 10.1038/sj.ejcn.1602636. Epub 2007 Jan 31. — View Citation

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. doi: 10.1093/jn/130.5.1197. — View Citation

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. — View Citation

Micka A, Siepelmeyer A, Holz A, Theis S, Schon 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. — View Citation

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. — View Citation

Salerno-Goncalves 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. — View Citation

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. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Change in blood monocyte subsets	Monocyte subsets will be analyzed using flow cytometry.	Day 8, 26, 37, 39, and 58
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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