Probiotic Effect on Dietary Nitrate to Plasma Nitrite Production ( OPEDNPN )

NCT06375694 | Recruiting

• 1 other identifier: IRB00025485
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

Nitric Oxide (NO) is an important molecule that is produced naturally in the body and that helps maintain healthy blood flow. Low availability of NO contributes to many diseases while administration of NO is therapeutic. In addition to being made naturally in the body, NO can be obtained through the diet via the Nitrate-Nitrite-NO cycle. Nitrate, which is abundant in green leafy vegetables and beetroot juice, is partially converted to nitrite by oral bacteria. The nitrate and nitrite are taken up into the blood and nitrite is converted into NO. Remaining nitrate in the blood is taken back up into the mouth by salivary glands and the cycle continues. Emerging studies suggest that the Nitrate-Nitrite-NO cycle may contribute to cardiovascular health. In addition, there have been many studies where dietary nitrate is given to increase NO and treat various conditions. The current study rests on the premise that the quality of the oral microbiome plays a major role in the Nitrate-Nitrite-NO cycle and hence cardiovascular health and the efficacy of dietary nitrate interventions. Investigators have begun to identify oral bacterial species that are effective nitrite producers as well as though that are nitrite depleters (those that interfere with nitrite production from nitrate). In laboratory experiments, certain bacterial species have been shown to block nitrate to nitrite conversion by other oral bacteria. These nitrite depleting species are found in a commercially available oral probiotic designed to improve oral health. The purpose of this study is to examine if use of the probiotic negatively affects the Nitrate-Nitrite-NO cycle. Nitrate to Nitrite conversion will be assessed by measuring plasma levels of nitrite before and after consumption of nitrate-rich beetroot juice. Dietary nitrate to plasma nitrite conversion will assessed at baseline and after one week of consumption of the probiotic or a placebo (follow-up). The primary hypothesis of this study is that participants that consume the probiotic will have lower nitrate to nitrite conversion at follow-up compared to baseline and that there will be no significant change in nitrate to nitrite conversion between baseline and follow-up for participants who consume the placebo. While this study does not aim to treat any specific disease, it is intended to elucidate a basic physiological function that may be relevant to cardiovascular health and certain NO-based therapeutics.

Conditions

Hypertension; Cardiovascular Diseases; Diabetes

Keywords

Nitric Oxide; Nitrate; Microbiome

Outcome Measures

Primary Outcomes (1)

• Dietary Nitrate Conversion to Plasma Nitrite

  The main outcome is the plasma nitrite level 2.5 after consuming Beet Juice minus the plasma nitrite level prior to drinking beet juice. Blood will be collected prior to drinking one Beet it Sport shot and 2.5 hours after drinking the shot. Plasma nitrite will be measured from these blood draws. This outcome will be measured at two visits: baseline and followup (day 8) and the increase in plasma nitrite at the two visits will be compared. Between the two visits the participants will consume the Probiotic or Placebo for 7 days.

  The two visits will be 8 days apart.

Secondary Outcomes (1)

• Percentage Lactobacillus

  The two visits will be 8 days apart.

Study Arms (2)

Probiotic

ACTIVE COMPARATOR

Participants will take the commercially available oral probiotic (Herbiotics Oral + Ent Probiotic) twice a day for 7 days as instructed by the manufacturer. This entails one lozenge twice a day taken by mouth and slowly chewed or allowed to melt in the mouth.

Dietary Supplement: Herbiotics Oral + Ent Probiotic

Placebo

PLACEBO COMPARATOR

Participants will take the commercially available Honest Placebo Pills by Zeebo twice a day for 7 days. This entails one tablet twice a day taken by mouth and slowly chewed or allowed to melt in the mouth.

Dietary Supplement: Placebo

Interventions

Herbiotics Oral + Ent Probiotic DIETARY_SUPPLEMENT

Chewable Tablets containing Lactobacillus species.

Probiotic

Placebo DIETARY_SUPPLEMENT

Honest Placebo Pills by Zeebo

Placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Healthy adult volunteers ages 18-70

You may not qualify if:

• Individuals with a history of difficult blood draws. More than 2 blood draws in one week; on anti-coagulant or anti-platelet therapy (e.g. aspirin, Coumadin, etc.); known pregnancy; in police custody or a prisoner; common illness within 2 weeks of potential enrollment. The cumulative volume of blood drawn from a healthy adult over the prior eight-week period would exceed 550 ml including the current draw.
• In addition, individuals uncomfortable spitting into a tube, dry mouth (xerostomia) or dry eyes, Patients suffering from autoimmune diseases such as Sjogren's syndrome, rheumatoid arthritis, systemic lupus erythematosus, or progressive systemic sclerosis, since individuals with these autoimmune inflammatory diseases exhibit persistent xerostomia, individuals with active caries diagnosis or history of periodontitis

Sponsors & Collaborators

• Wake Forest University: lead
• University of South Florida: collaborator

Study Sites (1)

Wake Forest University

Winston-Salem, North Carolina, 27104, United States

RECRUITING

Related Publications (30)

• Leiva A, Fuenzalida B, Barros E, Sobrevia B, Salsoso R, Saez T, Villalobos R, Silva L, Chiarello I, Toledo F, Gutierrez J, Sanhueza C, Pardo F, Sobrevia L. Nitric Oxide is a Central Common Metabolite in Vascular Dysfunction Associated with Diseases of Human Pregnancy. Curr Vasc Pharmacol. 2016;14(3):237-59. doi: 10.2174/1570161114666160222115158.

  PMID: 26899560 BACKGROUND

• Almeida CB, Souza LE, Leonardo FC, Costa FT, Werneck CC, Covas DT, Costa FF, Conran N. Acute hemolytic vascular inflammatory processes are prevented by nitric oxide replacement or a single dose of hydroxyurea. Blood. 2015 Aug 6;126(6):711-20. doi: 10.1182/blood-2014-12-616250. Epub 2015 May 27.

  PMID: 26019278 BACKGROUND

• Maley JH, Lasker GF, Kadowitz PJ. Nitric oxide and disorders of the erythrocyte: emerging roles and therapeutic targets. Cardiovasc Hematol Disord Drug Targets. 2010 Dec 1;10(4):284-91. doi: 10.2174/187152910793743878.

  PMID: 21067512 BACKGROUND

• Eisenhut M. Severe hemolysis as a potential contributing factor in the pathophysiology of cerebral malaria. Clin Infect Dis. 2015 Apr 1;60(7):1138. doi: 10.1093/cid/ciu1149. Epub 2014 Dec 19. No abstract available.

  PMID: 25527655 BACKGROUND

• Donadee C, Raat NJ, Kanias T, Tejero J, Lee JS, Kelley EE, Zhao X, Liu C, Reynolds H, Azarov I, Frizzell S, Meyer EM, Donnenberg AD, Qu L, Triulzi D, Kim-Shapiro DB, Gladwin MT. Nitric oxide scavenging by red blood cell microparticles and cell-free hemoglobin as a mechanism for the red cell storage lesion. Circulation. 2011 Jul 26;124(4):465-76. doi: 10.1161/CIRCULATIONAHA.110.008698. Epub 2011 Jul 11.

  PMID: 21747051 BACKGROUND

• Gladwin MT, Kim-Shapiro DB. Storage lesion in banked blood due to hemolysis-dependent disruption of nitric oxide homeostasis. Curr Opin Hematol. 2009 Nov;16(6):515-23. doi: 10.1097/MOH.0b013e32833157f4.

  PMID: 19701085 BACKGROUND

• Hirai DM, Musch TI, Poole DC. Exercise training in chronic heart failure: improving skeletal muscle O2 transport and utilization. Am J Physiol Heart Circ Physiol. 2015 Nov;309(9):H1419-39. doi: 10.1152/ajpheart.00469.2015. Epub 2015 Aug 28.

  PMID: 26320036 BACKGROUND

• Voetsch B, Jin RC, Loscalzo J. Nitric oxide insufficiency and atherothrombosis. Histochem Cell Biol. 2004 Oct;122(4):353-67. doi: 10.1007/s00418-004-0675-z. Epub 2004 Aug 26.

  PMID: 15338226 BACKGROUND

• Bertoluci MC, Ce GV, da Silva AM, Wainstein MV, Boff W, Punales M. Endothelial dysfunction as a predictor of cardiovascular disease in type 1 diabetes. World J Diabetes. 2015 Jun 10;6(5):679-92. doi: 10.4239/wjd.v6.i5.679.

  PMID: 26069717 BACKGROUND

• Kapil V, Haydar SM, Pearl V, Lundberg JO, Weitzberg E, Ahluwalia A. Physiological role for nitrate-reducing oral bacteria in blood pressure control. Free Radic Biol Med. 2013 Feb;55:93-100. doi: 10.1016/j.freeradbiomed.2012.11.013. Epub 2012 Nov 23.

  PMID: 23183324 BACKGROUND

• Govoni M, Jansson EA, Weitzberg E, Lundberg JO. The increase in plasma nitrite after a dietary nitrate load is markedly attenuated by an antibacterial mouthwash. Nitric Oxide. 2008 Dec;19(4):333-7. doi: 10.1016/j.niox.2008.08.003. Epub 2008 Aug 30.

  PMID: 18793740 BACKGROUND

• Webb AJ, Patel N, Loukogeorgakis S, Okorie M, Aboud Z, Misra S, Rashid R, Miall P, Deanfield J, Benjamin N, MacAllister R, Hobbs AJ, Ahluwalia A. Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite. Hypertension. 2008 Mar;51(3):784-90. doi: 10.1161/HYPERTENSIONAHA.107.103523. Epub 2008 Feb 4.

  PMID: 18250365 BACKGROUND

• Lundberg JO, Weitzberg E, Gladwin MT. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov. 2008 Feb;7(2):156-67. doi: 10.1038/nrd2466.

  PMID: 18167491 BACKGROUND

• Helms CC, Liu X, Kim-Shapiro DB. Recent insights into nitrite signaling processes in blood. Biol Chem. 2017 Mar;398(3):319-329. doi: 10.1515/hsz-2016-0263.

  PMID: 27611767 BACKGROUND

• DeMartino AW, Kim-Shapiro DB, Patel RP, Gladwin MT. Nitrite and nitrate chemical biology and signalling. Br J Pharmacol. 2019 Jan;176(2):228-245. doi: 10.1111/bph.14484. Epub 2018 Oct 3.

  PMID: 30152056 BACKGROUND

• Presley TD, Perlegas AS, Bain LE, Ballas SK, Nichols JS, Sabio H, Gladwin MT, Kato GJ, Kim-Shapiro DB. Effects of a single sickling event on the mechanical fragility of sickle cell trait erythrocytes. Hemoglobin. 2010;34(1):24-36. doi: 10.3109/03630260903546999.

  PMID: 20113285 BACKGROUND

• Eggebeen J, Kim-Shapiro DB, Haykowsky M, Morgan TM, Basu S, Brubaker P, Rejeski J, Kitzman DW. One Week of Daily Dosing With Beetroot Juice Improves Submaximal Endurance and Blood Pressure in Older Patients With Heart Failure and Preserved Ejection Fraction. JACC Heart Fail. 2016 Jun;4(6):428-37. doi: 10.1016/j.jchf.2015.12.013. Epub 2016 Feb 10.

  PMID: 26874390 BACKGROUND

• Petrie M, Rejeski WJ, Basu S, Laurienti PJ, Marsh AP, Norris JL, Kim-Shapiro DB, Burdette JH. Beet Root Juice: An Ergogenic Aid for Exercise and the Aging Brain. J Gerontol A Biol Sci Med Sci. 2017 Sep 1;72(9):1284-1289. doi: 10.1093/gerona/glw219.

  PMID: 28329785 BACKGROUND

• Larsen FJ, Weitzberg E, Lundberg JO, Ekblom B. Dietary nitrate reduces maximal oxygen consumption while maintaining work performance in maximal exercise. Free Radic Biol Med. 2010 Jan 15;48(2):342-7. doi: 10.1016/j.freeradbiomed.2009.11.006. Epub 2009 Nov 12.

  PMID: 19913611 BACKGROUND

• Kapil V, Khambata RS, Robertson A, Caulfield MJ, Ahluwalia A. Dietary nitrate provides sustained blood pressure lowering in hypertensive patients: a randomized, phase 2, double-blind, placebo-controlled study. Hypertension. 2015 Feb;65(2):320-7. doi: 10.1161/HYPERTENSIONAHA.114.04675. Epub 2014 Nov 24.

  PMID: 25421976 BACKGROUND

• Velmurugan S, Kapil V, Ghosh SM, Davies S, McKnight A, Aboud Z, Khambata RS, Webb AJ, Poole A, Ahluwalia A. Antiplatelet effects of dietary nitrate in healthy volunteers: involvement of cGMP and influence of sex. Free Radic Biol Med. 2013 Dec;65:1521-1532. doi: 10.1016/j.freeradbiomed.2013.06.031. Epub 2013 Jun 24.

  PMID: 23806384 BACKGROUND

• Velmurugan S, Gan JM, Rathod KS, Khambata RS, Ghosh SM, Hartley A, Van Eijl S, Sagi-Kiss V, Chowdhury TA, Curtis M, Kuhnle GG, Wade WG, Ahluwalia A. Dietary nitrate improves vascular function in patients with hypercholesterolemia: a randomized, double-blind, placebo-controlled study. Am J Clin Nutr. 2016 Jan;103(1):25-38. doi: 10.3945/ajcn.115.116244. Epub 2015 Nov 25.

  PMID: 26607938 BACKGROUND

• Kerley CP, Cahill K, Bolger K, McGowan A, Burke C, Faul J, Cormican L. Dietary nitrate supplementation in COPD: an acute, double-blind, randomized, placebo-controlled, crossover trial. Nitric Oxide. 2015 Jan 30;44:105-11. doi: 10.1016/j.niox.2014.12.010. Epub 2014 Dec 19.

  PMID: 25534960 BACKGROUND

• Kerley CP, O'Neill JO, Reddy Bijjam V, Blaine C, James PE, Cormican L. Dietary nitrate increases exercise tolerance in patients with non-ischemic, dilated cardiomyopathy-a double-blind, randomized, placebo-controlled, crossover trial. J Heart Lung Transplant. 2016 Jul;35(7):922-6. doi: 10.1016/j.healun.2016.01.018. Epub 2016 Jan 16. No abstract available.

  PMID: 27009674 BACKGROUND

• Shaltout HA, Eggebeen J, Marsh AP, Brubaker PH, Laurienti PJ, Burdette JH, Basu S, Morgan A, Dos Santos PC, Norris JL, Morgan TM, Miller GD, Rejeski WJ, Hawfield AT, Diz DI, Becton JT, Kim-Shapiro DB, Kitzman DW. Effects of supervised exercise and dietary nitrate in older adults with controlled hypertension and/or heart failure with preserved ejection fraction. Nitric Oxide. 2017 Sep 30;69:78-90. doi: 10.1016/j.niox.2017.05.005. Epub 2017 May 23.

  PMID: 28549665 BACKGROUND

• Wilkerson DP, Hayward GM, Bailey SJ, Vanhatalo A, Blackwell JR, Jones AM. Influence of acute dietary nitrate supplementation on 50 mile time trial performance in well-trained cyclists. Eur J Appl Physiol. 2012 Dec;112(12):4127-34. doi: 10.1007/s00421-012-2397-6. Epub 2012 Apr 20.

  PMID: 22526247 BACKGROUND

• Kenjale AA, Ham KL, Stabler T, Robbins JL, Johnson JL, Vanbruggen M, Privette G, Yim E, Kraus WE, Allen JD. Dietary nitrate supplementation enhances exercise performance in peripheral arterial disease. J Appl Physiol (1985). 2011 Jun;110(6):1582-91. doi: 10.1152/japplphysiol.00071.2011. Epub 2011 Mar 31.

  PMID: 21454745 BACKGROUND

• Ormesher L, Myers JE, Chmiel C, Wareing M, Greenwood SL, Tropea T, Lundberg JO, Weitzberg E, Nihlen C, Sibley CP, Johnstone ED, Cottrell EC. Effects of dietary nitrate supplementation, from beetroot juice, on blood pressure in hypertensive pregnant women: A randomised, double-blind, placebo-controlled feasibility trial. Nitric Oxide. 2018 Nov 1;80:37-44. doi: 10.1016/j.niox.2018.08.004. Epub 2018 Aug 9.

  PMID: 30099096 BACKGROUND

• Hyde ER, Andrade F, Vaksman Z, Parthasarathy K, Jiang H, Parthasarathy DK, Torregrossa AC, Tribble G, Kaplan HB, Petrosino JF, Bryan NS. Metagenomic analysis of nitrate-reducing bacteria in the oral cavity: implications for nitric oxide homeostasis. PLoS One. 2014 Mar 26;9(3):e88645. doi: 10.1371/journal.pone.0088645. eCollection 2014.

  PMID: 24670812 BACKGROUND

• Rosier BT, Moya-Gonzalvez EM, Corell-Escuin P, Mira A. Isolation and Characterization of Nitrate-Reducing Bacteria as Potential Probiotics for Oral and Systemic Health. Front Microbiol. 2020 Sep 15;11:555465. doi: 10.3389/fmicb.2020.555465. eCollection 2020.

  PMID: 33042063 BACKGROUND

MeSH Terms

Conditions

Hypertension; Cardiovascular Diseases; Diabetes Mellitus

Condition Hierarchy (Ancestors)

Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Central Study Contacts

Daniel B Kim-Shapiro, PhD

CONTACT

336-758-4993; shapiro@wfu.edu

Jeanie Baird, MPA

CONTACT

336-758-5195; bairdjl@wfu.edu

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Participants will not know which group they are in. The lozenges will be distributed in unmarked bottles
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Participants will be randomized into two groups with one group receiving the oral probiotic and the other receiving the placebo. Each group will take their intervention 2X a day for 7 days.

Study Record Dates

• First Submitted: April 16, 2024
• First Posted: April 19, 2024
• Study Start: June 1, 2024
• Primary Completion: May 1, 2025
• Study Completion: May 1, 2025
• Last Updated: July 19, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: ANALYTIC CODE
• Time Frame: When saliva and tongue scrapings are sent to University of South Florida for microbiome analysis, the samples will include the code.
• Access Criteria: Scientific investigators on the team will have access to the codes - not any links to the original participants.

Locations

US (1)