Endothelial DysfunctionNCT06502535
Inulin and Nitrate's Effects on Vascular Health and Gut Microbiome
A study testing Inulin and Potassium nitrate and inulin in people with Endothelial Dysfunction and High Blood Pressure, run by University of Exeter at 1 site in United Kingdom.
Trial summary
Previous research has revealed that adults with pre-hypertensive and hypertensive blood pressure levels typically exhibit impaired vasodilation, which is a crucial aspect of blood vessel function, due to decreased nitric oxide production. Read more about this study
- Who is it for?
- Ages 45 to 74 years
- Conditions the study is for
- Endothelial Dysfunction, High Blood Pressure, Gut Microbiota Dysbiosis and Nutrition
- What is being tested?
- Inulin and Potassium nitrate and inulin
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 22 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 9 May 2023to 31 Jul 2024
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 45 to 74 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Able to provide informed consent
- Adults aged 45-74
- Adults with untreated elevated blood pressure as SBP 120 to 129 mm Hg and DBP < 80 mm Hg or untreated stage 1 hypertension (i.e., pre-hypertension) as SBP 130 to 139 mm Hg or DBP 80 to 89 mm Hg or untreated stage 2 hypertension as SBP equal to or higher than 140 mm Hg or DBP equal to or higher than 90 mm Hg (ACC/AHA and ESC/ESH guidelines and Blood Pressure UK)
- Weight-stable in the 3 months prior to enrolment (self-report)
Who cannot join
- Body mass index > 40 kg/m^2 at screening;
- History of symptomatic coronary artery disease, stroke, or other known atherosclerotic disease;
- History of gastrointestinal disease (e.g., irritable bowel syndrome, inflammatory bowel disease, coeliac disease, Chron's disease) or former abdominal surgery, weight loss surgery e.g., gastric by-pass (except for appendectomy);
- History of chronic viral hepatitis (including presence of hepatitis B surface antigen or hepatitis C antibody), or other chronic hepatic disorders;
- History of malignancy within the past 5 years, other than non-melanoma skin cancer;
- History of diabetes and/or any endocrine disorder;
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- Current use of nitrate medications, including glyceryl trinitrate (GTN), isosorbide dinitrate and isosorbide mononitrate and blood pressure medications;
- Consumption of a low calorie or other special diet during the last month prior to the study, or if following a slimming or medically prescribed diet, or a vegan or macrobiotic lifestyle;
- Use of antibiotics during the three months prior to screening;
- Consumption of pre- or probiotics during the last month prior to screening and during the study, unless discontinued 3 weeks before the start of the trial. This is referred to the use of supplements only and NOT foods containing probiotics and/or prebiotics foods;
- Consumption of dietary supplements such as vitamins C and E during the last month prior to the screening and during the trial, unless discontinued 3 weeks before the start of the trial;
- Consumption of fish oil 6 weeks prior to the screening and during the trial, unless discontinued 6 weeks before the start of the trial;
- Allergies or intolerance against the substances used in the study and/or food intolerances associated with gastrointestinal upset;
- Any apparent dependence on or abuse of alcohol, tobacco, and cannabis products;
- Pregnancy, breast-feeding, or plans to become pregnant during the duration of the study;
- Current use of nitrate supplements in the form of beetroot juice, beetroot crystals, potassium nitrate and sodium nitrate, including L-arginine or L-citrulline supplements.
- Self-reported use of antimicrobial mouthwash or tongue scrapes, unless discontinued during the trial.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: The Effects of Inulin and Inorganic Nitrate on Flow-Mediated Dilation and Gut Microbiome in Adults with Pre-Hypertension and Hypertension
Previous research has revealed that adults with pre-hypertensive and hypertensive blood pressure levels typically exhibit impaired vasodilation, which is a crucial aspect of blood vessel function, due to decreased nitric oxide production. Flow-mediated dilation (FMD) is a widely used technique for assessing vasodilation, which gauges the capacity of blood vessels to widen in response to increased blood flow. Nitrate supplements have been shown to enhance blood vessel function both in the short and long term by elevating nitric oxide (NO) production. Similarly, acetate, a by-product of fibre digestion, has demonstrated anti-inflammatory effects in the gut and may also increase NO production. However, further investigation is needed to determine whether these two supplements work synergistically to improve FMD responses by augmenting NO production in the human body. This study will involve administering inulin plus nitrate supplements to adults aged 45-74 with untreated high blood pressure (120-139/80-89 mmHg and 140/90 mmHg or higher) for a period of 4 weeks, followed by a subsequent 4-week period where only inulin supplements are consumed. The supplements will be provided in the form of powder, to be mixed with water, and will be given in a cross-over and counterbalanced order. Various measurements, including brachial artery function, faecal samples, blood pressure, plasma nitrate and nitrite levels, plasma short-chain fatty acid levels, red blood cell and whole blood S-Nitrosothiols, and salivary nitrate and nitrite levels, will be taken at the baseline and after each supplementation period. Additionally, acute supplementation measurements will be collected on two separate occasions before the start of the longer-term supplement regimen.
Read the detailed description
Endothelial dysfunction contributes to the increased cardiovascular risk associated with high blood pressure levels (e.g., 120-139/80-89 mmHg and 140/90 mmHg or higher), and it is considered as an early event in the development of atherosclerotic vascular disease. Mechanistically, endothelial dysfunction is characterised by a reduced bioavailability of the endothelium-derived molecule nitric oxide (NO), which is reflected by impaired brachial artery flow-mediated dilation (FMD). However, endothelial dysfunction is largely preventable by its early detection, thus approaches that might restore the loss of NO in the body could have obvious therapeutic potential.
Consumption of the prebiotic fibre inulin has been shown to increase the fermentation of bacterial-derived metabolites such as acetate by our gut microbiome. While increased acetate has local benefits in the gut (i.e., anti-inflammatory, lower luminal pH), it also has the potential to improve endothelial health. Research has shown that acetate can increase NO bioavailability via the activation of the NO synthase pathway by increasing phosphorylation of endothelial NO synthase (eNOS), a key enzyme in the maintenance of endothelial homeostasis, following a 15-day supplementation with inulin. Similarly, NO is produced following the consumption of nitrate, with individual responses being dependent on the basal eNOS activity. Therefore, individuals with compromised eNOS activity (e.g., pre- and hypertensive) might show an augmented response to nitrate supplementation. Since both nitrate and inulin supplementations can increase NO production, it is possible that their combined ingestion might enhance endothelial function to a greater extent. When supplemented in isolation, nitrate proved an effective dietary strategy to ameliorate endothelial dysfunction in older and clinical populations. For example, a 4-week chronic dietary nitrate supplementation (400 mg nitrate/day) was associated with an increased peak brachial artery FMD of 1.0% (95% CI, 0.3-1.5; p < 0.001), which was not evident in the placebo group. Similarly, following a 4-week dietary nitrate supplementation (400 mg nitrate/day), brachial artery FMD (%) values increased significantly in the nitrate group compared to the placebo group. Unlike nitrate, the effects of inulin on brachial artery FMD in humans are yet to be established. Preliminary findings demonstrated an enhancement of endothelial function after inulin supplementation in mice. These findings were further supported by another study which demonstrated a brachial artery FMD increase of ~1% following a 3-month prebiotic supplementation with 12 g fructo-oligosaccharides in clinical patients with less severe endothelial dysfunction.
To date, no studies that the investigators are aware of have explored the role of nitrate and inulin in combination; however, based on the above, these two nutrients have the potential to work synergistically. Therefore, the primary aim of this study is to assess whether adding nitrate to inulin during a 4-week chronic supplementation might lead to an increase in brachial artery FMD in middle-aged and youngest elderly adults (45-74 years old) with elevated blood pressure and compare this response to inulin supplemented in isolation. The secondary aims of this study include brachial artery FMD % changes at 4 h post-consumption of a single dose of 15 g inulin and 1300 mg potassium nitrate combined and 15 g inulin supplemented in isolation. This study will also explore whether changes in brachial artery FMD % following the two supplementations are mediated by potential changes in the gut microbiome composition and diversity that may occur following prebiotics supplementation. Further secondary outcomes of the study will investigate differences in plasma nitrate, nitrite, and short-chain fatty acids (SCFAs) following both types of supplementation. Additionally, the study will examine changes in the levels of S-nitrosothiols (RSNO) in red blood cells and whole blood. The study will also compare changes in resting blood pressure between the combined inulin and nitrate supplementation and the inulin-only supplementation.
- Being tested
- Inulin, Potassium nitrate and inulin
- Medical subject headings
- Hypertension
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
InulinDietary supplement
15 g inulin once daily for 4 weeks.
Potassium nitrate and inulinDietary supplement
1300 mg potassium nitrate once daily for 4 weeks and 15 g inulin once daily for 4 weeks.
| Study group | Role | What they receive |
|---|---|---|
| Inulin (15 g) | Experimental | Participants will receive 15 g inulin in powder form once daily for 4 weeks. Receives: Dietary Supplement: Inulin |
| Inulin (15 g) and potassium nitrate (1300 mg) | Experimental | Participants will receive 15 g inulin in powder form once daily for 4 weeks and 1300 mg potassium nitrate in powder form once daily for 4 weeks. Receives: Dietary Supplement: Potassium nitrate and inulin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Flow-mediated dilation (FMD) with ultrasound to detect a change in brachial artery FMD
Absolute percentage change in FMD response between the 'inulin plus nitrate' and 'inulin' supplementations, measured from baseline to the 4-week chronic supplementation.
Measured: Day 0, Month 3
Plasma nitrite and nitrate levels
Differences in the concentrations of plasma nitrate and nitrite between the 'inulin plus nitrate' and 'inulin' supplementations as assessed by chemiluminescence, measured from baseline to the 4-week chronic supplementation.
Measured: Day 0, Month 3
Plasma Short-Chain Fatty Acid (SCFA) levels
Differences in the concentrations of plasma acetate, butyrate, and propionate between the 'inulin plus nitrate' and 'inulin' supplementations as assessed by liquid chromatography coupled with tandem mass spectrometry, measured from baseline to the 4-week chronic supplementation.
Measured: Day 0, Month 3
Gut microbial composition using 16S sequencing
Changes in microbial composition, including alpha and beta diversity indexes, will be evaluated using the 16S rRNA V3-V4 region. These changes will be observed from baseline to the 4-week intervention following both inulin plus nitrate and inulin-only supplementation.
Measured: Day 0, Month 3
Gut microbial composition using 16S sequencing
Changes in microbial composition, including Least Discriminant Analysis (LDA) evaluated using the 16S rRNA V3-V4 region, will be observed from baseline to the end of the 4-week intervention following supplementation with inulin plus nitrate and inulin alone.
Measured: Day 0, Month 3
Gut microbial composition using 16S sequencing
Changes in microbial composition, including the relative abundances of Operational Taxonomic Units (OTUs), will be evaluated using the 16S rRNA V3-V4 region. These changes will be observed from baseline to the end of the 4-week intervention following supplementation with inulin plus nitrate and inulin alone.
Measured: Day 0, Month 3
Secondary outcomes (14)
Flow-mediated dilation (FMD) with ultrasound to detect a change in brachial artery FMD
Absolute percentage change in FMD response between the 'inulin plus nitrate' and 'inulin' supplementations, measured from baseline to 4 h post-consumption of the supplements.
Measured: Baseline, 4 hour post supplement consumption
Plasma nitrite and nitrate levels
Differences in the concentrations of plasma nitrate and nitrite between the 'inulin plus nitrate' and 'inulin' supplementations as assessed by chemiluminescence, measured from baseline to 4 h post-consumption of the supplements.
Measured: Baseline, 4 hour post supplement consumption
Plasma Short-Chain Fatty Acid (SCFA) levels
Differences in the concentrations of plasma acetate, butyrate, and propionate between the 'inulin plus nitrate' and 'inulin' supplementations as assessed by liquid chromatography coupled with tandem mass spectrometry, measured from baseline to 4 h post-consumption of the supplements.
Measured: Baseline, 4 hour post supplement consumption
S-nitrosothiols (RSNO) in red blood cells and whole blood
Differences in the concentrations of RSNO in red blood cells and whole blood following the 'inulin plus nitrate' and 'inulin' supplementations as assessed from chemiluminescence, measured from baseline to 4 h post-consumption of the supplements.
Measured: Baseline, 4 hour post supplement consumption
S-nitrosothiols (RSNO) in red blood cells and whole blood
Differences in the concentrations of RSNO in red blood cells and whole blood following the 'inulin plus nitrate' and 'inulin' supplementations as assessed from chemiluminescence, measured from baseline to the 4-week intervention.
Measured: Day 0, Month 3
Resting blood pressure
Differences in resting blood pressure following the 'inulin plus nitrate' and the 'inulin' supplementations as assessed by an automatic sphygmomanometer, measured from baseline to 4 h post-consumption of the supplements.
Measured: Baseline, 4 hour post supplement consumption
Resting blood pressure
Differences in resting blood pressure following the 'inulin plus nitrate' and the 'inulin' supplementations as assessed by an automatic sphygmomanometer, measured from baseline to the 4-week intervention.
Measured: Day 0, Month 3
Tolerability of inulin defined by gastrointestinal wellbeing
Tolerability of a 4-week intervention with inulin with or without nitrate, assessed by completion of gastrointestinal wellbeing questionnaires, also known as the Gastrointestinal Symptom Rating Scale (GSRS). GSRS score will be calculated as per Revicki 1997:
Response scale
- No discomfort at all
- Slight discomfort
- Mild discomfort
- Moderate discomfort
- Moderately severe discomfort
- Severe discomfort
- Very severe discomfort
The 14 items combine into five symptom clusters: Reflux, Abdominal pain, Indigestion, Diarrhoea and Constipation.
Measured: Day 0, Month 3
Rate of habitual fibre intake before and during the intervention
Participants will be categorised based on their habitual dietary fibre intake to determine if the effects of the supplemented inulin are independent of their overall fibre consumption.
The questionnaire includes 5 questions addressing the intake from the five main food groups contributing to fibre intake: fruit, vegetables, bread and cereals, nuts and seeds, and legumes. The intake of these food groups will be evaluated using the following scale:
Never Less than 1 serving per month 1-3 servings per month
1 serving per week 2-4 servings per week 5-6 servings per week
- serving per day
- servings per day
- servings per day
- servings per day
- servings per day
- or more servings per day
Measured: Pre intervention, at baseline
Dietary intake
4-day recall questionnaire filled out during 4 different occasions to evaluate dietary intake, including macronutrients and caloric intake.
Measured: Day 0, Month 3
Body weight
Changes in body weight in Kg following supplementation with 'inulin plus nitrate' and 'inulin' will be measured with the use of electronic scales.
Measured: Day 0, Month 3
Body fat percentage
Changes in body fat percentage following supplementation with 'inulin plus nitrate' and 'inulin' will be assessed using bioimpedance analysis.
Measured: Day 0, Month 3
Hip circumference
The changes in hip circumference, measured at the largest circumference around the buttocks, following supplementation with 'inulin plus nitrate' and 'inulin,' will be used to calculate the waist-to-hip ratio in conjunction with waist measurement, from baseline to the 4-week intervention.
Measured: Day 0, Month 3
Waist circumference
The changes in waist circumference, measured halfway between the lower ribs and the iliac crest, following supplementation with 'inulin plus nitrate' and 'inulin', will be used to calculate the waist-to-hip ratio in conjunction with hip measurement, from baseline to the 4-week intervention.
Measured: Day 0, Month 3
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Jul 2024
- Study start9 May 2023
- Primary completion31 Jul 2024
- Study completion31 Jul 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (16)Papers the sponsor has linked to this study.
- Other trials for Endothelial DysfunctionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Participants will be assigned randomly to receive either A) a combination of inulin and nitrate, or B) inulin alone. This will be done following a crossover and counterbalanced design, ensuring that all participants will receive both treatments in a randomised order.
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 22 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Exeter
- Sponsor type
- University, hospital or other
- Collaborators
- University of East Anglia
- Responsible party
- Sponsor
- Investigators
- Luciana Torquati, PhD, Principal investigator, University of ExeterJessica Virgili, MSc, Principal investigator, University of Exeter
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06502535
- Sponsor's protocol ID
- 550689
- Status last verified
- Jan 2025
- First submitted
- 14 May 2024
- Last updated
- 9 Jan 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Armani RG, Carvalho AB, Ramos CI, Hong V, Bortolotto LA, Cassiolato JL, Oliveira NF, Cieslarova Z, do Lago CL, Klassen A, Cuppari L, Raj DS, Canziani MEF. Effect of fructooligosaccharide on endothelial function in CKD patients: a randomized controlled trial. Nephrol Dial Transplant. 2021 Dec 31;37(1):85-91. doi: 10.1093/ndt/gfaa335.
PubMed 33411910Bhardwaj R, Dod H, Sandhu MS, Bedi R, Dod S, Konat G, Chopra HK, Sharma R, Jain AC, Nanda N. Acute effects of diets rich in almonds and walnuts on endothelial function. Indian Heart J. 2018 Jul-Aug;70(4):497-501. doi: 10.1016/j.ihj.2018.01.030. Epub 2018 Feb 1.
PubMed 30170643Boets E, Deroover L, Houben E, Vermeulen K, Gomand SV, Delcour JA, Verbeke K. Quantification of in Vivo Colonic Short Chain Fatty Acid Production from Inulin. Nutrients. 2015 Oct 28;7(11):8916-29. doi: 10.3390/nu7115440.
PubMed 26516911Carlstrom M, Liu M, Yang T, Zollbrecht C, Huang L, Peleli M, Borniquel S, Kishikawa H, Hezel M, Persson AE, Weitzberg E, Lundberg JO. Cross-talk Between Nitrate-Nitrite-NO and NO Synthase Pathways in Control of Vascular NO Homeostasis. Antioxid Redox Signal. 2015 Aug 1;23(4):295-306. doi: 10.1089/ars.2013.5481. Epub 2014 Feb 6.
PubMed 24224525Catry E, Bindels LB, Tailleux A, Lestavel S, Neyrinck AM, Goossens JF, Lobysheva I, Plovier H, Essaghir A, Demoulin JB, Bouzin C, Pachikian BD, Cani PD, Staels B, Dessy C, Delzenne NM. Targeting the gut microbiota with inulin-type fructans: preclinical demonstration of a novel approach in the management of endothelial dysfunction. Gut. 2018 Feb;67(2):271-283. doi: 10.1136/gutjnl-2016-313316. Epub 2017 Apr 4.
PubMed 28377388Craighead DH, Freeberg KA, Seals DR. Vascular Endothelial Function in Midlife/Older Adults Classified According to 2017 American College of Cardiology/American Heart Association Blood Pressure Guidelines. J Am Heart Assoc. 2020 Sep;9(17):e016625. doi: 10.1161/JAHA.120.016625. Epub 2020 Aug 20.
PubMed 32815446Heiss C, Rodriguez-Mateos A, Kelm M. Central role of eNOS in the maintenance of endothelial homeostasis. Antioxid Redox Signal. 2015 May 10;22(14):1230-42. doi: 10.1089/ars.2014.6158. Epub 2014 Dec 10.
PubMed 25330054Inaba Y, Chen JA, Bergmann SR. Prediction of future cardiovascular outcomes by flow-mediated vasodilatation of brachial artery: a meta-analysis. Int J Cardiovasc Imaging. 2010 Aug;26(6):631-40. doi: 10.1007/s10554-010-9616-1. Epub 2010 Mar 26.
PubMed 20339920Jones T, Dunn EL, Macdonald JH, Kubis HP, McMahon N, Sandoo A. The Effects of Beetroot Juice on Blood Pressure, Microvascular Function and Large-Vessel Endothelial Function: A Randomized, Double-Blind, Placebo-Controlled Pilot Study in Healthy Older Adults. Nutrients. 2019 Aug 2;11(8):1792. doi: 10.3390/nu11081792.
PubMed 31382524Kapil 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.
PubMed 25421976Kleinbongard P, Dejam A, Lauer T, Jax T, Kerber S, Gharini P, Balzer J, Zotz RB, Scharf RE, Willers R, Schechter AN, Feelisch M, Kelm M. Plasma nitrite concentrations reflect the degree of endothelial dysfunction in humans. Free Radic Biol Med. 2006 Jan 15;40(2):295-302. doi: 10.1016/j.freeradbiomed.2005.08.025. Epub 2005 Nov 10.
PubMed 16413411Koch CD, Gladwin MT, Freeman BA, Lundberg JO, Weitzberg E, Morris A. Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health. Free Radic Biol Med. 2017 Apr;105:48-67. doi: 10.1016/j.freeradbiomed.2016.12.015. Epub 2016 Dec 16.
PubMed 27989792Medina-Leyte DJ, Zepeda-Garcia O, Dominguez-Perez M, Gonzalez-Garrido A, Villarreal-Molina T, Jacobo-Albavera L. Endothelial Dysfunction, Inflammation and Coronary Artery Disease: Potential Biomarkers and Promising Therapeutical Approaches. Int J Mol Sci. 2021 Apr 8;22(8):3850. doi: 10.3390/ijms22083850.
PubMed 33917744Park KH, Park WJ. Endothelial Dysfunction: Clinical Implications in Cardiovascular Disease and Therapeutic Approaches. J Korean Med Sci. 2015 Sep;30(9):1213-25. doi: 10.3346/jkms.2015.30.9.1213. Epub 2015 Aug 13.
PubMed 26339159Rios-Covian D, Ruas-Madiedo P, Margolles A, Gueimonde M, de Los Reyes-Gavilan CG, Salazar N. Intestinal Short Chain Fatty Acids and their Link with Diet and Human Health. Front Microbiol. 2016 Feb 17;7:185. doi: 10.3389/fmicb.2016.00185. eCollection 2016.
PubMed 26925050
Study at a glance
From the registry record, last updated by the sponsor on 9 Jan 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effects of Inulin and Inorganic Nitrate on Flow-Mediated Dilation and Gut Microbiome in Adults with Pre-Hypertension and Hypertension
- ClinicalTrials.gov ID
- NCT06502535
- Acronym / sponsor ID
- 550689
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 22 participants (actual)
- Lead sponsor
- University of ExeterUniversity, hospital or other
- Collaborators
- University of East Anglia
- Study start
- 9 May 2023 (actual)
- Primary completion
- 31 Jul 2024 (actual)
- Study completion
- 31 Jul 2024 (actual)
- First posted
- 16 Jul 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Previous research has revealed that adults with pre-hypertensive and hypertensive blood pressure levels typically exhibit impaired vasodilation, which is a crucial aspect of blood vessel function, due to decreased nitric oxide production. Flow-mediated dilation (FMD) is a widely used technique for assessing vasodilation, which gauges the capacity of blood vessels to widen in response to increased blood flow. Nitrate supplements have been shown to enhance blood vessel function both in the short and long term by elevating nitric oxide (NO) production. Similarly, acetate, a by-product of fibre digestion, has demonstrated anti-inflammatory effects in the gut and may also increase NO production. However, further investigation is needed to determine whether these two supplements work synergistically to improve FMD responses by augmenting NO production in the human body. This study will involve administering inulin plus nitrate supplements to adults aged 45-74 with untreated high blood pressure (120-139/80-89 mmHg and 140/90 mmHg or higher) for a period of 4 weeks, followed by a subsequent 4-week period where only inulin supplements are consumed. The supplements will be provided in the form of powder, to be mixed with water, and will be given in a cross-over and counterbalanced order. Various measurements, including brachial artery function, faecal samples, blood pressure, plasma nitrate and nitrite levels, plasma short-chain fatty acid levels, red blood cell and whole blood S-Nitrosothiols, and salivary nitrate and nitrite levels, will be taken at the baseline and after each supplementation period. Additionally, acute supplementation measurements will be collected on two separate occasions before the start of the longer-term supplement regimen.
Detailed description
Endothelial dysfunction contributes to the increased cardiovascular risk associated with high blood pressure levels (e.g., 120-139/80-89 mmHg and 140/90 mmHg or higher), and it is considered as an early event in the development of atherosclerotic vascular disease. Mechanistically, endothelial dysfunction is characterised by a reduced bioavailability of the endothelium-derived molecule nitric oxide (NO), which is reflected by impaired brachial artery flow-mediated dilation (FMD). However, endothelial dysfunction is largely preventable by its early detection, thus approaches that might restore the loss of NO in the body could have obvious therapeutic potential.
Consumption of the prebiotic fibre inulin has been shown to increase the fermentation of bacterial-derived metabolites such as acetate by our gut microbiome. While increased acetate has local benefits in the gut (i.e., anti-inflammatory, lower luminal pH), it also has the potential to improve endothelial health. Research has shown that acetate can increase NO bioavailability via the activation of the NO synthase pathway by increasing phosphorylation of endothelial NO synthase (eNOS), a key enzyme in the maintenance of endothelial homeostasis, following a 15-day supplementation with inulin. Similarly, NO is produced following the consumption of nitrate, with individual responses being dependent on the basal eNOS activity. Therefore, individuals with compromised eNOS activity (e.g., pre- and hypertensive) might show an augmented response to nitrate supplementation. Since both nitrate and inulin supplementations can increase NO production, it is possible that their combined ingestion might enhance endothelial function to a greater extent. When supplemented in isolation, nitrate proved an effective dietary strategy to ameliorate endothelial dysfunction in older and clinical populations. For example, a 4-week chronic dietary nitrate supplementation (400 mg nitrate/day) was associated with an increased peak brachial artery FMD of 1.0% (95% CI, 0.3-1.5; p < 0.001), which was not evident in the placebo group. Similarly, following a 4-week dietary nitrate supplementation (400 mg nitrate/day), brachial artery FMD (%) values increased significantly in the nitrate group compared to the placebo group. Unlike nitrate, the effects of inulin on brachial artery FMD in humans are yet to be established. Preliminary findings demonstrated an enhancement of endothelial function after inulin supplementation in mice. These findings were further supported by another study which demonstrated a brachial artery FMD increase of ~1% following a 3-month prebiotic supplementation with 12 g fructo-oligosaccharides in clinical patients with less severe endothelial dysfunction.
To date, no studies that the investigators are aware of have explored the role of nitrate and inulin in combination; however, based on the above, these two nutrients have the potential to work synergistically. Therefore, the primary aim of this study is to assess whether adding nitrate to inulin during a 4-week chronic supplementation might lead to an increase in brachial artery FMD in middle-aged and youngest elderly adults (45-74 years old) with elevated blood pressure and compare this response to inulin supplemented in isolation. The secondary aims of this study include brachial artery FMD % changes at 4 h post-consumption of a single dose of 15 g inulin and 1300 mg potassium nitrate combined and 15 g inulin supplemented in isolation. This study will also explore whether changes in brachial artery FMD % following the two supplementations are mediated by potential changes in the gut microbiome composition and diversity that may occur following prebiotics supplementation. Further secondary outcomes of the study will investigate differences in plasma nitrate, nitrite, and short-chain fatty acids (SCFAs) following both types of supplementation. Additionally, the study will examine changes in the levels of S-nitrosothiols (RSNO) in red blood cells and whole blood. The study will also compare changes in resting blood pressure between the combined inulin and nitrate supplementation and the inulin-only supplementation.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
- Model description
- Participants will be assigned randomly to receive either A) a combination of inulin and nitrate, or B) inulin alone. This will be done following a crossover and counterbalanced design, ensuring that all participants will receive both treatments in a randomised order.
| Arm | Type | Receives |
|---|---|---|
| Inulin (15 g) | Experimental | Dietary Supplement: InulinParticipants will receive 15 g inulin in powder form once daily for 4 weeks. |
| Inulin (15 g) and potassium nitrate (1300 mg) | Experimental | Dietary Supplement: Potassium nitrate and inulinParticipants will receive 15 g inulin in powder form once daily for 4 weeks and 1300 mg potassium nitrate in powder form once daily for 4 weeks. |
Who may qualify
- Ages
- 45 to 74 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Able to provide informed consent
- Adults aged 45-74
- Adults with untreated elevated blood pressure as SBP 120 to 129 mm Hg and DBP < 80 mm Hg or untreated stage 1 hypertension (i.e., pre-hypertension) as SBP 130 to 139 mm Hg or DBP 80 to 89 mm Hg or untreated stage 2 hypertension as SBP equal to or higher than 140 mm Hg or DBP equal to or higher than 90 mm Hg (ACC/AHA and ESC/ESH guidelines and Blood Pressure UK)
- Weight-stable in the 3 months prior to enrolment (self-report)
Key exclusion criteria (17 listed)
- Body mass index > 40 kg/m^2 at screening;
- History of symptomatic coronary artery disease, stroke, or other known atherosclerotic disease;
- History of gastrointestinal disease (e.g., irritable bowel syndrome, inflammatory bowel disease, coeliac disease, Chron's disease) or former abdominal surgery, weight loss surgery e.g., gastric by-pass (except for appendectomy);
- History of chronic viral hepatitis (including presence of hepatitis B surface antigen or hepatitis C antibody), or other chronic hepatic disorders;
- History of malignancy within the past 5 years, other than non-melanoma skin cancer;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Inulin15 g inulin once daily for 4 weeks. | Dietary supplement | Inulin (15 g) |
| Potassium nitrate and inulin1300 mg potassium nitrate once daily for 4 weeks and 15 g inulin once daily for 4 weeks. | Dietary supplement | Inulin (15 g) and potassium nitrate (1300 mg) |
Primary outcome
Flow-mediated dilation (FMD) with ultrasound to detect a change in brachial artery FMD
Time frame: Day 0, Month 3
Absolute percentage change in FMD response between the 'inulin plus nitrate' and 'inulin' supplementations, measured from baseline to the 4-week chronic supplementation.
Plasma nitrite and nitrate levels
Time frame: Day 0, Month 3
Differences in the concentrations of plasma nitrate and nitrite between the 'inulin plus nitrate' and 'inulin' supplementations as assessed by chemiluminescence, measured from baseline to the 4-week chronic supplementation.
Plasma Short-Chain Fatty Acid (SCFA) levels
Time frame: Day 0, Month 3
Differences in the concentrations of plasma acetate, butyrate, and propionate between the 'inulin plus nitrate' and 'inulin' supplementations as assessed by liquid chromatography coupled with tandem mass spectrometry, measured from baseline to the 4-week chronic supplementation.
Gut microbial composition using 16S sequencing
Time frame: Day 0, Month 3
Changes in microbial composition, including alpha and beta diversity indexes, will be evaluated using the 16S rRNA V3-V4 region. These changes will be observed from baseline to the 4-week intervention following both inulin plus nitrate and inulin-only supplementation.
Gut microbial composition using 16S sequencing
Time frame: Day 0, Month 3
Changes in microbial composition, including Least Discriminant Analysis (LDA) evaluated using the 16S rRNA V3-V4 region, will be observed from baseline to the end of the 4-week intervention following supplementation with inulin plus nitrate and inulin alone.
Gut microbial composition using 16S sequencing
Time frame: Day 0, Month 3
Changes in microbial composition, including the relative abundances of Operational Taxonomic Units (OTUs), will be evaluated using the 16S rRNA V3-V4 region. These changes will be observed from baseline to the end of the 4-week intervention following supplementation with inulin plus nitrate and inulin alone.
14 secondary outcomes
Flow-mediated dilation (FMD) with ultrasound to detect a change in brachial artery FMD
Time frame: Baseline, 4 hour post supplement consumption
Plasma nitrite and nitrate levels
Time frame: Baseline, 4 hour post supplement consumption
Plasma Short-Chain Fatty Acid (SCFA) levels
Time frame: Baseline, 4 hour post supplement consumption
S-nitrosothiols (RSNO) in red blood cells and whole blood
Time frame: Baseline, 4 hour post supplement consumption
S-nitrosothiols (RSNO) in red blood cells and whole blood
Time frame: Day 0, Month 3
Resting blood pressure
Time frame: Baseline, 4 hour post supplement consumption
Resting blood pressure
Time frame: Day 0, Month 3
Tolerability of inulin defined by gastrointestinal wellbeing
Time frame: Day 0, Month 3
Rate of habitual fibre intake before and during the intervention
Time frame: Pre intervention, at baseline
Dietary intake
Time frame: Day 0, Month 3
Body weight
Time frame: Day 0, Month 3
Body fat percentage
Time frame: Day 0, Month 3
Hip circumference
Time frame: Day 0, Month 3
Waist circumference
Time frame: Day 0, Month 3
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Jan 2025.
- Background: PubMed 33411910Armani RG, Carvalho AB, Ramos CI, Hong V, Bortolotto LA, Cassiolato JL, Oliveira NF, Cieslarova Z, do Lago CL, Klassen A, Cuppari L, Raj DS, Canziani MEF. Effect of fructooligosaccharide on endothelial function in CKD patients: a randomized controlled trial. Nephrol Dial Transplant. 2021 Dec 31;37(1):85-91. doi: 10.1093/ndt/gfaa335.
- Background: PubMed 30170643Bhardwaj R, Dod H, Sandhu MS, Bedi R, Dod S, Konat G, Chopra HK, Sharma R, Jain AC, Nanda N. Acute effects of diets rich in almonds and walnuts on endothelial function. Indian Heart J. 2018 Jul-Aug;70(4):497-501. doi: 10.1016/j.ihj.2018.01.030. Epub 2018 Feb 1.
- Background: PubMed 26516911Boets E, Deroover L, Houben E, Vermeulen K, Gomand SV, Delcour JA, Verbeke K. Quantification of in Vivo Colonic Short Chain Fatty Acid Production from Inulin. Nutrients. 2015 Oct 28;7(11):8916-29. doi: 10.3390/nu7115440.
- Background: PubMed 24224525Carlstrom M, Liu M, Yang T, Zollbrecht C, Huang L, Peleli M, Borniquel S, Kishikawa H, Hezel M, Persson AE, Weitzberg E, Lundberg JO. Cross-talk Between Nitrate-Nitrite-NO and NO Synthase Pathways in Control of Vascular NO Homeostasis. Antioxid Redox Signal. 2015 Aug 1;23(4):295-306. doi: 10.1089/ars.2013.5481. Epub 2014 Feb 6.
- Background: PubMed 28377388Catry E, Bindels LB, Tailleux A, Lestavel S, Neyrinck AM, Goossens JF, Lobysheva I, Plovier H, Essaghir A, Demoulin JB, Bouzin C, Pachikian BD, Cani PD, Staels B, Dessy C, Delzenne NM. Targeting the gut microbiota with inulin-type fructans: preclinical demonstration of a novel approach in the management of endothelial dysfunction. Gut. 2018 Feb;67(2):271-283. doi: 10.1136/gutjnl-2016-313316. Epub 2017 Apr 4.
- Background: PubMed 32815446Craighead DH, Freeberg KA, Seals DR. Vascular Endothelial Function in Midlife/Older Adults Classified According to 2017 American College of Cardiology/American Heart Association Blood Pressure Guidelines. J Am Heart Assoc. 2020 Sep;9(17):e016625. doi: 10.1161/JAHA.120.016625. Epub 2020 Aug 20.
- Background: PubMed 25330054Heiss C, Rodriguez-Mateos A, Kelm M. Central role of eNOS in the maintenance of endothelial homeostasis. Antioxid Redox Signal. 2015 May 10;22(14):1230-42. doi: 10.1089/ars.2014.6158. Epub 2014 Dec 10.
- Background: PubMed 20339920Inaba Y, Chen JA, Bergmann SR. Prediction of future cardiovascular outcomes by flow-mediated vasodilatation of brachial artery: a meta-analysis. Int J Cardiovasc Imaging. 2010 Aug;26(6):631-40. doi: 10.1007/s10554-010-9616-1. Epub 2010 Mar 26.
- Background: PubMed 31382524Jones T, Dunn EL, Macdonald JH, Kubis HP, McMahon N, Sandoo A. The Effects of Beetroot Juice on Blood Pressure, Microvascular Function and Large-Vessel Endothelial Function: A Randomized, Double-Blind, Placebo-Controlled Pilot Study in Healthy Older Adults. Nutrients. 2019 Aug 2;11(8):1792. doi: 10.3390/nu11081792.
- Background: PubMed 25421976Kapil 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.
- Background: PubMed 16413411Kleinbongard P, Dejam A, Lauer T, Jax T, Kerber S, Gharini P, Balzer J, Zotz RB, Scharf RE, Willers R, Schechter AN, Feelisch M, Kelm M. Plasma nitrite concentrations reflect the degree of endothelial dysfunction in humans. Free Radic Biol Med. 2006 Jan 15;40(2):295-302. doi: 10.1016/j.freeradbiomed.2005.08.025. Epub 2005 Nov 10.
- Background: PubMed 27989792Koch CD, Gladwin MT, Freeman BA, Lundberg JO, Weitzberg E, Morris A. Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health. Free Radic Biol Med. 2017 Apr;105:48-67. doi: 10.1016/j.freeradbiomed.2016.12.015. Epub 2016 Dec 16.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Luciana Torquati, PhD principal investigator
University of Exeter
Jessica Virgili, MSc principal investigator
University of Exeter
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Inulin and Potassium nitrate and inulin in people with Endothelial Dysfunction and High Blood Pressure, run by University of Exeter at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 9 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Flow-mediated dilation (FMD) with ultrasound to detect a change in brachial artery FMD (time frame: Day 0, Month 3). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06502535, which also lists 16 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Jan 2025.