Associations Between the Microbiome, Skeletal Muscle Perfusion, and Fitness Status

Overweight and Obesity Clinical Trial

Official title:

Associations Between the Microbiome, Skeletal Muscle Perfusion, and Fitness Status

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06009276
• Other study ID #: HSR230229
• Status: Recruiting
• Start date: August 30, 2023
• Est. completion date: August 7, 2024

Study information

• Verified date: November 2023
• Source: University of Virginia
• Contact: Casey C Derella, PhD
• Phone: 6092476377
• Email: bxg7vn[@]virginia.edu
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The purpose of the study is to determine associations between fitness status, bacteria in the mouth, and the blood flow to muscle. This study is trying to find out if fitness status impacts the bacteria that are present in the oral microbiome (environment in the mouth) or the ability of the body to send blood to the skeletal muscle.

Participants will complete all or some of the following:

• A mouth swab to assess the bacteria in their mouths.

• Produce a saliva sample into a tube.

• Cycle on a bike until you reach maximum effort.

• Undergo blood draws

• Wear a 24-hour non-invasive device that monitors blood pressure.

• Undergo a test to assess blood flow to the muscles measured with an ultrasound.

• Drink 70mL (1/3 of a cup) of concentrated beetroot juice once

Description:

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. Nitric oxide (NO) is a gaseous diatomic free-radical and is essential for a plethora of physiological functions involved in cardiometabolic health and CVD risk. NO bioavailability is associated with greater tissue perfusion, mitochondrial function, glucose regulation, and overall reduced CVD risk. The primary source of circulating NO is vascular endothelial nitric oxide synthase.

Unfortunately, the endothelium can be disrupted/damaged via a variety of CVD risk factors such as hypertension, smoking, hyperlipidemia, diabetes, inflammation, and hypercholesteremia. Disruption of the vascular endothelium and loss of bioavailable NO is a preliminary step in the progression of atherosclerosis and CVD. Decreased NO bioavailability and vascular dysfunction have been shown in a variety of clinical conditions including patients heart failure and peripheral artery disease (PAD).

Recently, an exogenous approach to increasing NO bioavailability via oral supplementation of inorganic nitrate (NO3-) has been utilized to increase NO bioavailability in various healthy and clinical populations. Briefly, inorganic NO3- is swallowed, absorbed into the circulation, and sequestered back into the salivary glands. NO3- is then secreted into the oral cavity, where bacteria containing nitrate reductase enzymes convert NO3- to nitrite (NO2-), which is again swallowed and absorbed into the circulation. NO2- in the plasma is then easily reduced to NO via non-enzymatic reactions.

This study aims to better elucidate the relationship between the oral microbiome abundance and diversity and NO3- to NO2- to NO conversion across a variety of subject populations ranging from healthy subjects to those with risk factors for CVD and people with diagnosed CVD. We also aim to examine the relationship between oral microbiome NO3- reduction and impaired skeletal muscle perfusion and exercise capacity as NO bioavailability plays a large role in these physiological processes.

The results of this study may allow us to better understand how novel interventions to modify the oral microbiome may improve cardiometabolic health and physical function in individuals with CVD and outline potential new therapeutic approaches.

The primary objective of this preliminary study is to compare the abundance and diversity of oral NO3- reducing bacteria in a variety of subjects with varying cardiometabolic health status and their ability to convert oral inorganic nitrate to nitrite measured in the saliva and plasma.

A secondary objective is to determine associations between the abundance and diversity of oral NO3- reducing bacteria and both skeletal muscle tissue perfusion during exercise and exercise capacity. A tertiary objective is to determine the stability of these relationships over time following lifestyle modifications (i.e., exercise, diet).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 70
• Est. completion date: August 7, 2024
• Est. primary completion date: August 7, 2024
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Subjects must be able to communicate meaningfully with the investigator and must be legally competent to provide written informed consent.

• Subjects may be of either sex with age 18 years.

Exclusion Criteria:

• Oral antibiotic use within previous four weeks

• Oral disease or poor oral health as determined by the Oral Health Questionnaire

• Using an antibacterial mouthwash or a mouthwash containing chlorhexidine and unwilling to discontinue use

• Tobacco smokers

• Pregnant or lactating females

• Hypersensitivity to any ultrasound contrast agent

• Inability to perform exercise

• Unable to communicate effectively in English to the study team.

• Diagnosis of chronic renal failure (GFR < 60 ml/min/1.73m)

• Subjects taking nitroglycerine (or inorganic nitrates), PDE-5 inhibitors (ex: Cialis, Viagra), and xanthine oxidase inhibitors (ex: Allopurinol).

Related Conditions & MeSH terms

• Heart Failure
• Heart Failure, Diastolic
• Heart Failure, Systolic
• Overweight
• Overweight and Obesity
• Peripheral Arterial Disease
• Peripheral Vascular Diseases

Locations

Country	Name	City	State
United States	UVA Student Health and Wellness Building	Charlottesville	Virginia

Sponsors (1)

Lead Sponsor	Collaborator
University of Virginia

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Peripheral and Central Blood Pressures	Brachial artery blood pressures will be obtained using a standard sphygmomanometer. Aortic blood pressures will be obtained using applanation tonometry (SphygmoCor version 8.0, AtCor Medical).	Baseline, 4-weeks, 12-weeks, 6-months
Other	24-hour ambulatory blood pressure	Blood pressure will be monitored using a standard ambulatory brachial artery blood pressure cuff (SunTech Oscar 2, SunTech Medical). Blood pressure measurements are programmed to be taken every 30-minutes during the day and every hour at night. This allows for monitoring of nighttime blood pressure changes and variations throughout the day.	Baseline, 4-weeks, 12-weeks, 6-months
Other	Skeletal muscle microvascular perfusion (near-infra-red- spectroscopy)	Tissue oxygenation will be captured noninvasively using non-invasive, near-infrared spectrometry (NIRS, PortaMon, Artinis Medical Systems B.V., The Netherlands) positioned on the gastrocnemius or vastus lateralis muscle.	Baseline, 4-weeks, 12-weeks, 6-months
Other	Flow-Mediated Dilation	Participants will be placed in a supine position with their left forearm slightly extended and supinated with legs straight. The arteries will be imaged using a high-resolution 7.5MHz linear array transducer at rest, during 5 minutes of forearm occlusion via cuff inflation, and continuously for 3 minutes post-occlusion; an EKG trigger will be used to capture images during end-diastole of the cardiac cycle.	Baseline, 4-weeks, 12-weeks, 6-months
Other	Serum Glucose	A blood sample will be obtained to measure serum glucose.	Baseline, 4-weeks, 12-weeks, 6-months
Other	Insulin	A blood sample will be obtained to measure insulin.	Baseline, 4-weeks, 12-weeks, 6-months
Other	Lipids	A blood sample will be obtained to measure lipids.	Baseline, 4-weeks, 12-weeks, 6-months
Other	Hemoglobin	A blood sample will be obtained to measure hemoglobin.	Baseline, 4-weeks, 12-weeks, 6-months
Other	Hematocrit	A blood sample will be obtained to measure hematocrit.	Baseline, 4-weeks, 12-weeks, 6-months
Other	Plasma Nitrate	A fasting blood draw will be taken. Following the blood draw, the participant will take one dose of Beetroot juice. The participant will then return to the lab three hours later for a second blood draw to assess level of nitrate in the plasma.	Baseline, 4-weeks, 12-weeks, 6-months
Other	Plasma Nitrite	A fasting blood draw will be taken. Following the blood draw, the participant will take one dose of Beetroot juice. The participant will then return to the lab three hours later for a second blood draw to assess level of nitrite in the plasma.	Baseline, 4-weeks, 12-weeks, 6-months
Primary	Oral Nitrate Reducing Capacity	Assessment of the oral microbiome's ability to reduce nitrate to nitrite. This will be measured through a swab on the dorsal surface of the tongue, an unstimulated saliva sample, and a rinse of a standard nitrate solution.	Baseline, 4-weeks, 12-weeks, 6-months
Secondary	Skeletal muscle perfusion	An I.V. will be placed and contrast ultrasound measurement of skeletal muscle blood flow of the calf, quad, and forearm at rest will be performed by the PI or a research sonographer using continuous infusion of Definity (2.3 mL diluted to 30 mL infused 1.5 ml/min) at a mechanical index (peak negative acoustic pressure/[frequency]) of 0.15 (defined by the American Society of Echocardiography contrast guidelines as low power).	Baseline, 4-weeks, 12-weeks, 6-months
Secondary	Aerobic Capacity	Peak aerobic capacity (VO2peak) will be assessed using a symptom-limited graded exercise test on a cycle ergometer.	Baseline, 4-weeks, 12-weeks, 6-months