Ketone Ester for Microbiome Health

(BREAK Trial)

Overseen By John C Newman, MD, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: University of California, San Francisco

Must not be taking: Opioids, Antidiarrheals, Antispasmodics, others

Disqualifiers: Cancer, Uncontrolled cardiac, Gastrointestinal, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 7 days

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if a ketone ester supplement can improve gut health by altering the gut microbiome, which consists of bacteria and other microorganisms in the digestive system. Researchers seek to discover whether taking a ketone ester can reduce signs of aging in the gut and identify any overall changes it might cause. Participants will take a ketone ester daily for a week and will need to provide stool samples and measure their ketone levels. This trial suits individuals aged 18 to 40 with a BMI between 18.5 and 39.9, who do not have severe digestive issues or recent antibiotic use. As an unphased trial, this study offers a unique opportunity to contribute to groundbreaking research on gut health and aging.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does exclude those who have used medications affecting gut function within 30 days before starting. It's best to discuss your specific medications with the study team.

What prior data suggests that this ketone ester is safe for human consumption?

Research has shown that the ketone ester bis-octanoyl (R)-1,3-butanediol is generally safe and well-tolerated by healthy older adults when taken daily. One study found that this ketone ester did not cause significant side effects. Additionally, ketone esters effectively raise blood ketone levels with few negative effects. This suggests that the ketone ester used in this trial is likely safe for participants, particularly for short-term use as in this study. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Unlike traditional treatments for microbiome health that typically focus on probiotics or dietary changes, this study treatment uses an exogenous ketone ester, specifically bis-octanoyl-(R)-1,3-butanediol (C8). Researchers are excited about this because ketone esters provide an alternative energy source for gut bacteria, potentially supporting a healthier microbiome composition. This novel mechanism of action distinguishes it from other treatments, which usually do not directly supply energy to gut microbes. By directly influencing the microbiome's energy dynamics, this treatment could offer a more targeted approach to enhancing gut health.

What evidence suggests that this treatment might be an effective treatment for microbiome health?

Research suggests that ketone esters, such as bis-octanoyl-(R)-1,3-butanediol (C8), might improve gut health. In this trial, participants will receive 25g of this ketone ester daily. Studies have shown that daily intake of this ketone ester is safe and well-tolerated by healthy older adults. This treatment uses ketones from outside the body, serving as an alternative energy source and potentially benefiting gut bacteria. Although the direct effects on the gut are still under investigation, ketone esters have shown promise in other health areas. Early findings suggest they might help reduce liver fat and improve blood sugar control, indicating potential wider benefits for metabolism. ^{6 7 8 9 10}

Who Is on the Research Team?

John C Newman, MD, PhD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

This trial is for healthy adults interested in the potential benefits of a ketone ester on gut health. Participants will need to be comfortable with daily drink consumption, urine testing, and stool sample collection over a week.

Inclusion Criteria

My BMI is between 18.5 and 39.9.

Subject has an email address and internet access via computer, phone, or other device, and is willing and able to maintain internet access throughout the trial to complete virtual visits via video conference and electronic questionnaires

Subject has no health conditions that would prevent them from fulfilling the study requirements as judged by the Clinical Investigator on the basis of medical history and routine laboratory test results

Exclusion Criteria

Subject has been hospitalized within 30 days of Virtual Visit 1

I have taken antibiotics within the last 60 days.

I am currently being treated for cancer, under surveillance, or was diagnosed within the last two years, excluding non-melanoma skin cancer.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 week

Treatment

Participants take a ketone ester drink every day for seven days and collect stool samples

7 days

Daily self-administration and sample collection

Follow-up

Participants are monitored for changes in microbiome composition and tolerability symptoms

2 weeks

Sample collection and symptom recording

What Are the Treatments Tested in This Trial?

Interventions

• Exogenous ketone ester

Trial Overview The study investigates if consuming a ketone ester drink daily for six days can positively alter the gut microbiome and reduce age-related changes. It involves tracking diet, monitoring ketones via urine tests, and analyzing stool samples before, during, and after intake.

How Is the Trial Designed?

Group I: 25g Bis-octanoyl-(R)-1,3-butanediol (C8) Experimental Treatment 1 Intervention

Participants will receive 25g of the ketone ester bis-octanoyl-(R)-1,3-butanediol (C8) daily.

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

Published Research Related to This Trial

3-Hydroxybutyrate (3HB) has the potential to enhance gut health by regulating the gut microbiome and promoting stem cell expansion, suggesting its role as a key player in gut physiology.

Using poly-hydroxybutyrate (PHB) as a prebiotic can effectively donate 3HB to the gut, potentially improving the gut environment and maintaining microbiome integrity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New prebiotics by ketone donation. Satoh, T.[2023]

Ketogenic diets (KDs) significantly alter gut microbiota composition, specifically leading to a depletion of bifidobacteria, which is distinct from the effects of high-fat diets (HFDs).

Ketone bodies produced during KDs inhibit the growth of bifidobacteria and are associated with a reduction in pro-inflammatory Th17 cells in the gut, suggesting that KDs may have anti-inflammatory effects through microbiome modulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketogenic Diets Alter the Gut Microbiome Resulting in Decreased Intestinal Th17 Cells. Ang, QY., Alexander, M., Newman, JC., et al.[2022]

The engineered probiotic Escherichia coli Nissle 1917 (EcN) successfully produced the ketone body (R)-3-hydroxybutyrate (3HB) in the guts of mice, significantly increasing levels of beneficial short-chain fatty acids and promoting the growth of healthy gut bacteria.

This modified EcN (EcNL4) effectively improved symptoms of colitis in mice, outperforming both wild-type EcN and direct 3HB administration in various health markers, suggesting a novel approach for treating colonic diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Construction of a sustainable 3-hydroxybutyrate-producing probiotic Escherichia coli for treatment of colitis. Yan, X., Liu, XY., Zhang, D., et al.[2023]

Two validated LC-MS methods were developed to accurately measure ketone ester and its metabolites in human plasma, ensuring reliable pharmacokinetic profiling for potential therapeutic use.

The study found that ketone ester undergoes non-saturable metabolism in human plasma, indicating its metabolic stability at high concentrations, and that human serum albumin plays a role in its metabolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quantitative Determination of (R)-3-Hydroxybutyl (R)-3-Hydroxybutyrate (Ketone Ester) and Its Metabolites Beta-hydroxybutyrate, 1-3-Butanediol, and Acetoacetate in Human Plasma Using LC-MS. Panse, N., Halquist, M., Gerk, PM.[2023]

Citations

1. withpower.com withpower.com/trial/phase-microbiome-analysis-4-2025-bfbbb

Ketone Ester for Microbiome Health (BREAK Trial) The ketone ester treatment is unique because it involves the use of exogenous ketones, specifically 3-hydroxybutyrate (3HB), which can improve gut health by ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11695072/

Daily consumption of ketone ester, bis-octanoyl (R) The results of this pilot study demonstrate that this cohort of healthy older adults tolerably and safely consumed up to 25 g per day of the ketone ester, bis- ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39137624/?utm_source=FeedFetcher&utm_medium=rss&utm_campaign=None&utm_content=1T5FW5K6kI73iaYFcm6n6ILcuJDBKumLJYi5zjRCdcUGYRRQ1&fc=None&ff=20240821173439&v=2.18.0.post9+e462414

Daily consumption of ketone ester, bis-octanoyl (R) - PubMed Daily consumption of ketone ester, bis-octanoyl (R)-1,3-butanediol, is safe and tolerable in healthy older adults in a randomized, parallel ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT07097506

Effect of Ketone Esters on Liver Fat Content and Metabolic ... The goal of this clinical trial is to determine whether ingestion of a ketone ester drink helps improve liver health and blood glucose control.

5. mdpi.com mdpi.com/2072-6643/17/19/3125

Clinical Benefits of Exogenous Ketosis in Adults with Disease In VLCADD [74], ketone ester supplementation improved muscle bioenergetics, while in McArdle disease, results were inconsistent: one ketone ester trial [75] ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S1279770724004160

Daily consumption of ketone ester, bis-octanoyl (R) Daily consumption of ketone ester, bis-octanoyl (R)-1,3-butanediol, is safe and tolerable in healthy older adults in a randomized, parallel arm, double-blind, ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10635199/

Rationale and protocol for a safety, tolerability and feasibility ... The primary objective of this randomized, placebo-controlled, double-blinded, parallel-group, pilot trial is to determine tolerability of 12-weeks of KE ...

8. mdpi.com mdpi.com/2072-6643/13/6/2066

Tolerability and Safety of a Novel Ketogenic Ester, Bis ... In this study, we determined the tolerability and safety of a novel exogenous ketone diester, bis-hexanoyl-(R)-1,3-butanediol (BH-BD), in a 28-day, randomized, ...

9. researchgate.net researchgate.net/publication/380427960_Daily_consumption_of_ketone_ester_bis-octanoyl_R-13-butanediol_is_safe_and_tolerable_in_healthy_older_adults_a_randomized_parallel_arm_double-blind_placebo-controlled_pilot_study

(PDF) Daily consumption of ketone ester, bis-octanoyl (R) The primary objective of this trial was to determine tolerability and safety of KE ingestion in older adults. Design: Randomized, placebo- ...

10. frontiersin.org frontiersin.org/journals/nutrition/articles/10.3389/fnut.2024.1485280/full

Exogenous ketone bodies and the ketogenic diet as a ... Studies have demonstrated that 1,3-butanediol ketone esters can reliably produce dose-dependent ketosis of 1–7 mM with minimal adverse side effects (15).