Beta-Hydroxybutyrate for Crohn's Disease

(BHB Trial)

Overseen By Juan P Robayo, Research Program Manager, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Texas at Austin

Must not be taking: Antibiotics, Acid suppressors, Probiotics

Disqualifiers: Ketogenic diet, Intermittent fasting, C. difficile, others

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

Compensation: Varies

Number of Visits: 2

Duration: 4 weeks

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a supplement called beta-hydroxybutyrate (BHB) can benefit people with Crohn's disease, an inflammatory bowel condition causing pain and digestive issues. The trial aims to determine if BHB can reduce inflammation and harmful gut bacteria in these patients. Participants will take BHB capsules three times daily for four weeks and provide food, blood, and stool samples. Researchers will compare those taking BHB with those who are not to assess its impact. This trial is for individuals with Crohn's disease who are starting a new treatment plan at UT Digestive Health Clinic and are willing to follow the study requirements. As a Phase 1, Phase 2 trial, it focuses on understanding how BHB works in people and measuring its effectiveness in an initial, smaller group.

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 require that you are starting a new therapy for Crohn's disease. If you are using certain supplements or diets, like BHB supplements, a ketogenic diet, or intermittent fasting, you must stop those before joining.

Is there any evidence suggesting that beta-hydroxybutyrate is likely to be safe for humans?

Research has shown that beta-hydroxybutyrate (BHB) is generally safe for use. It has been studied for its potential to prevent inflammation in the colon and improve gut health, suggesting that most people tolerate it well. Although detailed information on side effects remains limited, other studies using BHB have not raised major safety concerns. As this trial is in its early stages, it aims to assess the safety of BHB and its tolerability. Researchers continue to collect detailed information about any possible side effects. Prospective participants should consult their healthcare provider to weigh the potential benefits and risks. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Crohn's disease?

Beta-Hydroxybutyrate (BHB) is unique in the treatment of Crohn's Disease because it introduces a novel approach by using a ketone body as a supplement. Most current treatments for Crohn's, like corticosteroids and immunosuppressants, aim to reduce inflammation or suppress the immune system. However, BHB works differently by potentially providing anti-inflammatory effects through its role as an energy source for cells, which may help to stabilize and repair the gut lining. Researchers are excited because this new mechanism could offer a complementary strategy to existing therapies, potentially improving outcomes for patients with Crohn's Disease.

What evidence suggests that beta-hydroxybutyrate might be an effective treatment for Crohn's disease?

Research has shown that Beta-Hydroxybutyrate (BHB) might aid people with Crohn's Disease by improving gut health. It alters the gut bacteria mix and reduces inflammation. Some studies found that BHB can lower inflammation, a major issue in Crohn's Disease. Early results also suggest that BHB might help maintain a strong gut lining, crucial for a healthy digestive system. In this trial, one group of participants will receive standard care therapy plus BHB supplementation, while another group will receive standard care therapy alone. Although more research is needed, these early findings are promising for using BHB as a treatment option. ^{1 2 3 6 7}

Who Is on the Research Team?

Linda Feagins

Principal Investigator

University of Texas at Austin

Are You a Good Fit for This Trial?

This trial is for individuals with Crohn's Disease or Irritable Bowel Syndrome who are starting new treatments. Participants will take a ketone body supplement, beta-hydroxybutyrate (BHB), and must be willing to document their food intake and provide blood and fecal samples at the start and end of the 4-week study.

Inclusion Criteria

Managed at UT Digestive Health Clinic

I am starting a new treatment involving specific targeted drugs.

Willing to provide consent for participation

Exclusion Criteria

Unwilling to provide signed consent

Currently or recently (within 4 weeks) following a ketogenic diet

I have not taken antibiotics in the last 3 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants take beta-hydroxybutyrate (BHB) supplements for 4 weeks, documenting food consumption and providing blood and fecal samples.

4 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of adverse events and disease activity.

4 weeks

Long-term Follow-up

Assessment of patient adherence to the intervention and ability to enroll patients within the target timeframe.

12 months

What Are the Treatments Tested in This Trial?

Interventions

• Beta-Hydroxybutyrate

Trial Overview The study tests if taking BHB supplements three times daily for four weeks can make it easier for patients to manage Crohn's disease by reducing inflammation and pro-inflammatory bacteria in the gut compared to those not taking the supplement.

How Is the Trial Designed?

Group I: Standard of care therapy plus BHB supplementation (intervention). Active Control 1 Intervention

Arm does receives the BHB supplement

Group II: standard of care therapy (control) Active Control 1 Intervention

Arm does not receive the BHB supplement

Who Is Running the Clinical Trial?

University of Texas at Austin

Lead Sponsor

Trials

387

Recruited

86,100+

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]

Neutralizing antibodies against TNF-alpha have been confirmed to play a significant role in Crohn's disease, highlighting the importance of cytokines in the disease's pathophysiology.

While n-3 fatty acids showed some potential benefits in ulcerative colitis, including significant improvements in clinical activity in some studies, their overall efficacy remains inconclusive, particularly in Crohn's disease, with mixed results from various trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lipid treatment of inflammatory bowel disease. Endres, S., Lorenz, R., Loeschke, K.[2019]

In a study of 20 patients with Crohn's disease, serum levels of certain fatty acids, particularly n3 polyunsaturated fatty acids, were found to be significantly lower compared to 18 healthy controls, indicating a potential deficiency in these beneficial fats.

The research suggests that while essential fatty acids are generally not deficient in Crohn's disease, lower levels of n3 polyunsaturated fatty acids may correlate with disease activity, highlighting their possible role in managing the condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Serum n3 polyunsaturated fatty acids are depleted in Crohn's disease. Kuroki, F., Iida, M., Matsumoto, T., et al.[2019]

Poly-D-3-hydroxybutyric acid (PHB) can be degraded by intestinal microbiota, acting as a slow-release source of 3-hydroxybutyrate (3-HB), which is beneficial in suppressing inflammation in models of inflammatory bowel disease (IBD).

In a study using a dextran sulfate sodium-induced IBD model, a PHB diet not only increased 3-HB levels in feces and blood but also reduced weight loss and inflammation, while promoting regulatory T cell accumulation in the rectum, suggesting its potential as a treatment for IBD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The novel sustained 3-hydroxybutyrate donor poly-D-3-hydroxybutyric acid prevents inflammatory bowel disease through upregulation of regulatory T-cells. Suzuki, R., Mishima, M., Nagane, M., et al.[2023]

3-Hydroxybutyrate (3HB) has been shown to significantly reduce colonic inflammation and the risk of colorectal cancer (CRC) in mouse models, indicating its potential as a preventive food supplement for colon diseases.

The protective effects of 3HB are mediated through its receptor GPR109a, which decreases harmful immune cell populations, such as M1 macrophages and myeloid-derived suppressor cells, thereby reducing inflammation and cancer risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Applications and Mechanism of 3-Hydroxybutyrate (3HB) for Prevention of Colonic Inflammation and Carcinogenesis as a Food Supplement. Li, Z., Zhang, S., Zhang, Y., et al.[2022]

Exogenous β-hydroxybutyrate (BHB) and a ketogenic diet (KD) significantly reduced disease activity and improved colon health in rats with dextran sodium sulfate (DSS)-induced ulcerative colitis, indicating their potential as therapeutic interventions.

Both BHB and KD effectively inhibited the NLRP3 inflammasome activation and reduced inflammatory markers, suggesting they not only alleviate symptoms of ulcerative colitis but also promote healing of the intestinal barrier and restore microbiota balance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Unveiling the therapeutic potential of exogenous β-hydroxybutyrate for chronic colitis in rats: novel insights on autophagy, apoptosis, and pyroptosis. Abdelhady, R., Saber, S., Ahmed Abdel-Reheim, M., et al.[2023]

In a study of 30 children with Crohn's disease, those with active disease showed lower levels of alpha-linolenic acid in their plasma compared to those in remission, indicating a potential link between disease activity and fatty acid profiles.

Children with a body mass index below the 50th centile had altered fatty acid levels, including low linoleic and alpha-linolenic acids and high arachidonic acid, suggesting that nutritional status and disease severity may influence essential fatty acid metabolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Essential fatty acid status in paediatric Crohn's disease: relationship with disease activity and nutritional status. Trebble, TM., Wootton, SA., May, A., et al.[2019]

The study developed pH-responsive nanoparticles (CSA-PENPs) using biosynthesized polyhydroxybutyrate (PHB) and Eudragit FS, which effectively targeted drug delivery to inflamed tissues in a murine model of colitis.

CSA-PENPs demonstrated enhanced therapeutic efficacy by providing sustained release of cyclosporine A (CSA) directly to the affected areas, leading to significant anti-inflammatory effects compared to conventional CSA-loaded nanoparticles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cupriavidus necator-Produced Polyhydroxybutyrate/Eudragit FS Hybrid Nanoparticles Mitigates Ulcerative Colitis via Colon-Targeted Delivery of Cyclosporine A. Lee, J., Saparbayeva, A., Hlaing, SP., et al.[2022]

The study identified that gut bacteria, particularly from the Proteobacteria and Firmicutes phyla, are capable of producing 2-hydroxybutyric acid (2HB), with Fusobacterium nucleatum being the most effective at synthesizing it.

Despite the presence of 2HB-producing bacteria in the gut, the research found that these bacteria have a limited impact on serum 2HB levels, indicating that while they contribute to intestinal 2HB concentrations, they do not significantly influence circulating 2HB in the bloodstream.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

2 Hydroxybutyric Acid-Producing Bacteria in Gut Microbiome and Fusobacterium nucleatum Regulates 2 Hydroxybutyric Acid Level In Vivo. Qin, F., Li, J., Mao, T., et al.[2023]

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]

Dietary changes, such as increasing calorie intake and fiber or using total parenteral nutrition, can be effective as primary treatments for Crohn's disease, suggesting that nutrition plays a crucial role in managing this condition.

Eicosapentaenoic acid may have therapeutic potential for ulcerative colitis by competing with arachidonic acid and reducing inflammation, although this is based on a small pilot study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nutritional therapy in ambulatory patients. O'Morain, CA.[2020]

In a study of 36 patients with Crohn's disease who had undergone ileal resection, it was found that they had lower levels of unsaturated fatty acids in their blood compared to healthy individuals, indicating a potential deficiency in these important nutrients.

Despite the lower blood levels, the patients had higher proportions of unsaturated fatty acids in their adipose tissue, suggesting that their bodies may be compensating for this deficiency due to an increased demand for fatty acid precursors needed for prostaglandin synthesis in the remaining bowel.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fatty acid composition in serum lipids and adipose tissue in patients with morbus Crohn after ileal resection. Johansson, C., Walldius, G., Rössner, S.[2018]

Citations

1. withpower.com withpower.com/trial/phase-2-crohn-disease-3-2024-546cb

Beta-Hydroxybutyrate for Crohn's Disease (BHB Trial) Beta-Hydroxybutyrate (BHB) is unique for Crohn's Disease as it acts as a ketone body that can improve gut health by altering the gut microbiome and reducing ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S221343442500009X

Free acid β-hydroxybutyrate supplementation does not ... This study aimed to investigate how continuous high-dose feeding with free acid BHB influences experimental colitis compared to a ketogenic diet.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6421268/

Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and ... SCFAs are an important fuel for intestinal epithelial cells and are known to strengthen the gut barrier function.

4. faseb.onlinelibrary.wiley.com faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fj.202200919R

The novel sustained 3‐hydroxybutyrate donor poly‐D‐3 ... The novel sustained 3-hydroxybutyrate donor poly-D-3-hydroxybutyric acid prevents inflammatory bowel disease through upregulation of regulatory ...

5. centerwatch.com centerwatch.com/clinical-trials/listings/NCT06351124/beta-hydroxybutyrate-feasibility-treating-ibd

Beta-Hydroxybutyrate Feasibility Treating IBD This clinical trial aims to understand the feasibility of patients taking ketone body supplement beta-hydroxybutyrate (BHB) for 4 weeks with ...

6. biorxiv.org biorxiv.org/content/10.1101/2025.01.19.633758v1.full.pdf

Free acid β-hydroxybutyrate supplementation does not ... hydroxybutyric acid prevents inflammatory bowel disease through upregulation of. 580 regulatory T-cells. FASEB J, 37(1), e22708. https://doi ...

7. go.drugbank.com go.drugbank.com/drugs/DB16506

beta-Hydroxybutyric acid: Uses, Interactions, Mechanism of ... Beta-hydroxybutyrate has potential applications in a variety of diseases and human aging and is currently being investigated against COVID-19.