Bismuth Subsalicylate for Gut Health in Healthy Adults

Overseen By Suchitra K Hourigan, M.D.

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must not be taking: Antibiotics, Salicylates, Anticoagulants, others

Disqualifiers: Pregnancy, GI ulcers, Bleeding disorder, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 7

Duration: 2 days

30 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Many kinds of good or normal bacteria live on your skin and inside your stomach and intestines (gut). These bacteria are important to your health. What you eat, where you live, and what medicines you take can affect the bacteria in your gut. Bismuth subsalicylate (BSS) is an ingredient in common medicines for mild diarrhea and stomach pain. Products that contain BSS include Pepto-Bismol, Kao-Tin, and Pink Bismuth. But how BSS affects the bacteria in a person s gut is not fully understood. Objective: To see how BSS affects gut bacteria in healthy people. Eligibility: Healthy people aged 18 to 50 years. Design: Participants will have 6 clinic visits in up to 18 weeks. Only 1 visit must be at the NIH clinic; others may be either in-person or remote. BSS is a liquid taken by mouth. Participants will take a dose of BSS 4 times a day for 2 days. They will take the same amount of BSS as a person would take to treat diarrhea or related problems. Stool samples will be collected at each study visit. For remote visits, participants will be given a collection kit; they will collect the sample at home and send it in. Participants will take surveys at each visit. They will answer questions about their diet and health. Participants may also provide optional samples of blood, saliva, and urine. Participants may have up to 2 optional colonoscopies. A long tube will be inserted via the rectum to collect tissue samples from the intestine. Participants will be sedated or placed under anesthesia for the procedure.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as antibiotics, BSS, salicylates (like aspirin), and anticoagulants, before participating. If you are on any of these, you may need to stop them to join the study.

What evidence supports the effectiveness of the drug Bismuth Subsalicylate for gut health?

Bismuth subsalicylate, the active ingredient in Pepto-Bismol, has been shown to reduce the severity of diarrhea and suppress Helicobacter pylori, a bacteria linked to stomach issues. It also interacts with certain dietary components to produce products active against Clostridium difficile, another gut-related bacteria. ^{1 2 3 4 5}

Is bismuth subsalicylate safe for use in humans?

Bismuth subsalicylate, found in products like Pepto-Bismol, has been used safely for over 80 years. Studies show that it is well-tolerated, with low absorption of bismuth and salicylate levels below toxicity. It is considered safe for short-term use and up to 3-4 weeks of extended dosing. ^{3 4 5 6 7}

How does the drug Bismuth Subsalicylate differ from other treatments for gut health?

Bismuth Subsalicylate is unique because it combines bismuth, which has antimicrobial properties, with subsalicylate, which can reduce inflammation and irritation in the gut. This dual action may offer a novel approach to maintaining gut health compared to other treatments that typically focus on either microbial balance or inflammation alone. ^{8 9 10 11 12}

Research Team

Suchitra K Hourigan, M.D.

Principal Investigator

National Institute of Allergy and Infectious Diseases (NIAID)

Eligibility Criteria

Healthy adults aged 18 to 50 who can consent and agree to use contraception if applicable. Excluded are those pregnant, breastfeeding, with recent diarrhea or bloody stools, poor English skills, on certain medications like antibiotics or anticoagulants within the last three months, using BSS recently, allergic to salicylates including aspirin, with bleeding disorders or GI ulcers.

Inclusion Criteria

Able to provide informed consent

Participants who can become pregnant must agree to use one effective method of contraception when engaging in sexual activities that can result in pregnancy, beginning at baseline (as early as week -6) until the final study visit. Acceptable methods of contraception include external or internal condom with spermicide, diaphragm or cervical cap with a spermicide, hormonal contraception, intrauterine device.

Willing to allow samples and data to be stored and shared for future research

Exclusion Criteria

I am currently taking aspirin or similar medications.

Any condition that, in the opinion of the study team, contraindicates participation in this study

I am not taking any medications that could interact with BSS.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Baseline Assessment

Participants provide baseline stool and optional blood, saliva, urine, and intestinal biopsy samples

1 week

1 visit (in-person or remote)

Treatment

Participants take BSS 4 times a day for 2 days

2 days

No additional visits required

Follow-up

Participants are monitored for changes in gut microbiome and host response with stool and optional blood, saliva, urine, and intestinal biopsy samples collected at specified intervals

4 weeks

5 visits (in-person or remote)

Treatment Details

Interventions

• Bismuth Subsalicylate

Trial Overview The trial tests how Bismuth subsalicylate (BSS), found in over-the-counter treatments for stomach issues like Pepto-Bismol affects gut bacteria. Participants take BSS four times daily for two days and provide stool samples at each visit over up to 16 weeks. Optional blood, saliva, urine samples and colonoscopies may be involved.

Participant Groups

Group I: Interventional Experimental Treatment 1 Intervention

The oral suspension formulation of BSS will be used in this study. It is self administered at 1050mg 4 times per day (1 to 6 hours apart) for 2 days.

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Findings from Research

All three bismuth compounds (De-Noltabs, Pepto-Bismol, and Roter) significantly reduced intragastric urease activity in Helicobacter pylori-positive patients after just one day of dosing, indicating their efficacy in suppressing H. pylori.

The study found no significant difference in effectiveness among the three compounds, suggesting that their action occurs locally in the stomach rather than requiring systemic absorption of bismuth.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of one-day oral dosing with three bismuth compounds for the suppression of Helicobacter pylori assessed by the 13C-urea breath test. Prewett, EJ., Luk, YW., Fraser, AG., et al.[2019]

The addition of bismuth subsalicylate to standard triple therapy for Helicobacter pylori infection resulted in a higher eradication rate of 89.7% compared to 80% in the placebo group, indicating its efficacy in treatment.

Patients receiving bismuth subsalicylate experienced fewer adverse effects, such as abdominal pain (20.7% vs. 52% in the placebo group) and no cases of dark feces in the placebo group, suggesting a safety advantage in using bismuth subsalicylate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Addition of bismuth subsalicylate to triple eradication therapy for Helicobacter pylori infection: efficiency and adverse events]. Hinostroza Morales, D., Díaz Ferrer, J.[2016]

Bismuth subsalicylate (BSS), found in Pepto-Bismol, can interact with dietary components to form water-soluble products that are effective against Clostridium difficile, a harmful bacteria that can cause severe gastrointestinal issues.

This study utilized mass spectrometry and the agar dilution method to demonstrate the potential of BSS in treating infections, highlighting its mechanism of action through the transformation of insoluble compounds into soluble, active forms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interaction of bismuth subsalicylate with fruit juices, ascorbic acid, and thiol-containing substrates to produce soluble bismuth products active against Clostridium difficile. Mahony, DE., Woods, A., Eelman, MD., et al.[2022]

In a 21-day double-blind, randomized, placebo-controlled trial involving 128 young healthy adults, subsalicylate bismuth significantly reduced the incidence of diarrhea, with only 23% of participants experiencing diarrhea compared to 61% in the placebo group.

Participants taking subsalicylate bismuth not only had fewer cases of diarrhea but also experienced fewer intestinal complaints and a lower rate of enteropathogens in their stools, indicating its efficacy in preventing gastrointestinal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prevention of traveler's diarrhea (emporiatric enteritis). Prophylactic administration of subsalicylate bismuth). DuPont, HL., Sullivan, P., Evans, DG., et al.[2022]

In a study evaluating treatments for Helicobacter pylori infection, both clindamycin combined with bismuth subsalicylate and bismuth alone improved clinical symptoms like abdominal pain and heartburn, but microbiological cure rates were very low, with only 1 out of 11 patients achieving success with bismuth alone.

The results suggest that treating H. pylori may require a combination of multiple antibiotics or additional medications to enhance effectiveness, as neither treatment group achieved significant eradication of the bacteria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Double-blind randomized trial of bismuth subsalicylate and clindamycin for treatment of Helicobacter pylori infection. Westblom, TU., Madan, E., Subik, MA., et al.[2019]

Pepto-Bismol, containing bismuth subsalicylate (BSS), is safe for use in treating gastrointestinal issues, with studies showing that even extended use for up to 6 weeks results in bismuth levels in the blood that are far below those associated with neurotoxicity.

The active ingredient, salicylic acid, is absorbed effectively, but the risk of toxicity remains low, as the peak plasma concentrations from the maximum daily dose are well below toxic levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bismuth subsalicylate: history, chemistry, and safety. Bierer, DW.[2019]

Bismuth preparations, such as tripotassium dicitrato bismuthate and bismuth subsalicylate, are safe for treating gastrointestinal disorders, with adverse reactions being mild and infrequent due to less than 1% systemic absorption of bismuth.

In clinical studies, even after repeated dosing, plasma bismuth concentrations remained well below toxic levels, indicating that these medications can be used effectively without significant risk of toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review article: safety of bismuth in the treatment of gastrointestinal diseases. Tillman, LA., Drake, FM., Dixon, JS., et al.[2019]

Healthy women exhibit lower intestinal permeability and greater microbial diversity compared to men, indicating potential sex-based differences in gut health.

Both sexes experience increased intestinal permeability after taking indomethacin, but only women show a significant decrease in fecal microbial diversity, suggesting that women's gut microbiota may be more sensitive to disturbances.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sex differences in NSAID-induced perturbation of human intestinal barrier function and microbiota. Edogawa, S., Peters, SA., Jenkins, GD., et al.[2023]

The NSAID BFMeT induced ileal ulcers in rats, but this effect was completely prevented in rats treated with antibiotics or those that were germ-free, indicating that intestinal bacteria play a crucial role in ulcer formation.

Specific beneficial bacteria, such as Bifidobacterium and Lactobacillus, were found to inhibit ulcer formation by suppressing the growth of harmful Gram-negative bacteria associated with ulcers, suggesting a protective mechanism against NSAID-induced damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of intestinal bacteria in ileal ulcer formation in rats treated with a nonsteroidal antiinflammatory drug. Uejima, M., Kinouchi, T., Kataoka, K., et al.[2019]

In a study involving mice, the combination of high-fat diet (HFD) and altered colonic health from intrarectal capsazepine administration led to significant damage to the colonic mucosal lining and increased intestinal permeability over 8 weeks.

This damage prevented the protective effects of the prebiotic isomaltooligosaccharides, highlighting that the health of the colonic mucosa is crucial for the effectiveness of dietary interventions like prebiotics in mitigating HFD-induced harm.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Capsazepine-Induced Altered Colonic Mucosal Health Limits Isomalto-oligosaccharide Action in High-Fat Diet-Fed C57BL/6J Mice. Kumar, V., Kumar, V., Kondepudi, KK., et al.[2023]

The study found that non-digestible fractions of spent coffee grounds (hgf-NDSCG) can induce apoptosis in human colon cancer cells (HT-29) through mechanisms involving oxidative stress reduction, particularly influenced by the source of gut microbiota (lean vs. overweight).

Lean microbiota showed a lower lethal concentration (LC50) for hgf-NDSCG, indicating that the gut flora composition can significantly affect the chemopreventive efficacy of hgf-NDSCG against colon cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Microbiota source impact in vitro metabolite colonic production and anti-proliferative effect of spent coffee grounds on human colon cancer cells (HT-29). Hernández-Arriaga, AM., Dave Oomah, B., Campos-Vega, R.[2019]

Bifidobacterium animalis ssp. lactis 420 significantly reduced the increase in stomach permeability caused by the NSAID indomethacin in a study involving 120 male Wistar rats.

While the probiotic did not significantly protect against visual mucosal damage, it did lower the incidence of severe NSAID-induced lesions from 50% to 33%, suggesting a potential benefit in reducing serious gastrointestinal side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bifidobacterium animalis ssp. lactis 420 Protects against Indomethacin-Induced Gastric Permeability in Rats. Lyra, A., Saarinen, M., Putaala, H., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Comparison of one-day oral dosing with three bismuth compounds for the suppression of Helicobacter pylori assessed by the 13C-urea breath test. [2019]

2. Peru pubmed.ncbi.nlm.nih.gov

[Addition of bismuth subsalicylate to triple eradication therapy for Helicobacter pylori infection: efficiency and adverse events]. [2016]

3. United States pubmed.ncbi.nlm.nih.gov

Interaction of bismuth subsalicylate with fruit juices, ascorbic acid, and thiol-containing substrates to produce soluble bismuth products active against Clostridium difficile. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Prevention of traveler's diarrhea (emporiatric enteritis). Prophylactic administration of subsalicylate bismuth). [2022]

5. England pubmed.ncbi.nlm.nih.gov

Double-blind randomized trial of bismuth subsalicylate and clindamycin for treatment of Helicobacter pylori infection. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Bismuth subsalicylate: history, chemistry, and safety. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Review article: safety of bismuth in the treatment of gastrointestinal diseases. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Sex differences in NSAID-induced perturbation of human intestinal barrier function and microbiota. [2023]

9. Australia pubmed.ncbi.nlm.nih.gov

Role of intestinal bacteria in ileal ulcer formation in rats treated with a nonsteroidal antiinflammatory drug. [2019]

10. United States pubmed.ncbi.nlm.nih.gov

Capsazepine-Induced Altered Colonic Mucosal Health Limits Isomalto-oligosaccharide Action in High-Fat Diet-Fed C57BL/6J Mice. [2023]

11. Canada pubmed.ncbi.nlm.nih.gov

Microbiota source impact in vitro metabolite colonic production and anti-proliferative effect of spent coffee grounds on human colon cancer cells (HT-29). [2019]

12. Egypt pubmed.ncbi.nlm.nih.gov

Bifidobacterium animalis ssp. lactis 420 Protects against Indomethacin-Induced Gastric Permeability in Rats. [2021]