Mechanisms of Probiotics and Antibiotic-Associated Diarrhea (OURBIOTIC)

Exploratory Pilot Studies to Demonstrate Mechanisms of Preventing Antibiotic-Associated Diarrhea and the Role for Probiotics

The focus of the study is to better understand the mechanisms causing antibiotic-associated diarrhea (AAD) and how probiotics may prevent some of the iatrogenic effects of antibiotic medications. One of the most common indications for probiotics is for prevention of antibiotic-associated diarrhea. Clinically, different probiotic strains have demonstrated the ability to prevent AAD; however, the mechanism of action behind this effect has not been elucidated. Data from several studies suggest that antibiotic-induced disruption of commensal bacteria in the colon results in a significant (up to 50%) reduction in short chain fatty acid (SCFA) production and a concomitant reduction in Na-dependent fluid absorption resulting in AAD. Probiotics have been shown to ameliorate a variety of gastrointestinal disease states and thus, the study investigators hypothesize that administration of a probiotic yogurt will protect against the development of AAD.

Study Overview

• Status: Completed
• Conditions: Antibiotic-associated Diarrhea
• Intervention / Treatment: Drug: Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet; Other: Control Yogurt; Biological: BB-12

Detailed Description

Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. One of the most common indications for probiotic treatment is the prevention of antibiotic-associated diarrhea (AAD). Unfortunately, the efficacy of many probiotic products used for AAD is not supported by rigorous independent research, and non-evidence-based clinical usage is common. Data from several studies are consistent with the notion that antibiotic-induced disruption of commensal bacteria in the colon results in a significant reduction of short chain fatty acid (SCFA) production and a concomitant reduction in Na-dependent fluid absorption resulting in AAD. The probiotic strain being studied, Bifidobacterium animalis subsp. lactis BB-12 (BB-12), has been shown to ameliorate a variety of gastrointestinal disease states and is known to produce acetate at concentrations up to 50 mM in vitro. Thus, the investigators hypothesize that administration of BB-12 at the same time as antibiotic consumption will protect against the development of AAD through its ability to generate acetate directly, and also increase other SCFAs through cross-feeding of certain bacteria in the Firmicutes phylum such Clostridium, Eubacterium and Roseburia, which use acetate to produce butyrate.

The primary aim is to determine the ability of BB-12 to impact antibiotic-induced reduction in SCFA as reflected by the levels of acetate, the most abundant primary colonic SCFA, and assess temporal intervals of probiotic administration. The primary hypothesis is that antibiotics will result in a reduction in fecal SCFA, but BB-12 supplementation will protect against antibiotic-induced SCFA reduction and/or be associated with a more rapid return to baseline SCFA levels as compared to controls. Antibiotics also result in a decrease in total microbial counts and diversity in the gut microbiota, disrupting the homeostasis of the gut ecosystem and allowing colonization by pathogens. We hypothesize that concurrent administration of the probiotic and antibiotic is not necessary for the probiotic impact on SCFA.

The secondary aim will be to determine the ability of BB-12 to impact antibiotic-induced disruption of the gut microbiota with 16S ribosomal ribonucleic acid (rRNA) profiling, and assess temporal intervals of probiotic administration. The secondary hypothesis is that antibiotics will result in a decrease in the overall number and diversity of bacterial species present in the fecal microbiota, and further BB-12 supplementation will protect against antibiotic-induced shifts in the microbiota and/or will be associated with a more rapid return to a baseline microbiota composition as compared to controls. We hypothesize that concurrent administration of the probiotic and antibiotic is not necessary for the probiotic effect on the composition of the gut microbiota.

The tertiary aim is to longitudinally characterize the gut microbiota with high-throughput metatranscriptomics in order to generate complementary information on the impact of antibiotics plus and minus BB-12 on overall microbiome function. We hypothesize that acetate produced by BB-12 in situ will cross-feed butyrate producers in the Firmicutes phylum resulting in an up-regulation of butyrate biosynthetic pathways.

The long-term goal is to determine the impact of BB-12 on a variety of gastrointestinal disease states and ages, through high-level independent research. This mechanism elucidation is important for directing future translational and effectiveness research.

• Study Type: Interventional
• Enrollment (Actual): 118
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Department of Family Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Has the ability to read, speak, and write in English
• Has a refrigerator (for proper storage of the study yogurt)
• Has reliable telephone access
• Is between ages of 18-65 years
• Agree to refrain from eating yogurts, yogurt drinks, and other foods specified in the provided list
• Agree to collect stool samples and participate in follow-up calls as specified

Exclusion Criteria:

• Diabetes or asthma that requires medication
• Allergy to strawberry
• Active diarrhea (three or more loose stools per day for two consecutive days)
• Any gastrointestinal (or digestive tract) medications, i.e. medicines for irritable bowel syndrome, gastroesophageal (acid) reflux disease, inflammatory bowel disease, etc.
• History of heart disease, including valvulopathies or cardiac surgery, any implantable device or prosthetic
• History of gastrointestinal surgery or disease
• Lactose intolerance that prevents participant from eating yogurt
• Allergy to milk-protein
• Allergy to any component of the product or the yogurt vehicle
• Allergy to penicillin or cephalosporin class antibiotics
• Allergy to any of the following medications: a) Penicillin; b) Erythromycin; c) Tetracycline; d) Trimethoprim; e) Ciprofloxacin
• Women who are breastfeeding, pregnant, or planning to become pregnant during the study
• Was a participant in the "YOBIOTIC" study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Concurrent control yogurt and amoxicillin-clavulanate; Yogurt without Bifidobacterium animalis subsp. lactis BB-12 (BB-12) and amoxicillin-clavulanate 875 mg-125 mg oral tablet, taken at the same time	Drug: Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet; Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet; Other Names: Augmentin; Amoxicillin/clavulanic acid; Other: Control Yogurt; Yogurt without Bifidobacterium animalis subsp. lactis BB-12 (BB-12)
Placebo Comparator: Control yogurt taken 4 hours after amoxicillin-clavulanate; Yogurt without Bifidobacterium animalis subsp. lactis BB-12 (BB-12) taken 4 hours after amoxicillin-clavulanate 875 mg-125 mg oral tablet	Drug: Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet; Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet; Other Names: Augmentin; Amoxicillin/clavulanic acid; Other: Control Yogurt; Yogurt without Bifidobacterium animalis subsp. lactis BB-12 (BB-12)
Active Comparator: Concurrent BB-12 yogurt and amoxicillin-clavulanate; Bifidobacterium animalis subsp. lactis BB-12-supplemented yogurt and amoxicillin-clavulanate 875 mg-125 mg oral tablet, taken at the same time	Drug: Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet; Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet; Other Names: Augmentin; Amoxicillin/clavulanic acid; Biological: BB-12; Bifidobacterium animalis subsp. lactis BB-12 (BB-12)-supplemented yogurt; Other Names: Bifidobacterium animalis subsp. lactis, BB-12
Active Comparator: BB-12 yogurt taken 4 hours after amoxicillin-clavulanate; Bifidobacterium animalis subsp. lactis BB-12-supplemented yogurt taken 4 hours after amoxicillin-clavulanate 875 mg-125 mg oral tablet	Drug: Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet; Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet; Other Names: Augmentin; Amoxicillin/clavulanic acid; Biological: BB-12; Bifidobacterium animalis subsp. lactis BB-12 (BB-12)-supplemented yogurt; Other Names: Bifidobacterium animalis subsp. lactis, BB-12
Other: Amoxicillin-clavulanate; Amoxicillin-clavulanate 875 mg-125 mg oral tablet	Drug: Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet; Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet; Other Names: Augmentin; Amoxicillin/clavulanic acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline Levels of Fecal Short-chain Fatty Acid (With a Particular Focus on Acetate)	Change from baseline levels of fecal short-chain fatty acid (with a particular focus on acetate)	day 7
Change From Baseline Levels of Fecal Short-chain Fatty Acid (With a Particular Focus on Acetate)	Change from baseline levels of fecal short-chain fatty acid (with a particular focus on acetate)	day 30

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change in Baseline Diversity of Bacterial Species in Fecal Microbiota	Percentage Change in Baseline Diversity of Bacterial Species in Fecal Microbiota (based on the Shannon Diversity Index, percentage of change): This outcome measures the percentage change in baseline diversity of bacterial species in the fecal microbiota, using the Shannon Diversity Index. Percent change within each treatment group was calculated comparing the Shannon diversity index at each follow-up day (i.e., day 7) to day 0 (baseline). The Shannon Diversity Index is a commonly used method to quantify microbial diversity, incorporating both the richness (the number of different species) and evenness (the distribution of species) within a sample. A positive percentage change reflects an increase in microbial diversity, while a negative percentage change indicates a decrease in microbial diversity compared to the microbial diversity at baseline.	day 7
Percentage Change in Baseline Diversity of Bacterial Species in Fecal Microbiota	Percentage Change in Baseline Diversity of Bacterial Species in Fecal Microbiota (based on the Shannon Diversity Index, percentage of change): This outcome measures the percentage change in baseline diversity of bacterial species in the fecal microbiota, using the Shannon Diversity Index. Percent change within each treatment group was calculated comparing the Shannon diversity index at each follow-up day (i.e., day 14) to day 0 (baseline). The Shannon Diversity Index is a commonly used method to quantify microbial diversity, incorporating both the richness (the number of different species) and evenness (the distribution of species) within a sample. A positive percentage change reflects an increase in microbial diversity, while a negative percentage change indicates a decrease in microbial diversity compared to the microbial diversity at baseline.	day 14

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline Levels of Fecal Short-chain Fatty Acid (With a Particular Focus on Acetate)	Change from baseline levels of fecal short-chain fatty acid (with a particular focus on acetate)	day 14
Change From Baseline Levels of Fecal Short-chain Fatty Acid (With a Particular Focus on Acetate)	Change from baseline levels of fecal short-chain fatty acid (with a particular focus on acetate)	day 21

Collaborators and Investigators

• Sponsor: Georgetown University
• Collaborators: University of Maryland, Baltimore; National Center for Complementary and Integrative Health (NCCIH); Penn State University
• Investigators: Principal Investigator: Daniel Merenstein, MD, Georgetown University

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2021
• Primary Completion (Actual): May 1, 2023
• Study Completion (Actual): May 1, 2023

Study Registration Dates

• First Submitted: June 1, 2020
• First Submitted That Met QC Criteria: June 1, 2020
• First Posted (Actual): June 4, 2020

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 4, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Diarrhea; Anti-Bacterial Agents; Anti-Infective Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; beta-Lactamase Inhibitors; Amoxicillin; Clavulanic Acid; Clavulanic Acids; Amoxicillin-Potassium Clavulanate Combination
• Other Study ID Numbers: 2020-2431; R33AT009622 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No