Mechanisms of Preventing Antibiotic-Associated Diarrhea and the Role for Probiotics (YOBIOTIC)

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; 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 of the R61 phase (N=60) 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. 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. The secondary aim will be to determine the ability of BB-12 to impact antibiotic-induced disruption of the gut microbiota with 16S (16 Svedberg) ribosomal ribonucleic acid (rRNA) profiling. 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. 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): 66
• 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
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Has the ability to read, speak, and write in English
2. Has refrigerator (for proper storage of the study yogurt)
3. Has reliable telephone access
4. Is between ages of 18-65 years
5. Agree to refrain from eating yogurts, yogurt drinks, and other foods specified in the provided What Not to Eat list
6. Agree to collect stool samples and participate in follow-up calls as specified

Exclusion Criteria:

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Control; Yogurt without Bifidobacterium animalis subsp. lactis BB-12 (BB-12) and 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; Other: Control; Yogurt without Bifidobacterium animalis subsp. lactis BB-12 (BB-12)
Experimental: BB-12; Bifidobacterium animalis subsp. lactis BB-12 (BB-12)-supplemented yogurt and 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; Biological: BB-12; Bifidobacterium animalis subsp. lactis BB-12-supplemented yogurt

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Level of Fecal Short-chain Fatty Acid (SCFA) Acetate	Level of fecal short-chain fatty acid acetate (SCFA) after administration of amoxicillin clavulanate	day 0 (post run-in), 7, 14, 21, 30

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Level of Fecal SCFA Propionate	Level of fecal short-chain fatty acid propionate after administration of amoxicillin clavulanate	day 0 (post run-in), 7, 14, 21, 30
Level of Fecal SCFA Butyrate	Level of fecal short-chain fatty acid butyrate (μM) after administration of amoxicillin clavulanate	day 0 (post run-in), 7, 14, 21, 30

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Community Diversity (Shannon Diversity Index) From Pre run-in Baseline	The Shannon diversity metric is a measure of community diversity and takes into account species richness (number of distinct taxa) and the relative abundance of each taxon. The Shannon diversity index was calculated for samples at each time point from subjects receiving control or BB-12 yogurt. The first of two baseline samples was collected from each subject at the time of enrollment (pre run-in) before a 30-day run-in period in which the consumption of dietary probiotics was stopped. A higher index indicates more diversity and a lower index indicates less diversity.	day 0 (pre run-in), 7, 14, 21, 30
Change in Community Diversity (Shannon Diversity Index) From Post run-in Baseline	The Shannon diversity metric is a measure of community diversity and takes into account species richness (number of distinct taxa) and the relative abundance of each taxon. The Shannon diversity index was calculated for samples at each time point from subjects receiving control or BB-12 yogurt. The second baseline sample was collected from each subject after a 30-day run-in period in which the consumption of dietary probiotics was stopped (post run-in). A higher index indicates more diversity and a lower index indicates less diversity.	day 0 (post run-in), 7, 14, 21, 30
Bray-Curtis Dissimilarity	Community divergence over time with respect to the baseline sample (post run-in, day 0)	day 0, 7, 14, 21, 30
Change in Diarrhea/Stool Frequency	Change in diarrhea/stool frequency from baseline	day 7, 14, 21, 30

Collaborators and Investigators

• Sponsor: Georgetown University
• Collaborators: University of Maryland, Baltimore; National Center for Complementary and Integrative Health (NCCIH)
• Investigators: Principal Investigator: Claire Fraser, PhD, University of Maryland, Baltimore

Publications and helpful links

General Publications

• Merenstein D, Fraser CM, Roberts RF, Liu T, Grant-Beurmann S, Tan TP, Smith KH, Cronin T, Martin OA, Sanders ME, Lucan SC, Kane MA. Bifidobacterium animalis subsp. lactis BB-12 Protects against Antibiotic-Induced Functional and Compositional Changes in Human Fecal Microbiome. Nutrients. 2021 Aug 17;13(8):2814. doi: 10.3390/nu13082814.

Study record dates

Study Major Dates

• Study Start (Actual): July 23, 2019
• Primary Completion (Actual): January 8, 2020
• Study Completion (Actual): January 8, 2020

Study Registration Dates

• First Submitted: November 18, 2018
• First Submitted That Met QC Criteria: November 26, 2018
• First Posted (Actual): November 28, 2018

Study Record Updates

• Last Update Posted (Actual): February 17, 2023
• Last Update Submitted That Met QC Criteria: February 15, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Diarrhea; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Amoxicillin; Clavulanic Acid; Clavulanic Acids; Amoxicillin-Potassium Clavulanate Combination
• Other Study ID Numbers: 2018-0736; 1R61AT009622-01A1 (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