Clinical trial NCT03755765: Mechanisms of Preventing Antibiotic-Associated Diarrhea and the Role for Probiotics
Official title: Exploratory Pilot Studies to Demonstrate Mechanisms of Preventing Antibiotic-Associated Diarrhea and the Role for Probiotics
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Antibiotic-associated Diarrhea
Lead sponsor: Georgetown University
Sponsor class: OTHER
Collaborators: name: National Center for Complementary and Integrative Health (NCCIH)
name: University of Maryland, Baltimore
First posted: 2018-11-28
Enrollment: 66
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Level of Fecal Short-chain Fatty Acid (SCFA) Acetate
timeFrame: day 0 (post run-in), 7, 14, 21, 30
Secondary outcomes:
measure: Level of Fecal SCFA Propionate
timeFrame: day 0 (post run-in), 7, 14, 21, 30
measure: Level of Fecal SCFA Butyrate
timeFrame: day 0 (post run-in), 7, 14, 21, 30
Other outcomes:
measure: Change in Community Diversity (Shannon Diversity Index) From Pre run-in Baseline
timeFrame: day 0 (pre run-in), 7, 14, 21, 30
measure: Change in Community Diversity (Shannon Diversity Index) From Post run-in Baseline
timeFrame: day 0 (post run-in), 7, 14, 21, 30
measure: Bray-Curtis Dissimilarity
timeFrame: day 0, 7, 14, 21, 30
measure: Change in Diarrhea/Stool Frequency
timeFrame: day 7, 14, 21, 30
Locations:
city: Washington
country: United States
facility: Georgetown University Department of Family Medicine
state: District of Columbia
Study officials:
affiliation: Georgetown University
name: Daniel Merenstein, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Maryland, Baltimore
name: Claire Fraser, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.