Mechanisms of Probiotics and Antibiotic-Associated Diarrhea
Mechanisms of Probiotics and Antibiotic-Associated Diarrhea
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.
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.
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