Mechanisms of Probiotics and Antibiotic-Associated Diarrhea
Condition: Antibiotic-associated Diarrhea
MeSH terms: Diarrhea
Study type: Interventional
Phase: Early Phase 1

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 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.
    

Intervention name(s): Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet; BB-12; Control Yogurt
Intervention type(s): Drug; Biological; Other
Intervention description(s): Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet; Bifidobacterium animalis subsp. lactis BB-12 (BB-12)-supplemented yogurt; Yogurt without Bifidobacterium animalis subsp. lactis BB-12 (BB-12)
Other intervention name(s): Augmentin; Amoxicillin/clavulanic acid; Bifidobacterium animalis subsp. lactis, BB-12
Intervention MeSH terms: Amoxicillin; Clavulanic Acid; Clavulanic Acids; Amoxicillin-Potassium Clavulanate Combination
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Other