Novel Immunotherapies for Comorbidity of Clostridium difficile and Inflammatory Bowel Disease

AbstractOver the past few decadesthere has been a significant increase in the incidence of Clostridium difficile infectionCDIin patients suffering from inflammatory bowel diseaseIBDwho then suffer from more severe disease outcomesThis is becoming a serious issue faced by clinicians in the management of the comorbidityThe current standard treatment for CDI is antibioticssuch as vancomycinwhich disrupts gut microbiota and induces high rates of recurrenceup toSince both IBD and CDI are associated with dysbiosis of gut microbiotaa treatment approach that is not associated with the induction of microbiota dysbiosis is urgently needed to curb the rapidly increasing incidence of CDI comorbidity with IBD !We propose to develop a nontraditional therapeutic against comorbidity of CDI in patients with IBD that does not promote bacterial resistancea major concern to public health worldwideOur goal is to develop a novel combinational immunotherapy by utilizing probiotic yeast Saccharomyces boulardii to deliver therapeutic antibodies against major Cdifficile toxins and inflammatory mediator tumor necrosis factor alphaTNFWe have already generated a lead Sboulardii strainFZstably secreting a tetra specific toxin neutralizing antibody called ABABThis antibody simultaneously targets the two major virulence factors toxin ATcdAand toxin BTcdBat the site of Cdifficile infection and exhibits significant protection against CDIIn this projectwe will construct another Sboulardii strain to stably secrete an anti TNFneutralizing antibodySb aTNFWe will then evaluate therapeutic efficacy of oral FZcombined with Sb aTNF for treating CDI comorbidity with IBD in mouse disease modelsWith this proof of concept studywe expect to demonstrate the feasibility of a novel immunotherapeutic modality based on probiotic yeast for oral delivery of therapeutic antibodies to intestines where the comorbidity of CDI and IBD occursThis will justify a larger development effort in a Phase II study to generate a final lead of combinational yeast immunotherapy to treat the comorbidity of CDI and IBD NarrativeThe comorbidity of Clostridium difficile infectionCDIand inflammatory bowel diseaseIBDcauses tremendous morbidity and mortality but the treatment is unmet medical needThis project aims to develop novel therapeutics against the comorbidity