Antibiotic resistant Clostridium difficile (C. difficile) poses an urgent threat to public health. The incidence and disease severity of C. difficile infection (CDI) have increased rapidly in recent years largely due to the use of broad-spectrum antibiotics and recent emergence of antibiotic resistant hypervirulent strains. Current standard-of-care with antibiotics is not optimal and is associated with high rates of relapses and risks of antibiotic resistance. Two major toxins, TcdA and TcdB, expressed by the bacteria during colonization of the large intestine, are primarily responsible for intestinal disease manifestations such as diarrhea and pseudomembranous colitis, but systemic complications ocurr in severely complicated CDI that are often associated with death. The pathogenesis of systemic complications in CDI is unknown. Using an ultrasensitive immunocytotoxicity assay, toxemia was first demonstrated in animal models of CDI and linked to severe disease outcomes. Moreover, we demonstrated that parenteral toxin-neutralizing antibodies relieved the severity of CDI. Although systemic antibodies may potentially leak through toxin-breached intestinal epithelia and enter the lumen to neutralize toxins, direct delivery of these antibodies at the site of infection may prevent toxin pathogenesis at the beginning. Moreover, the current monoclonal antibody approaches target single epitopes of the toxins and are less efficacious against toxin variants from different clinical isolates. In response, we have previously developed a novel tetra-specific recombinant antibody that potently and broadly neutralizes both toxins. A probiotic Saccharomyces boulardii allowing constitutive secretion of the tetra-specific antibody at the site of CDI was then engineered, and protection against primary and recurrent CDI were demonstrated in both mouse prophylactic and therapeutic disease models. This innovative yeast immunotherapy is inexpensive to manufacture, orally administered, and should not be associated with risks of antibiotic resistance. Therefore, it has the potential to be an effective prophylactic against CDI and a therapeutic for CDI patients.