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Recent studies have suggested the potential of probiotic organisms to be adapted for the synthesis and delivery of oral therapeutics. The probiotic yeast  Saccharomyces boulardii  would be especially well suited for this purpose due to its ability, in contrast to probiotic prokaryotes, to perform eukaryotic post translational modifications. This probiotic yeast thus has the potential to express a broad array of therapeutic proteins. Currently, however, use of wild type (WT)  S. boulardii  relies on antibiotic resistance for the selection of transformed yeast. Here we report the creation of auxotrophic mutant strains of  S. boulardii  that can be selected without antibiotics and demonstrate that these yeast can express functional recombinant protein even when recovered from gastrointestinal immune tissues in mice. A UV mutagenesis approach was employed to generate three uracil auxotrophic  S. boulardii  mutants that show a low rate of reversion to wild type growth. These mutants can express recombinant protein and are resistant  in vitro  to low pH, bile acid salts, and anaerobic conditions. Critically, oral gavage experiments using C57BL/6 mice demonstrate that mutant  S. boulardii  survive and are taken up into gastrointestinal immune tissues on a similar level as WT  S. boulardii . Mutant yeast recovered from gastrointestinal immune tissues furthermore retain expression of functional recombinant protein. These data show that auxotrophic mutant  S. boulardii  can safely express recombinant protein without antibiotic selection and can deliver recombinant protein to gastrointestinal immune tissues. These auxotrophic mutants of  S. boulardii  pave the way for future experiments to test the ability of  S. boulardii  to deliver therapeutics and mediate protection against gastrointestinal disorders.

Functional Heterologous Protein Expression by Genetically Engineered Probiotic Yeast Saccharomyces boulardii