Systemically administered monoclonal antibodies (mAbs) have become an indispensable tool in many areas of medicine. However, a lot of potential drug targets reside in the gut, where localized delivery, through the oral route, would be more appropriate. Our group has recently demonstrated that oral intake of yeast-secreted dried and feed-admixed nanobodies (VHHs) fused to the Fc part of IgA and targeted to the F4 adhesin of swine Enterotoxigenic E. coli prevents colonization of the pathogen in weaned piglets. In contrast, VHH-IgG and the native VHHs were not efficacious. However, the exact molecular mechanisms with relation to different aspects of the construct needed for stability, efficacy and safety, as well as its potential for applicability in humans, remains to be investigated. For this, physiologically relevant 2D organoid models as well as porcine and murine in vivo models will be used. A better understanding of the antibody format is of critical importance to guide the development of a platform technology that could be used to treat a variety of GI-related diseases. As benchmark indications, we aim to provide novel nutraceutical options for a better control of diabetes and C. difficile infection in humans. Both targets represent an area where novel approaches are highly needed to cope with the increasing incidence and where oral therapy has strong prophylactic and therapeutic potential.