A high-throughput screening platform for discovering bacterial species and small molecules that modify animal physiology

Abstract

AbstractThe gut microbiome has been proposed to influence many aspects of animal development and physiology. However, both the specific bacterial species and the molecular mechanisms by which bacteria exert these effects are unknown in most cases. Here, we established a high throughput screening platform using the model animalCaenorhabditis elegansfor identifying bacterial species and mechanisms that influence animal development and physiology. From our initial screens we found that manyBacillusspecies can restore normal animal development to insulin signaling mutant animals that otherwise do not develop to adulthood. To determine howBacilliinfluence animal development we screened a complete non-essential gene knockout library ofBacillus subtilisfor mutants that no longer restored development to adulthood. We found theBacillusgenespeBis required for animal development. In the absence ofspeB,B. subtilisproduces excess N1-aminopropylagmatine. This polyamine is taken up by animal intestinal cells via the polyamine transporter CATP-5. When this molecule is taken up in sufficient quantities it inhibits animal mitochondrial function and causes diverse species of animals to arrest their development. To our knowledge, these are the first observations thatB. subtiliscan produce N1-aminopropylagmatine and that polyamines produced by intestinal microbiome species can antagonize animal development and mitochondrial function. Given thatBacillispecies are regularly isolated from animal intestinal microbiomes, including from humans, we propose that altered polyamine production from intestinalBacilliis likely to also influence animal development and metabolism in other species and potentially even contribute developmental and metabolic pathologies in humans. In addition, our findings demonstrate thatC. eleganscan be used as a model animal to conduct high throughput screens for bacterial species and bioactive molecules that alter animal physiology.