Abstract
The mammalian gut microbiome protects the host through colonization resistance (CR) against the incursion of exogenous and often harmful microorganisms, but identifying the exact microbes responsible for the gut microbiota-mediated CR against a particular pathogen remains a challenge. To address this limitation, we developed a computational method: generalized microbe-phenotype triangulation (GMPT). We first systematically validated GMPT using a classical population dynamics model in community ecology and demonstrated its superiority over baseline methods. We then tested GMPT on simulated data generated from the ecological network inferred from a real community (GnotoComplex microflora) and real microbiome data on two mouse studies on Clostridioides difficile infection. We demonstrated GMPT's ability to streamline the discovery of microbes that are potentially responsible for microbiota-mediated CR against pathogens. GMPT holds promise to advance our understanding of CR mechanisms and facilitate the rational design of microbiome-based therapies for preventing and treating enteric infections.