Omnidirectional Interaction Networks Modulating Phenotypic Plasticity in the Gut Microbiota Towards Ulcerative Colitis

ABSTRACT Changes to gut microbiomes are linked to inflammatory bowel disease, but little is known about how microbial change is modulated in complex gut microbiota systems. Here, we address this issue by revealing the influence of microbial interactions on gut microbiota response to ulcerative colitis (UC) using a spouse‐pair cohort design composed of an UC patient and his healthy spouse living in the same household environment. We calculate the difference in abundance of a microbial species between each pair of spouses as a proxy of UC‐induced phenotypic plasticity (uPP). We classify all microbes into functionally distinct modules based on the similarity of uPP across household environments. An integrative network and GLMY homology analysis identifies a pathobiont‐centric hub module and its disease‐specific topological motifs, characterized by UC‐associated microbial dysbiosis. We find that a marked increase in microbial plasticity is mediated by profound restructuring of microbial interactomes in the microbial communities. By inferring multilayer interactome networks, our model positions phenotypic plasticity as a systematic mechanistic force of UC, paving the way for its ecology‐informed diagnostics and interventions.