Microbial guild architecture transduces multi-component botanical inputs into multi-receptor-mediated gut motility restoration

How ecological architectures within the gut microbiome convert complex inputs into specific host physiological outcomes remains poorly understood. We used CDD-2101, a multi-component botanical drug operating under an FDA (U.S. Food and Drug Administration) Investigational New Drug program, as a defined ecological perturbation in functional constipation (FC). Integrating a randomized, double-blind, placebo-controlled clinical trial with genome-resolved metagenomics, targeted metabolomics, staged prediction modeling, and receptor-level validation, we show that clinical efficacy of CDD-2101 depends on remodeling a function-specific substructure of the stable Two Competing Guilds (TCG) architecture. We term this substructure the FC-TCG, demonstrate its role along the gut-motility axis, and confirm its effect in three independent gut hypomotility cohorts. The two guilds responded asymmetrically: the intervention selectively suppressed the C1B guild (the pathobiont guild) while largely sparing the C1A guild, the foundation guild that anchors the core gut community, restoring its ecological dominance, producing a coordinated metabolic shift that elevates lithocholic acid and propionic acid. Through gnotobiotic transplantation and receptor antagonism, we demonstrate that lithocholic acid and propionic acid restore gut motility via concurrent engagement of Takeda G protein-coupled receptor 5 (TGR5) and G-protein coupled receptor 43 (GPR43). These findings identify microbial guild architecture as a function-resolved signal-transducing layer that converts multi-component botanical intervention into multi-receptor-mediated gut motility restoration, reframing the gut microbiome from a compositional system into a structural transducer between complex environmental inputs and host physiology.