Microbial guild architecture transduces multi-component botanical inputs into multi-receptor-mediated gut motility restoration
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
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.
Highlights
-
A gut motility-supporting Two-Competing-Guilds module (FC-TCG) was identified via a randomized clinical trial with quality-controlled botanical intervention as an ecological perturbation.
-
Guild architecture translates multi-component botanical inputs into coordinated metabolite signals.
-
Guild restructuring increases lithocholic acid and propionic acid to restore gut motility by activating TGR5 and GPR43.
-
Microbial guilds constitute a signal-transducing layer linking complex environmental inputs to host physiology.
Significance Statement
This study establishes a mechanistic link between stable microbial guild architecture and host physiological control. By resolving the Two-Competing-Guilds (TCG) structure into a function-specific module, it demonstrates how complex environmental inputs restructure the ecological system into coordinated metabolites programs and receptor-level signaling. The findings show that, among the gut microbiome ecological system, microbial guilds act as a signal-transducing layer that converts botanical complexity into targeted host responses. This provides a generalizable system level strategy for dissecting microbiome-mediated mechanisms of multi-component interventions and advances a systems-level understanding of environment– microbiome–host interactions.
