Dynamic feedback BacGuard anchors microbial metabolism to host symbiosis in real-time ulcerative colitis therapy

The escalating global burden of ulcerative colitis (UC) underscores the limitations of conventional anti-inflammatory therapies. Although multi-omics insights have propelled gut microbiota modulation to the forefront of therapeutic innovation, current strategies relying on probiotics or fecal transplants remain constrained by empirical designs due to the lack of spatiotemporal precision and real-time monitoring of microbial metabolic vitality in situ. In this study, BacGuard, a metabolically orthogonal microgel platform, was developed to unify the probiotic surveillance and guided dynamic dose regulation with spatially targeted microbiota-associated metabolic modulation. Our core design featured a β-xylosidase-activated chemiluminescent probe (XOS-CL) that was conjugated with xylooligosaccharide-based hyperbranched polymers (HBXOK) and orally delivered via microgels. Thereby, this system enabled real-time monitoring of probiotic abundance and metabolic activity in the colon through enzyme-responsive signaling, while simultaneously promoting short-chain fatty acid (SCFA) production via redirected bacterial metabolic flux. This dual-action system created a self-reinforcing therapeutic loop and optically quantifying the microbial activity in a dynamic manner. By resolving the causal disconnects between enzymatic activity, microbiota proliferation, and host interactions, the BacGuard bridged the diagnostic metrics to functional therapeutic outcomes. Anchoring both sensing and treatment to microbial metabolic flux, our platform reimagined the precision gut ecosystem engineering, establishing an image-guided dynamic dose regulation framework that actively preserved the microbiota-host symbiosis through in-time and function-adaptive modulation.