In vivo systematic analysis of microbiota-prebiotic crosstalk reveals a synbiotic that effectively ameliorates...

Systematic identification of prebiotic-microbe interactions is essential for developing precision microbiome-targeted interventions to improve human health. In this study, we developed an in vivo systematic screening platform to evaluate microbiota-prebiotic crosstalk and applied it to identify a synbiotic combination effective against dextran sulfate sodium (DSS)-induced colitis in mice. Specifically, we first established a humanized gut microbiota mouse model by colonizing mice with 73 microbial strains, which showed highly abundant and prevalent in the human gut. Concurrently, we administered the mice with 28 different prebiotic or prebiotic candidates, including polyphenols, polysaccharides, vitamins, and minerals common in the market. Following the DSS-induced colitis, we evaluated the protective effects of each microbiota-prebiotic pairing. Fourteen prebiotic or prebiotic candidates, designated as the ESS group, significantly alleviated colitis, partly by enriching specific beneficial microbes such as Bacteroides thetaiotaomicron, Akkermansia muciniphila, and Erysipelatoclostridium ramosum prior to disease onset. Further experiments revealed two symbiotic combinations with the strongest anti-inflammatory effects: calcium-magnesium tablets (CMT) combined with either B. thetaiotaomicron or A. muciniphila. Mechanistically, CMT promoted the growth of B. thetaiotaomicron and alleviated inflammation by upregulating genes associated with probiotic activity. Finally, in an intervention trial involving healthy human volunteers, CMT selectively increased B. thetaiotaomicron abundance without altering the overall gut microbiota composition. Together, our study presents a systematic framework for elucidating microbe-prebiotic interactions, identifying synbiotic combinations with therapeutic potential, and advancing precision microbiome-based strategies for disease prevention and treatment.