Inorganic nitrogen metabolic reprogramming of the gut microbiome drives fecal microbiota transplantation in ulcerative colitis.

Although fecal microbiota transplantation (FMT) shows promise for ulcerative colitis (UC), its clinical success appears to be contingent upon the degree of donor microbiota engraftment. Using an LD50-based ecological model, our study reveals that inorganic nitrogen utilization capacity (IN-uc) critically determines gut microbial assembly in high oxidative stress environments, which significantly influences microbial engraftment outcomes. Building on this mechanistic insight, we engineer a probiotic-metabolite consortia designed to synergistically increase IN-uc in the gut ecosystem. We find that PM-mix14 alleviates oxidative stress-mediated colonization barriers of donor microbiota by catalyzing the conversion of excess reactive nitrogen species through multi-step reactions, promotes L-glutamate biosynthesis and ATP production, thereby ensuring greater similarity in the structure and function of the recipient microbiota to those of the donor. In multiple male murine models of colitis, PM-mix14 supplementation during FMT significantly improves microbial engraftment fidelity, which is correlated with increased anti-inflammatory responses and attenuated colonic pathology. Network meta-analysis of multiple clinical datasets further substantiates the prognostic value of donor gut microbial IN-uc in UC remission. Our findings establish the gut microbial IN-uc as an ecological driver of microbiota engraftment and present a rationally designed microbial therapy that optimizes FMT efficacy through targeted metabolic reprogramming.