Baseline microbial ecology encodes probiotic responsiveness through distinct metabolic and network configurations

Probiotic efficacy in inflammatory bowel disease varies widely between individuals, and the sources of that variability remain poorly understood. D-lactate is a microbiota-derived metabolite that accumulates during intestinal inflammation and is associated with epithelial barrier dysfunction, which motivated our use of a consortium selected to contribute none of it. Here we show that its benefit is not an intrinsic property of the administered strains but is determined by the pre-existing ecological state of the recipient microbiome. Across three independent mouse resources, preventive administration reduced disease severity and histopathological damage only where baseline communities carried higher diversity and more complex co-occurrence architecture; in those animals the consortium preserved community structure and metabolic output, restoring disease-disrupted metabolites, and selectively raising butyrate and propionate. Sustained exogenous D-lactate did not abolish protection, placing D-lactate as a tractable readout of ecological restoration rather than its effector. Responsiveness is encoded in the baseline microbiota and predictable before intervention, establishing probiotic efficacy as a stratifiable property of the host microbiome.