Enteric pathogens are exposed to a dynamic polymicrobial environment in the gastrointestinal tract¹. This microbial community has been shown to be important during infection, but there are few examples illustrating how microbial interactions can influence the virulence of invading pathogens². Here we show that expansion of a group of antibiotic-resistant, opportunistic pathogens in the gut—the enterococci—enhances the fitness and pathogenesis of Clostridioides difficile. Through a parallel process of nutrient restriction and cross-feeding, enterococci shape the metabolic environment in the gut and reprogramme C. difficile metabolism. Enterococci provide fermentable amino acids, including leucine and ornithine, which increase C. difficile fitness in the antibiotic-perturbed gut. Parallel depletion of arginine by enterococci through arginine catabolism provides a metabolic cue for C. difficile that facilitates increased virulence. We find evidence of microbial interaction between these two pathogenic organisms in multiple mouse models of infection and patients infected with C. difficile. These findings provide mechanistic insights into the role of pathogenic microbiota in the susceptibility to and the severity of C. difficile infection.

肠道病原体暴露在胃肠道^{1 的}动态多微生物环境中。这种微生物群落已被证明在感染期间很重要，但很少有例子说明微生物相互作用如何影响入侵病原体的毒力²。在这里，我们表明肠道中一组耐抗生素的机会性病原体（肠球菌）的扩增增强了艰难梭菌的适应性和发病机制。通过营养限制和交叉喂养的并行过程，肠球菌塑造肠道内的代谢环境并重新规划艰难梭菌的代谢。肠球菌提供可发酵的氨基酸，包括亮氨酸和鸟氨酸，从而增加C. difficile在抗生素扰动的肠道中的适应性。肠球菌通过精氨酸分解代谢平行消耗精氨酸为艰难梭菌提供了代谢线索，促进了毒力的增加。我们在多种小鼠感染模型和感染艰难梭菌的患者中发现了这两种病原体之间微生物相互作用的证据。这些发现提供了对致病菌群在艰难梭菌感染的易感性和严重性中的作用的机制见解。