Leveraging systems biology approaches, we illustrate how metabolically distinct species of Clostridia protect against or worsen Clostridioides difficile infection in mice by modulating the pathogen’s colonization, growth, and virulence to impact host survival. Gnotobiotic mice colonized with the amino acid fermenter Paraclostridium bifermentans survive infection with reduced disease severity, while mice colonized with the butyrate-producer, Clostridium sardiniense, succumb more rapidly. Systematic in vivo analyses revealed how each commensal alters the gut-nutrient environment to modulate the pathogen’s metabolism, gene regulatory networks, and toxin production. Oral administration of P. bifermentans rescues conventional, clindamycin-treated mice from lethal C. difficile infection in a manner similar to that of monocolonized animals, thereby supporting the therapeutic potential of this commensal species. Our findings lay the foundation for mechanistically informed therapies to counter C. difficile disease using systems biology approaches to define host-commensal-pathogen interactions in vivo.

利用系统生物学方法，我们说明了代谢上不同的梭菌属物种如何通过调节病原体的定植、生长和毒力来影响宿主存活，从而防止或加重小鼠的艰难梭菌感染。定植了氨基酸发酵菌双发酵副梭菌的定生小鼠在感染后存活下来，疾病严重程度降低，而定植了丁酸盐生产者沙丁氏梭菌的小鼠死得更快。系统的体内分析揭示了每种共生菌如何改变肠道营养环境以调节病原体的新陈代谢、基因调控网络和毒素产生。口服给药P. bifermentans以类似于单克隆动物的方式从致命的艰​​难梭菌感染中拯救传统的、克林霉素处理的小鼠，从而支持这种共生物种的治疗潜力。我们的研究结果为使用系统生物学方法来定义体内宿主-共生-病原体相互作用来对抗艰难梭菌疾病的机械知情疗法奠定了基础。