Human gut microbiota interactions shape the long-term growth dynamics and evolutionary adaptations ofClostridioides difficile

Abstract

Clostridioides difficilecan transiently or persistently colonize the human gut, posing a risk factor for infections. This colonization is influenced by complex molecular and ecological interactions with human gut microbiota. By investigatingC. difficiledynamics in human gut communities over hundreds of generations, we show patterns of stable coexistence, instability, or competitive exclusion. Lowering carbohydrate concentration shifted a community containingC. difficileand the prevalent human gut symbiontPhocaeicola vulgatusfrom competitive exclusion to coexistence, facilitated by increased cross-feeding. In this environment,C. difficileadapted via single-point mutations in key metabolic genes, altering its metabolic niche from proline to glucose utilization. These metabolic changes substantially impacted inter-species interactions and reduced disease severity in the mammalian gut. In sum, human gut microbiota interactions are crucial in shaping the long-term growth dynamics and evolutionary adaptations ofC. difficile, offering key insights for developing anti-C. difficilestrategies.