Phocaeicola vulgatus shapes the long-term growth dynamics and evolutionary adaptations of Clostridioides difficile.

Clostridioides difficile can transiently or persistently colonize the human gut, posing a risk for infections. This colonization is influenced by complex molecular and ecological interactions with the human gut microbiota. By investigating C. difficile dynamics in human gut communities over hundreds of generations, we show patterns of stable coexistence, instability, or competitive exclusion. Lowering carbohydrate concentrations shifted a community containing C. difficile and the prevalent human gut symbiont Phocaeicola vulgatus from competitive exclusion to coexistence, facilitated by increased cross-feeding. In this environment, two key mutations in C. difficile altered its metabolic niche from proline to glucose utilization. These metabolic changes in C. difficile substantially impacted gut microbiota inter-species interactions and reduced disease severity in mice. In sum, interactions with P. vulgatus are crucial in shaping the long-term growth dynamics and evolutionary adaptations of C. difficile, offering key insights for developing anti-C. difficile strategies.