This study investigates the role of specific bacterial species in providing resistance to *Clostridium difficile* infection, a major cause of antibiotic-induced diarrhea. By treating mice with different antibiotics that result in distinct changes to the intestinal microbiota, the researchers correlated the loss of specific bacterial taxa with the development of *C. difficile* infection. Mathematical modeling and clinical studies identified resistance-associated bacteria common to both mice and humans. The study found that *Clostridium scindens*, a bile acid 7-dehydroxylating bacterium, is associated with resistance to *C. difficile* infection and enhances resistance in a bile acid-dependent manner. Adoptive transfer of *C. scindens* and a consortium of four intestinal bacteria ameliorated *C. difficile* infection in antibiotic-exposed animals. The mechanism of *C. scindens*-mediated resistance involves the synthesis of secondary bile acids, which inhibit *C. difficile* growth. These findings suggest that targeting specific bacteria or their metabolic products could be a therapeutic approach for preventing *C. difficile* infection.This study investigates the role of specific bacterial species in providing resistance to *Clostridium difficile* infection, a major cause of antibiotic-induced diarrhea. By treating mice with different antibiotics that result in distinct changes to the intestinal microbiota, the researchers correlated the loss of specific bacterial taxa with the development of *C. difficile* infection. Mathematical modeling and clinical studies identified resistance-associated bacteria common to both mice and humans. The study found that *Clostridium scindens*, a bile acid 7-dehydroxylating bacterium, is associated with resistance to *C. difficile* infection and enhances resistance in a bile acid-dependent manner. Adoptive transfer of *C. scindens* and a consortium of four intestinal bacteria ameliorated *C. difficile* infection in antibiotic-exposed animals. The mechanism of *C. scindens*-mediated resistance involves the synthesis of secondary bile acids, which inhibit *C. difficile* growth. These findings suggest that targeting specific bacteria or their metabolic products could be a therapeutic approach for preventing *C. difficile* infection.