Capturing the environment of the Clostridioides difficile infection cycle

Clostridioides difficile (formerly Clostridium difficile ) infection is a substantial health and economic burden worldwide. Great strides have been made over the past several years in characterizing the physiology of C. difficile infection, particularly regarding how gut microorganisms and their host work together to provide colonization resistance. As mammalian hosts and their indigenous gut microbiota have co-evolved, they have formed a complex yet stable relationship that prevents invading microorganisms from establishing themselves. In this Review, we discuss the latest advances in our understanding of C. difficile physiology that have contributed to its success as a pathogen, including its versatile survival factors and ability to adapt to unique niches. Using discoveries regarding microorganism–host and microorganism–microorganism interactions that constitute colonization resistance, we place C. difficile within the fiercely competitive gut environment. A comprehensive understanding of these relationships is required to continue the development of precision medicine-based treatments for C. difficile infection. Clostridioides difficile infection has a notable health and economic burden worldwide. In this Review, the authors provide insights into the physiology of C. difficile and how it survives and has adapted to the gut environment, including insights into host–microorganism and microorganism–microorganism relationships. Key points Clostridioides difficile (formerly Clostridium difficile ) infection has a substantial health-care burden worldwide. While infection mostly manifests in health-care settings, the pathogen can be acquired in both health-care and community environments. Multiple microorganism–microorganism and microorganism–host interactions act in concert to suppress C. difficile in the gut. C. difficile has developed several unique survival mechanisms to facilitate proliferation in the competitive environment of the gut. Characterizing the multi-levelled interactions between C. difficile , the host and the indigenous microbiota requires systems biology approaches that account for the complexity of the host–microorganism interface. Understanding the interactions of C. difficile with the gut environment should inform patient care as these mechanisms are leveraged to develop novel treatment options that target specific aspects of this complex host–pathogen–microbiota interaction.