Mining the microbiome to modulate host defense against clostridioides difficile infections

Abstract

The intestinal microbiota consists of numerous microbes forming a dynamic ecosystem in close association with the host. One of the many functions of the microbiota is the colonization resistance against intestinal pathogens. Alterations in the composition of the microbiota, for example caused by antibiotics, may cause the loss of colonization resistance, making the host vulnerable towards infections, e.g. with Clostridioides difficile. C. difficile is a spore-forming anaerobic bacterium which can cause severe diarrhea and life-threatening complications in infected individuals. In many developed countries, C. difficile infection is a major cause of antibiotic-related nosocomial infections. The disease affects mostly elderly individuals. Antibiotics are the standard treatment, however, up to 30% of the patients are suffering from recurrent C. difficile infections. Transfer of fecal matter from a healthy individual to the patient is able to cure these infections. Recent studies have demonstrated that the conversion of primary to secondary bile acids by commensal bacteria is important for colonization resistance, but further evidence suggested that the restoration of the secondary bile acid production may not be sufficient for complete protection. In the present study, the effect of the microbiota on C. difficile infection has been explored. Therefore, a C. difficile mouse model has been established initially by exploring the effect of different ages and microbiota compositions on the severity of C. difficile infections. Second, the effect of specific mutations in the genome of C. difficile on the ability to colonize mice and to produce spores has been examined. Third, the inhibitory effect of specifically isolated commensal bacteria of the microbiota of resistant mouse models on C. difficile infections has been explored in depth in order to create a consortium of bacteria that protects the host against C. difficile. Our findings confirm that the age of the mice, comparable as in humans, is important for the severity of the disease of mice. They also confirm that secondary bile acids are indeed important to protect the host against C. difficile infections. However, in our model, adding a secondary bile acid producer to the microbiota is not sufficient for complete protection of the mice, but together with other commensal bacteria, secondary bile acid producing bacteria are able to provide complete resistance against C. difficile induced pathogenesis.