Gut microbiota-centered risk factors and altered immunometabolism in the pathogenesis and prophylaxis of Clostridium difficile infection

Aim: Clostridium difficile (C. diff.) infection (CDI) is the major contributor of nosocomial infection globally. The current review aims to provide a comprehensive understanding of the mechanisms behind the critical role of intestinal 3Ms (i.e., microbiota, metabolome, and metabolism) in the pathogenesis and prophylaxis of recurrent CDI. Material and methods: Primarily centering around the mechanisms related to gut microbiota-dependent risk factors, we have discussed why gut microbial diversity and abundance are critical determinants of infection risk. Additionally, emphasis has been given on the intestine-specific molecular mechanisms related to the modulation of the global metabolome and signaling processes which trigger disease susceptibility. Key findings: Patients with CDI harbor altered gut microbial phenotype compared to healthy individuals and asymptomatic careers. Clinical and experimental (germ-free mice, mono-strain interactions, longitudinal trails) evidences indicate that alterations of the gut microbiota due to antibiotic exposure, advanced age, immunocompromised conditions and prolonged hospitalization could lead to gastrointestinal colonization of C. diff. Further, the gut microbiota mediated modulation of the mucosal signaling (farnesoid X receptor, aryl hydrocarbon receptor, conserved nuclear receptors, immunological signaling) and the luminal metabolomic signatures play critical role in the disease susceptibility and progression. The use of live biotherapeutics and fecal microbiota transplantation are currently the most suitable prophylactic strategy against recurrent CDI. Significance: The current review highlights the host-microbiota interaction which dictates the intestinal signaling responsible for the pathogenesis of recurrent CDI.