A commensal protozoan attenuates Clostridioides difficile pathogenesis in mice through regulating the arginine-ornithine metabolic axis and the host intestinal immune response

Antibiotic-induced dysbiosis is a major risk factor for Clostridioides difficile infection (CDI), and fecal microbiota transplantation (FMT) is recommended for treating CDI. However, the underlying mechanisms remain elusive. Here, we reveal that Tritrichomonas musculis (T.mu), an integral member of the mouse gut commensal microbiota, reduces CDI-induced intestinal damage by inhibiting neutrophil recruitment and IL-1β secretion, while promoting Th1 cell differentiation and IFN-γ secretion, which in turn enhances goblet cell production and mucin secretion to protect the intestinal mucosa. T.mu can actively metabolize arginine, not only influencing the host’s arginine-ornithine metabolic pathway, but also shaping the metabolic environment for microbial community in the host’s intestinal lumen. This leads to a relatively low ornithine state in the intestinal lumen in C. difficile-infected mice. These changes modulate C. difficile’s virulence and the host intestinal immune response, and thus collectively alleviating CDI. These findings strongly suggest the interaction between an intestinal commensal eukaryote, a pathogenic bacterium, and the host immune system via inter-related arginine-ornithine metabolic axis in the regulation of pathogenesis, and provide new insights for treating CDI.