Microbiota-Regulated IL-25 Increases Eosinophil Number to Provide Protection during Clostridium difficile Infection

Abstract

Summary Clostridium difficile infection (CDI) is the most common cause of hospital-acquired infection in the United States. Host susceptibility and the severity of infection are influenced by disruption of the microbiota and the immune response. However, how the microbiota regulates immune responses to mediate CDI outcome remains unclear. Here, we investigated the role of the microbiota-linked cytokine IL-25 during infection. Intestinal IL-25 was suppressed during CDI in humans and mice. Restoration of IL-25 reduced CDI-associated mortality and tissue pathology even though equivalent levels of C. difficile bacteria and toxin remained in the gut. IL-25 protection was mediated by gut eosinophils, as demonstrated by an increase in intestinal eosinophils and a loss of IL-25 protection upon eosinophil depletion. These findings support a mechanism whereby the induction of IL-25-mediated eosinophilia can reduce host mortality during active CDI. This work may provide targets for future development of microbial or immune-based therapies.

Role of the leukocyte response in normal and immunocompromised host after Clostridium difficile infection

“…In animal studies, Buonomo et al demonstrated a protective role of tissue eosinophils in mice, and this effect was mediated by IL-25 secretion. In this study, restoration of IL-25 levels in a murine model of C. difficile infection led to reduced mortality, whilst eosinophil depletion resulted in loss of the protection mediated by IL-25 [20]. In another study by the same group, C. difficile Binary toxin CDT ( C. difficile transferase) was able to induce inflammation in a murine model by binding to eosinophil Toll-like receptor 2 (TLR-2), resulting in activation of NFκB and suppression of eosinophil response via indirect induction of eosinophil apoptosis.…”

Role of Eosinophils and Tumor Necrosis Factor Alpha in Interleukin-25-Mediated Protection from Amebic Colitis

“…Recently, Buonomo et al have reported that IL-25 also is protective against Clostridium difficile infection through eosinophil induction (24). Additionally, C. difficile infection with strains containing CDT ( Clostridium difficile transferase toxin) causes more severe pathology because they suppress the accumulation of eosinophils in the lamina propria of the colon (32).…”

“…Three readers blinded to the identity of the samples scored epithelial disruption (24). The scale was between 0 and 5.…”

Tuft Cells: New Players in Colitis

“…Immunohistochemistry indicates that patients infected with C. difficile produce less IL-25 in colonic biopsies, a phenotype also observed in a mouse model of C. difficile -mediated colitis [12] . In this study, restoring IL-25 levels in mice increased survival via an unanticipated mechanism of eosinophil-dependent protection of the gut barrier (Figure 1).…”

“…In this study, restoring IL-25 levels in mice increased survival via an unanticipated mechanism of eosinophil-dependent protection of the gut barrier (Figure 1). Moreover, treating mice with an anti-Siglec-F antibody ablated the protective phenotype of IL-25 [12] . Together, these data suggest that IL-25-mediated induction of eosinophils protects the host from C. difficile -induced disease.…”