Aging Dampens the Intestinal Innate Immune Response during Severe Clostridioides difficile Infection and Is Associated with Altered Cytokine Levels and Granulocyte Mobilization.

(formerly ) is the most common cause of hospital-acquired infection, and advanced age is a risk factor for infection. Disruption of the intestinal microbiota and immune responses contribute to host susceptibility and severity of infection. However, the specific impact of aging on immune responses during infection remains to be well described. This study explores the effect of age on cellular and cytokine immune responses during infection. Young mice (2 to 3 months old) and aged mice (22 to 28 months old) were rendered susceptible to infection with the antibiotic cefoperazone and then infected with strains with varied disease-causing potentials. We observe that the host age and the infecting strain influenced the severity of disease associated with infection. Tissue-specific CD45 immune cell responses occurred at the time of peak disease severity in the ceca and colons of all mice infected with a high-virulence strain of ; however, significant deficits in intestinal neutrophils and eosinophils were detected in aged mice, with a corresponding decrease in circulating CXCL1, an important neutrophil recruiter and activator. Interestingly, this lack of intestinal granulocyte response in aged mice during severe infection was accompanied by a simultaneous increase in circulating white blood cells, granulocytes, and interleukin 17A (IL-17A). These findings demonstrate that age-related alterations in neutrophils and eosinophils and systemic cytokine and chemokine responses are associated with severe infection and support a key role for intestinal eosinophils in mitigating -mediated disease severity.