SUMMARY Commensal intestinal microbes are collectively beneficial in preventing local tissue injury and augmenting systemic antimicrobial immunity. However, given the near-exclusive focus on bacterial species in establishing these protective benefits, the contributions of other types of commensal microbes remain poorly defined. Here we show that commensal fungi can functionally replace intestinal bacteria, by conferring protection against injury to mucosal tissues and positively calibrating the responsiveness of circulating immune cells. Susceptibility to colitis and influenza A virus infection that occur upon commensal bacteria eradication are efficiently overturned by monocolonization with either Candida albicans or Saccharomyces cerevisiae. The protective benefits of commensal fungi are mediated by mannans, a highly conserved component of fungal cell walls, since intestinal stimulation with this moiety alone overrides disease susceptibility in mice depleted of commensal bacteria. Thus, commensal enteric fungi safeguard local and systemic immunity by providing tonic microbial stimulation that can functionally replace intestinal bacteria.

Highlights d C. albicans intestinal colonization protects against C. albicans invasive infection d Systemic fungal-specific Th17 CD4 + T cell accumulation with intestinal colonization d Tonic neutrophil stimulation augments host defense against extracellular pathogens d Antimicrobial immunity balanced by susceptibility to allergic airway inflammation

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