Intestinal fungi are an important component of the microbiota, and recent studies have unveiled their potential in modulating host immune homeostasis and inflammatory disease. Nonetheless, the mechanisms governing immunity to gut mycobiota remain unknown. We identified CX3CR1+ mononuclear phagocytes (MNPs) as essential for the initiation of innate and adaptive immune responses to intestinal fungi. CX3CR1+ MNPs express antifungal receptors and activate antifungal responses in a Syk dependent manner. Genetic ablation of CX3CR1+ MNPs led to changes in the gut fungal communities and to severe colitis that was rescued by antifungal treatment. A missense mutation in the gene encoding CX3CR1 led to impaired antifungal responses in Crohn’s Disease patients. These results unravel the role of CX3CR1+ MNPs as mediators of the interactions between intestinal mycobiota and host immunity during health and disease.

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Summary Sensing of the gut microbiota, including fungi, regulates mucosal immunity. Whether fungal sensing in the gut can influence immunity at other body sites is unknown. Here we show that fluconazole-induced gut fungal dysbiosis has persistent effects on allergic airway disease in a house dust mite challenge model. Mice with a defined community of bacteria, but lacking intestinal fungi were not susceptible to fluconazole-induced dysbiosis, while colonization with a fungal mixture recapitulated the detrimental effects. Gut resident mononuclear phagocytes (MNPs) expressing the fractalkine receptor CX3CR1 were essential for the effect of gut fungal dysbiosis on peripheral immunity. Depletion of CX3CR1+ MNPs or selective inhibition of Syk signaling downstream of fungal sensing in these cells ameliorated lung allergy. These results indicate that disruption of intestinal fungal communities can have persistent effects on peripheral immunity and aggravate disease severity through fungal sensing by gut resident CX3CR1+ MNPs.

Fungal strain-level diversity defines host-mycobiota interactions and inflammation in inflammatory bowel disease.

Secretory immunoglobulin A (sIgA) plays an important role in gut barrier protection by shaping the resident microbiota community, restricting the growth of bacterial pathogens, and enhancing host protective immunity via immunological exclusion. Here, we found that a portion of microbiota-driven sIgA response is induced by and directed towards intestinal fungi. Analysis of the human gut mycobiota bound by sIgA revealed a preference for hyphae; a fungal morphotype associated with virulence. C. albicans was a potent inducer of IgA class switch recombination (CSR) among plasma cells, through an interaction dependent on intestinal phagocytes and hyphal programming. Characterization of sIgA affinity and polyreactivity showed that hyphae-associated virulence factors were bound by these antibodies and that sIgA influenced C. albicans morphotypes in the murine gut. Furthermore, an increase of granular hyphal morphologies in Crohn’s Disease (CD) patients compared to healthy controls, correlated with a decrease of antifungal sIgA antibody titers with affinity to hyphae-associated virulence factors. Thus, in addition to their importance in gut bacterial regulation, sIgA targets the uniquely fungal phenomenon of hyphal formation. Our findings indicate that antifungal sIgA produced in the gut can play a role in regulating intestinal fungal commensalism by coating fungal morphotypes linked to virulence, thereby providing a protective mechanism that might be dysregulated in CD patients.