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.

No abstract

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.

Highlights d High gut Candida before FMT is associated with clinical response in ulcerative colitis d Decreases in Candida post-FMT are indicative of ameliorated disease severity d Increased anti-Candida antibodies in placebo controls were abrogated in FMT recipients d Pre-FMT Candida associates with bacterial diversity and genera linked to responsiveness