Sensing Fungal Dysbiosis by Gut-Resident CX3CR1+ Mononuclear Phagocytes Aggravates Allergic Airway Disease

Abstract

Abstract 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. However, how mycobiota influence immunity in gut distal sites is not well understood. We developed protocols for gut-targeted depletion of phagocytes to investigate the influence of fungi on gut-lung crosstalk. 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 mediate gut-lung-directed immune crosstalk and aggravate disease severity through fungal sensing by gut-resident CX3CR1+ MNPs. Highlights Gut fungal dysbiosis persistently aggravates allergic airway disease (AAD) in mice. Gut colonization by commensal fungi is both required and sufficient to aggravate AAD in a mycobiome-free mouse model. Intestinal CX3CR1+ mononuclear phagocytes (MNPs) are essential for the systemic effects of gut fungal dysbiosis on AAD. Inhibition of Syk-mediated fungal sensing in intestinal CX3CR1+ MNPs ameliorates AAD.