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

• Published in: Cell host & microbe Vol. 24; no. 6; pp. 847 - 856.e4
• Main Authors: Li, Xin, Leonardi, Irina, Semon, Alexa, Doron, Itai, Gao, Iris H., Putzel, Gregory Garbès, Kim, Youngjun, Kabata, Hiroki, Artis, David, Fiers, William D., Ramer-Tait, Amanda E., Iliev, Iliyan D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.12.2018
• Subjects: Animals; CX3C Chemokine Receptor 1; CX3CR1+ mononuclear phagocytes; Dysbiosis; Fungi; gut-lung axis; Hypersensitivity; Intestines; Mice; mycobiome; mycobiota dysbiosis; Phagocytes; mycobiome; gut-lung axis; CX3CR1+ mononuclear phagocytes; fungi; mycobiota dysbiosis; CX3CR1(+) mononuclear phagocytes
• ISSN: 1931-3128; 1934-6069; 1934-6069
• DOI: 10.1016/j.chom.2018.11.003

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. [Display omitted] •Fungal dysbiosis persistently aggravates allergic airway disease (AAD) in mice•Gut colonization by commensal fungi is both required and sufficient to aggravate AAD•Intestinal CX3CR1+ mononuclear phagocytes (MNPs) are essential for the effects•Inhibition of Syk-mediated fungal sensing in intestinal CX3CR1+ MNPs ameliorates AAD How mycobiota influence immunity in gut distal sites is not well understood. Li et al. developed protocols for gut-targeted depletion of phagocytes and mycobiota-free mice to investigate the influence of fungi on gut-lung crosstalk. They reveal that intestinal phagocytes sense fungal dysbiosis and mediate gut-lung-directed immunity to aggravate allergic airway disease.