Gut dysbiosis promotes M2 macrophage polarization and allergic airway inflammation via fungi-induced PGE₂.
Although imbalances in gut microbiota composition, or "dysbiosis," are associated with many diseases, the effects of gut dysbiosis on host systemic physiology are less well characterized. We report that gut dysbiosis induced by antibiotic (Abx) treatment promotes allergic airway inflammation by shifting macrophage polarization in the lung toward the alternatively activated M2 phenotype. Adoptive transfer of alveolar macrophages derived from Abx-treated mice was sufficient to increase allergic airway inflammation. Abx treatment resulted in the overgrowth of a commensal fungal Candida species in the gut and increased plasma concentrations of prostaglandin E₂ (PGE₂), which induced M2 macrophage polarization in the lung. Suppression of PGE₂ synthesis by the cyclooxygenase inhibitors aspirin and celecoxib suppressed M2 macrophage polarization and decreased allergic airway inflammatory cell infiltration in Abx-treated mice. Thus, Abx treatment can cause overgrowth of particular fungal species in the gut and promote M2 macrophage activation at distant sites to influence systemic responses including allergic inflammation.
Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Yun-Gi
YG
Kim
Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Kankanam Gamage Sanath
KG
Udayanga
Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Naoya
N
Totsuka
Department of Pediatrics and Communicable Diseases, Microbiology, and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Jason B
JB
Weinberg
Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Gabriel
G
Núñez
Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Life Science Center of Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan. Electronic address: ashibuya@md.tsukuba.ac.jp.
Akira
A
Shibuya
D019264:Adoptive Transfer; D000667:Ampicillin / Q000009:adverse effects; D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects; D001241:Aspirin / Q000494:pharmacology; D002175:Candida / Q000276:immunology; D002177:Candidiasis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D002438:Cefoperazone / Q000009:adverse effects; D000068579:Celecoxib; D002981:Clindamycin / Q000009:adverse effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000494:pharmacology; D064806:Dysbiosis / Q000139:chemically induced / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D005243:Feces / Q000382:microbiology; D041981:Gastrointestinal Tract / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D007249:Inflammation / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008168:Lung / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008262:Macrophage Activation / Q000187:drug effects; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D002981:Clindamycin; D000667:Ampicillin; D002438:Cefoperazone; D000068579:Celecoxib; D015232:Dinoprostone; D001241:Aspirin