title: Orai1-Mediated Antimicrobial Secretion from Pancreatic Acini Shapes the Gut Microbiome and Regulates Gut Innate Immunity.
abstract: The gut microbiome participates in numerous physiologic functions and communicates intimately with the host immune system. Antimicrobial peptides are critical components of intestinal innate immunity. We report a prominent role for antimicrobials secreted by pancreatic acini in shaping the gut microbiome that is essential for intestinal innate immunity, barrier function, and survival. Deletion of the Ca2+channel Orai1 in pancreatic acini of adult mice resulted in 60%-70% mortality within 3 weeks. Despite robust activation of the intestinal innate immune response, mice lacking acinar Orai1 exhibited intestinal bacterial outgrowth and dysbiosis, ultimately causing systemic translocation, inflammation, and death. While digestive enzyme supplementation was ineffective, treatments constraining bacterial outgrowth (purified liquid diet, broad-spectrum antibiotics) rescued survival, feeding, and weight gain. Pancreatic levels of cathelicidin-related antimicrobial peptide (CRAMP) were reduced, and supplement of synthetic CRAMP prevented intestinal disease. These findings reveal a critical role for antimicrobial pancreatic secretion in gut innate immunity.
authors.affiliation: National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Malini
authors.initials: M
authors.lastname: Ahuja
authors.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Daniella M
authors.initials: DM
authors.lastname: Schwartz
authors.affiliation: National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Mayank
authors.initials: M
authors.lastname: Tandon
authors.affiliation: National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Aran
authors.initials: A
authors.lastname: Son
authors.affiliation: National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Zeng
authors.affiliation: National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: William
authors.initials: W
authors.lastname: Swaim
authors.affiliation: Office of Research Services, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Eckhaus
authors.affiliation: Office of Research Services, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Hoffman
authors.affiliation: Department of Neuroscience, Sichuan University, Chengdu 610041, China.
authors.forename: Yiyuan
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Neuroscience, Sichuan University, Chengdu 610041, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Xiao
authors.affiliation: Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Worley
authors.affiliation: National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: shmuel.muallem@nih.gov.
authors.forename: Shmuel
authors.initials: S
authors.lastname: Muallem
mesh_terms: D061354:Acinar Cells / Q000378:metabolism*; D000818:Animals; D000890:Anti-Infective Agents / Q000378:metabolism*; D020013:Calcium Signaling; D016923:Cell Death; D005089:Exocytosis; D000069196:Gastrointestinal Microbiome; D041981:Gastrointestinal Tract / Q000276:immunology* / Q000378:metabolism*; D017353:Gene Deletion; D006706:Homeostasis; D007113:Immunity, Innate; D007249:Inflammation / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D007422:Intestines / Q000382:microbiology / Q000473:pathology; D051379:Mice; D050296:Microbial Viability; D000071740:ORAI1 Protein / Q000172:deficiency / Q000378:metabolism*; D010179:Pancreas / Q000166:cytology*; D014176:Protein Biosynthesis
chemical_list: D000890:Anti-Infective Agents; D018836:Inflammation Mediators; D000071740:ORAI1 Protein; C520430:Orai1 protein, mouse