TY - JOUR
T1 - Orai1-Mediated Antimicrobial Secretion from Pancreatic Acini Shapes the Gut Microbiome and Regulates Gut Innate Immunity
AU - Ahuja, Malini
AU - Schwartz, Daniella M.
AU - Tandon, Mayank
AU - Son, Aran
AU - Zeng, Mei
AU - Swaim, William
AU - Eckhaus, Michael
AU - Hoffman, Victoria
AU - Cui, Yiyuan
AU - Xiao, Bo
AU - Worley, Paul F.
AU - Muallem, Shmuel
N1 - Publisher Copyright:
© 2017
PY - 2017/3/7
Y1 - 2017/3/7
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cmet.2017.02.007
DO - 10.1016/j.cmet.2017.02.007
M3 - Article
C2 - 28273482
AN - SCOPUS:85014571306
SN - 1550-4131
VL - 25
SP - 635
EP - 646
JO - Cell Metabolism
JF - Cell Metabolism
IS - 3
ER -