Orai1-Mediated Antimicrobial Secretion from Pancreatic Acini Shapes the Gut Microbiome and Regulates Gut Innate Immunity

Malini Ahuja, Daniella M. Schwartz, Mayank Tandon, Aran Son, Mei Zeng, William Swaim, Michael Eckhaus, Victoria Hoffman, Yiyuan Cui, Bo Xiao, Paul F. Worley, Shmuel Muallem

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)635-646
Number of pages12
JournalCell Metabolism
Volume25
Issue number3
DOIs
StatePublished - Mar 7 2017

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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