Editors' ChoiceHost-Microbe Interactions

Shaping the gut microbiome from the pancreas

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Sci. Signal.  28 Mar 2017:
Vol. 10, Issue 472, eaan3016
DOI: 10.1126/scisignal.aan3016

The Ca2+ channel Orai1 in pancreatic acinar cells helps to suppress inflammation-associated bacterial strains in the gut.

Dysfunction of the intestinal microbiome can lead to infection and chronic inflammatory disorders. The composition of the intestinal microbiome is controlled by antimicrobial peptides secreted by intestinal cells, such as the Paneth cells and pancreatic acinar cells. Exocytosis in pancreatic exocrine cells requires the Ca2+ channel Orai1. Ahuja et al. found that inducible deletion of Orai1 in the pancreatic acinar cells resulted in 65% mortality in mice fed a standard solid diet. These mice (referred to as Orai1–/– mice by the authors) showed signs of gastrointestinal inflammation, bacterial overgrowth, and systemic infection despite having a functional intestinal innate immune system. Orai1–/– mice survived and had less gastrointestinal inflammation when fed a purified liquid diet, which is given to patients with gastrointestinal inflammation, instead of the solid diet. Ca2+ release and influx in response to various stimuli were reduced in acinar cells from Orai1–/– mice on a purified liquid diet. The abundance of the antimicrobial cathelicidin-derived peptide CRAMP was reduced in Orai1–/– pancreatic acini, which was associated with an increase in inflammation-promoting bacterial strains in the intestinal microbiome, and CRAMP supplementation improved the survival of Orai1–/– mice on the solid diet. Both Ahuja et al. and commentary by Tilg and Adolph note that mice with a global deletion of Orai1 do not show the same mortality on a solid diet as mice with a targeted deletion of Orai1 in pancreatic acinar cells. Nonetheless, these results suggest that Orai1 inhibitors, which are being developed to treat various diseases, may have undesirable side effects on the intestinal microbiome.

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