The imbalance in the intestinal microbiota repertoire, called dysbiosis, underlies the development of inflammatory diseases in the intestine and distant organ systems. Whether and how distant organs regulate the commensal gut bacteria and intestinal homeostasis via microbe-targeted molecules has remained poorly explored. In this study, we show that the gallbladder regulates intestinal immune homeostasis through the production of surfactant protein D (SP-D) that is delivered to the intestine via bile. The importance of the gallbladder-derived SP-D was underscored by an intestinal dysbiosis in SP-D–deficient mice and susceptibility of these mice to dextran sodium sulfate sodium-induced colitis. Our study thus revealed a unique interorgan regulation of intestinal homeostasis by SP-D with potential clinical implications such as cholecystectomy.

Abstract

The commensal microbiota within the gastrointestinal tract is essential in maintaining homeostasis. Indeed, dysregulation in the repertoire of microbiota can result in the development of intestinal immune–inflammatory diseases. Further, this immune regulation by gut microbiota is important systemically, impacting health and disease of organ systems beyond the local environment of the gut. What has not been explored is how distant organs might in turn shape the microbiota via microbe-targeted molecules. Here, we provide evidence that surfactant protein D (SP-D) synthesized in the gallbladder and delivered into intestinal lumen binds selectively to species of gut commensal bacteria. SP-D–deficient mice manifest intestinal dysbiosis and show a susceptibility to dextran sulfate sodium-induced colitis. Further, fecal transfer from SP-D–deficient mice to wild-type, germ-free mice conveyed colitis susceptibility. Interestingly, colitis caused a notable increase in Sftpd gene expression in the gallbladder, but not in the lung, via the activity of glucocorticoids produced in the liver. These findings describe a unique mechanism of interorgan regulation of intestinal immune homeostasis by SP-D with potential clinical implications such as cholecystectomy.