Dual epithelial and immune cell function of Dvl1 regulates gut microbiota composition and intestinal homeostasis
Haim Belinson, … , Richard M. Locksley, Ophir D. Klein
Haim Belinson, … , Richard M. Locksley, Ophir D. Klein
Published July 7, 2016
Citation Information: JCI Insight. 2016;1(10):e85395. https://doi.org/10.1172/jci.insight.85395.
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Research Article Gastroenterology

Dual epithelial and immune cell function of Dvl1 regulates gut microbiota composition and intestinal homeostasis

Abstract

Homeostasis of the gastrointestinal (GI) tract is controlled by complex interactions between epithelial and immune cells and the resident microbiota. Here, we studied the role of Wnt signaling in GI homeostasis using Disheveled 1 knockout (Dvl1–/–) mice, which display an increase in whole gut transit time. This phenotype is associated with a reduction and mislocalization of Paneth cells and an increase in CD8+ T cells in the lamina propria. Bone marrow chimera experiments demonstrated that GI dysfunction requires abnormalities in both epithelial and immune cells. Dvl1–/– mice exhibit a significantly distinct GI microbiota, and manipulation of the gut microbiota in mutant mice rescued the GI transit abnormality without correcting the Paneth and CD8+ T cell abnormalities. Moreover, manipulation of the gut microbiota in wild-type mice induced a GI transit abnormality akin to that seen in Dvl1–/– mice. Together, these data indicate that microbiota manipulation can overcome host dysfunction to correct GI transit abnormalities. Our findings illustrate a mechanism by which the epithelium and immune system coregulate gut microbiota composition to promote normal GI function.

Authors

Haim Belinson, Adam K. Savage, Douglas Fadrosh, Yien-Ming Kuo, Din Lin, Ricardo Valladares, Ysbrand Nusse, Anthony Wynshaw-Boris, Susan V. Lynch, Richard M. Locksley, Ophir D. Klein

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Figure 2

Abnormal colonic immune response in Dvl1–/– mice.

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Abnormal colonic immune response in Dvl1–/– mice. The gastrointestinal t...
The gastrointestinal tracts of 12-week-old wild-type (WT) and Disheveled 1 knockout (Dvl1–/–) mice were processed for histology. (A) Sections were stained with hematoxylin and eosin, and representative images are shown. Scale bar: 100 μm. (B) Sections of proximal colon were stained with DAPI (nuclei) and immunostained for CD45, and representative images are shown. Images are oriented from proximal (P) to distal (D), from left to right, respectively. Arrowheads denote the patch structures. Scale bar: 1,000 μm. (C and D) Enlargement of inserts in B. Scale bar: 250 μm. (E) Sections of proximal colon were stained with DAPI and immunostained for B220 and Iba-1, and representative images are shown. Images are oriented from proximal (P) to distal (D), from left to right, respectively. Arrowheads denote the patch structure. Scale bar: 1,000 μm. (F and G) Enlargement of inserts in E. Scale bar: 250 μm. (H) Sections from proximal colon of Dvl1–/– mice were stained with DAPI and immunostained for B220 and Iba-1, and a representative image of the patch region is shown. Scale bar: 100 μm. (I) Sections from proximal colon of Dvl1–/– mice were immunostained for CD3, CD4, and CD8, and a representative image of the patch region is shown. Scale bar: 100 μm. (J) Whole colons from WT and Dvl1–/– mice were fixed and stained with DAPI and immunostained for B220 and CD3, and representative images from the mid colon region are shown. Scale bar: 500 μm. (K) Enlargement of inserts in F. Scale bar: 2,000 μm.