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 5

T cells are required to induce abnormal GI physiological function.

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T cells are required to induce abnormal GI physiological function. Bone ...
Bone marrow chimera of wild-type (WT) and Disheveled 1 knockout (Dvl1–/–) mice were prepared by subjecting recipient mice to sublethal doses of radiation and injecting them with hematopoietic progenitor cells from donor mice. (A) Stool produced over a 1-hour time period was measured and dry stool output was calculated prior to irradiation and following bone marrow chimera preparation (D, donor; R, recipient). Results are presented as box plot, (n = 3, 2-way ANOVA P < 0.02, Bonferroni *P < 0.04 for comparison of the Dvl1–/– dry stool weight with those from WT). (B and C) The GI tract of WT and Dvl1–/– bone marrow chimera mice was processed for histology and sections were stained with DAPI (nuclei) and immunostained for lysozyme (B), or DAPI, CD4, and CD8 (C), and representative images are shown. Scale bar: 100 μm. (D and E) Dvl1–/– mice were backcrossed with Rag2–/– mice and at 8 weeks of age mice were tested for stool produced over a 1-hour time period. Dry stool output (D) and percentage of water in the stool (E) were calculated. Results are presented as box plot, 2-way ANOVA P < 0.05, Bonferroni *P < 0.05 for comparison of the Dvl1–/– dry stool weight with those from all the other mice groups; 2-way ANOVA effect of Rag2–/– P < 0.001; **P < 0.002 for comparison of the Rag2–/– and Dvl1–/– Rag2–/– percentage of water in the stool with those from the other mice groups.