Dual epithelial and immune cell function of Dvl1 regulates gut microbiota composition and intestinal homeostasis
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
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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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 3

Abnormal GI inflammatory response in Dvl1–/– mice.

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Abnormal GI inflammatory response in Dvl1–/– mice. Ileum and proximal co...
Ileum and proximal colon of 15-week-old wild-type (WT) and Disheveled 1 knockout (Dvl1–/–) mice were processed for flow cytometry. (A) Lymphoid cell markers were used to determine the number of specific lymphoid cell populations per cm tissue. Results are presented as box plot, Bonferroni *P < 0.001 for comparison of the Dvl1–/– mice CD8+ αβT cells with those from WT. (B) Sections from ileum and proximal colon of WT and Dvl1–/– mice were stained with DAPI (nuclei) and immunostained for CD4 and CD8, and representative images are shown. Scale bar: 100 μm. (C and D) Markers of the activation state of CD8+ αβT cells were used to determine the number of activated CD8+ αβT cells per cm tissue. Results are presented as box plot, Bonferroni *P < 0.05 for comparison of the Dvl1–/– mice CD8+ αβT cells with those from WT. (E) Myeloid cell markers were used to determine the number of specific myeloid cell populations per cm tissue. Results are presented as box plot, Bonferroni *P < 0.05 for comparison of the Dvl1–/– mice F4/80+ cells (macrophages) with those from WT. (F) Sections from ileum and proximal colon of WT and Dvl1–/– mice were stained with DAPI and immunostained for Iba-1 (macrophages), and representative images are shown. Scale bar: 100 μm.