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 6

Abnormal microbiome composition in Dvl1–/– mice.

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Abnormal microbiome composition in Dvl1–/– mice. Ileum and proximal colo...
Ileum and proximal colon of wild-type (WT) and Disheveled 1 knockout (Dvl1–/–) mice were processed for 16S rRNA gene profiling. (A–C) Ileum of 6-week-old WT and Dvl1–/– mice 16S rRNA gene profiling of alpha diversity indices (phylotype richness, Pielou’s evenness, and Faith’s phylogenetic diversity) was analyzed compared to WT mice. Results are presented as box plots, *P < 0.05 for comparing the results of the Dvl1–/– with those of the WT mice. (D) 16S rRNA gene profiling of beta diversity from ileum of individual 6-week-old WT and Dvl1–/– mice using weighted UniFrac distance matrix is presented. Permanova statistical analysis revealed significant differences (P = 0.019) in microbiota composition of Dvl1–/– and WT mice. (E) Relative abundance of Helicobacter OTU (10961) and Flexispira OTU (1141335) in the ileum and mid colon of 6- and 12-week-old WT and Dvl1–/– mice was measured. Results are presented as box plots. *q < 5.0 × 10–2, **q < 5.0 × 10–5, ***q < 5.0 × 10–11 for comparing the results of Dvl1–/– mice with age-matched WT mice. (F) WT and Dvl1–/– mice were cohoused (CH) or standardly housed (SH) by genotype from the day of weaning. CH and SH mice stool produced over a 1-hour time period was measured weekly and dry stool output was calculated. Results are presented as mean ± SEM. *P < 0.01 for 2-way ANOVA effect by genotype; **P < 0.03 for 2-way ANOVA effect by genotype × housing; and Bonferroni P < 0.04 for comparison of the Dvl1–/– SH dry stool weight with those from all other mouse groups. (G) 16S rRNA gene profiling of beta diversity from ileum of individual 12-week-old WT and Dvl1–/– mice using unweighted UniFrac distance matrix is presented. Permanova statistical analysis revealed significant difference (P = 0.036) in microbiota composition of the different groups. (H and I) The GI tract of standard and cohoused WT and Dvl1–/– mice were processed for histology and sections were stained with DAPI (nuclei) and immunostained for MMP7 (H), or DAPI, CD4, and CD8 (I), and representative images are shown. Scale bar: 100 μm.