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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.

SUBMITTER: Belinson H

PROVIDER: S-EPMC4979554 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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

Belinson Haim H Savage Adam K AK Fadrosh Douglas D Kuo Yien-Ming YM Lin Din D Valladares Ricardo R Nusse Ysbrand Y Wynshaw-Boris Anthony A Lynch Susan V SV Locksley Richard M RM Klein Ophir D OD

JCI insight 20160701 10

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 ...[more]

PMID: 27525310

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Project description:Establishing and maintaining beneficial interactions between the host and associated gut microbiota are pivotal requirements for host health. Autophagy is an important catabolic recycling pathway that degrades long-lived proteins and some organelles by lysosome to maintain cellular homeostasis. Although impaired autophagy is thought to be closely correlated with Crohn's disease (CD), the functional role of autophagy in the maintenance of gut microbiota is poorly understood. As autophagy-related 5 (Atg5) is a key gene associated with the extension of the phagophoric membrane in autophagic vesicles, we established a gut-specific Atg5 knockout mouse model, and we found that the disruption of autophagic flux in the intenstinal epithelium cells dramatically altered the composition of the gut microbiota and reduced alpha diversity. Microbial function prediction indicated that the pathway allocated for infectious diseases was enriched in Atg5-/- mice. "Candidatus Arthromitus" and the Pasteurellaceae family were increased in Atg5-/- mice, whereas Akkermansia muciniphila and the Lachnospiraceae family were reduced. Transcriptome analysis revealed that two key inflammatory bowel disease (IBD)-related transcription factors, RORC and TBX21, of host cells were upregulated in Atg5-/- mice, thus elevating the Muc2-related immunological response. The findings suggest that intestinal autophagy plays a vital role in modulating the diversity and composition of gut microbiota.IMPORTANCE The homeostasis of host-microbiota interactions is of great importance to host health. Previous studies demonstrated that disruption of autophagy was linked to inflammatory bowel disease. However, the interaction mechanism of gut microbiota regulated by autophagy was obscure. In an intestinal epithelium-specific autophagy-related 5 (Atg5) knockout mouse model, we observed a significant alteration and decreased diversity in the gut microbiota of Atg5-deficient mice compared with that of wild-type mice. Although the numbers of some organisms (e.g., Akkermansia muciniphila and members of the Lachnospiraceae family) associated with the control of inflammation decreased, those of proinflammationory bacteria (e.g., "Candidatus Arthromitus") and potential pathogens (the Pasteurellaceae family) increased in Atg5-/- mice. Differential gene expression analysis revealed that two key genes, RORC and TBX21, involved in inflammatory bowel disease were upregulated in Atg5-/- mice. Our study suggests that Atg5 deficiency results in an imbalance of the host-microbe interaction and deterioration of the gut microenvironment.

Dataset Information

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

Publications

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

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