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Impaired Autophagy in Intestinal Epithelial Cells Alters Gut Microbiota and Host Immune Responses.

ABSTRACT: 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.

SUBMITTER: Yang L

PROVIDER: S-EPMC6121970 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Impaired Autophagy in Intestinal Epithelial Cells Alters Gut Microbiota and Host Immune Responses.

Yang Lingyu L Liu Chao C Zhao Wenjing W He Chuan C Ding Jinmei J Dai Ronghua R Xu Ke K Xiao Lu L Luo Lingxiao L Liu Shuyun S Li Wei W Meng He H

Applied and environmental microbiology 20180831 18

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 ...[more]

PMID: 30006408

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Project description:Gut microbiome plays an essential role in modulating host immune responses. However, little is known about the interaction of microbiota, their metabolites and relevant inflammatory responses in the gut. By treating the mice with three different antibiotics (enrofloxacin, vancomycin, and polymixin B sulfate), we aimed to investigate the effects of different antibiotics exposure on gut microbiota, microbial metabolism, inflammation responses in the gut, and most importantly, pinpoint the underlying interactions between them. Although the administration of different antibiotics can lead to different effects on mouse models, the treatment did not affect the average body weight of the mice. A heavier caecum was observed in vancomycin treated mice. Treatment by these three antibiotics significantly up-regulated gene expression of various cytokines in the colon. Enrofloxacin treated mice seemed to have an increased Th1 response in the colon. However, such a difference was not found in mice treated by vancomycin or polymixin B sulfate. Vancomycin treatment induced significant changes in bacterial composition at phylum and family level and decreased richness and diversity at species level. Enrofloxacin treatment only induced changes in composition at family presenting as an increase in Prevotellaceae and Rikenellaceae and a decrease in Bacteroidaceae. However, no significant difference was observed after polymixin B sulfate treatment. When compared with the control group, significant metabolic shift was found in the enrofloxacin and vancomycin treated group. The metabolic changes mainly occurred in Valine, leucine, and isoleucine biosynthesis pathway and beta-Alanine metabolism in enrofloxacin treated group. For vancomycin treatment metabolic changes were mainly found in beta-Alanine metabolism and Alanine, aspartate and glutamate metabolism pathway. Moreover, modifications observed in the microbiota compositions were correlated with the metabolite concentrations. For example, concentration of pentadecanoic acid was positively correlated with richness of Rikenellaceae and Prevotellaceae and negatively correlated with Enterobacteriaceae. This study suggests that the antibiotic-induced changes in gut microbiota might contribute to the inflammation responses through the alternation of metabolic status, providing a novel insight regarding a complex network that integrates the different interactions between gut microbiota, metabolic functions, and immune responses in host.

Dataset Information

Impaired Autophagy in Intestinal Epithelial Cells Alters Gut Microbiota and Host Immune Responses.

Publications

Impaired Autophagy in Intestinal Epithelial Cells Alters Gut Microbiota and Host Immune Responses.

Similar Datasets

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