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Dual-specificity phosphatase 6 deficiency regulates gut microbiome and transcriptome response against diet-induced obesity in mice

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Abstract

The gut microbiota plays profound roles in host metabolism and the inflammatory response associated with the development of obesity. Dusp6-deficient mice have been shown to be resistant to diet-induced obesity, but the mechanism behind this remains unclear. 16S ribosomal RNA gene analysis demonstrated that dusp6-deficient mice harbour unique gut microbiota with resistance to diet-induced-obesity-mediated alteration of the gut microbiome. Using a germ-free mouse model, we found that faecal/gut microbiota derived from dusp6-deficient mice significantly increased energy expenditure and reduced weight gain in recipient wild-type mice fed on a high-fat diet. On analysis of the intestinal transcriptome of dusp6-deficient mice, we found that dusp6 deficiency mainly induced biological processes involved in metabolism and the extracellular matrix, particularly the peroxisome proliferator-activated receptor gamma (Pparγ) pathway and tight-junction genes. Furthermore, dusp6-deficient mice have a high-fat-diet-specific transcriptomic response to reverse the expression of genes associated with intestinal barrier functions and mucosal immunity involved in microbiome homeostasis. This study demonstrates that dusp6 deficiency is a strong genetic factor shaping gut microbiota, and that it confers obesity protection by ameliorating the gut microbiota response to diet-mediated stress.

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Figure 1: Dusp6-deficient-mice-derived faecal microbiota increases DIO resistance in FMT recipient mice.
Figure 2: Dusp6-deficient mice are resistant to HFD-mediated alteration of the gut microbiome.
Figure 3: Colonization of gut microbiota derived from dusp6-deficient mice contributes to obesity resistance in FMT recipient mice.
Figure 4: Intestine transcriptome analysis of dusp6-deficient and WT mice.
Figure 5: Dusp6 deficiency modulates intestinal mucosal immunity to adapt HFD challenging.
Figure 6: Dusp6 deficiency confers HFD-specific modulation to maintain physiological barrier function.

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  • 14 July 2017

    In the PDF version of this article previously published, the year of publication provided in the footer of each page and in the 'How to cite' section was erroneously given as 2017, it should have been 2016. This error has now been corrected. The HTML version of the article was not affected.

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Acknowledgements

The authors thank N.H. Salzman (Department of Pediatrics, Medical College of Wisconsin) for the gift of SFB plasmid CTL5-6 and C.-T. Chen (NHRI) for providing Caco-2 cells. The authors thank P.-J. Tsai (Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University) for assistance with TEER analysis. The authors acknowledge the Taiwan Mouse Clinic (MOST 104-2325-B-001-011), which is funded by the National Research Program for Biopharmaceuticals (NRPB) at the Ministry of Science and Technology (MOST) of Taiwan, for technical support regarding mouse energy expenditure and NMR experiments. This work was supported by the following grants: 104-IMPP05 from NHRI and 103-2320-B-400-017, 104-2320-B-400-019-MY3 and 104-2320-B-400-020-MY2 from MOST (J.W.R., C.T.H. and C.Y.K.); 105-IMPP01 and 105-IMSP01 from NHRI and 105-2314-B-400-027 from MOST (T.H.T.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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J.-W.R., C.-C.K., H.-L.C. and C.-Y.K. designed the study. J.-W.R., C.-T.H. and Y.-T.T. performed and evaluated the experiments. J.-W.R., S.S., Y.-C.L. and C.-Y.K. performed bioinformatic analyses. T.-H.T. provided DUSP6 research resources including knock-out mice. J.-W.R., S.S. and C.-Y.K. wrote the manuscript. C.-Y.K. supervised the entire work.

Corresponding author

Correspondence to Cheng-Yuan Kao.

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Supplementary Information

Supplementary Figures 1–5, Supplementary Tables 1,2,4, Supplementary References. (PDF 5164 kb)

Supplementary Table 3

KEGG pathways: PPAR pathway and tight-junction pathway. (XLSX 2854 kb)

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Ruan, JW., Statt, S., Huang, CT. et al. Dual-specificity phosphatase 6 deficiency regulates gut microbiome and transcriptome response against diet-induced obesity in mice. Nat Microbiol 2, 16220 (2017). https://doi.org/10.1038/nmicrobiol.2016.220

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