Gut microbe-derived extracellular vesicles induce insulin resistance, thereby impairing glucose metabolism in skeletal muscle
Youngwoo Choi, Yonghoon Kwon, Dae-Kyum Kim, Jinseong Jeon, Su Chul Jang, Taejun Wang, Minjee Ban, Min-Hye Kim, Seong Gyu Jeon, Min-Sun Kim, Cheol Soo Choi, Young-Koo Jee, Yong Song Gho, Sung Ho Ryu, Yoon-Keun Kim, Youngwoo Choi, Yonghoon Kwon, Dae-Kyum Kim, Jinseong Jeon, Su Chul Jang, Taejun Wang, Minjee Ban, Min-Hye Kim, Seong Gyu Jeon, Min-Sun Kim, Cheol Soo Choi, Young-Koo Jee, Yong Song Gho, Sung Ho Ryu, Yoon-Keun Kim
Abstract
Gut microbes might influence host metabolic homeostasis and contribute to the pathogenesis of type 2 diabetes (T2D), which is characterized by insulin resistance. Bacteria-derived extracellular vesicles (EVs) have been suggested to be important in the pathogenesis of diseases once believed to be non-infectious. Here, we hypothesize that gut microbe-derived EVs are important in the pathogenesis of T2D. In vivo administration of stool EVs from high fat diet (HFD)-fed mice induced insulin resistance and glucose intolerance compared to regular diet (RD)-fed mice. Metagenomic profiling of stool EVs by 16S ribosomal DNA sequencing revealed an increased amount of EVs derived from Pseudomonas panacis (phylum Proteobacteria) in HFD mice compared to RD mice. Interestingly, P. panacis EVs blocked the insulin signaling pathway in both skeletal muscle and adipose tissue. Moreover, isolated P. panacis EVs induced typical diabetic phenotypes, such as glucose intolerance after glucose administration or systemic insulin injection. Thus, gut microbe-derived EVs might be key players in the development of insulin resistance and impairment of glucose metabolism promoted by HFD.
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References
- Gordon J. I. Honor thy gut symbionts redux. Science 336, 1251–1253 (2012).
- Flint H. J., Scott K. P., Louis P. & Duncan S. H. The role of the gut microbiota in nutrition and health. Nature reviews. Gastroenterology & hepatology 9, 577–589 (2012).
- Nicholson J. K. et al. Host-gut microbiota metabolic interactions. Science 336, 1262–1267 (2012).
- Tremaroli V. & Backhed F. Functional interactions between the gut microbiota and host metabolism. Nature 489, 242–249 (2012).
- Hooper L. V., Littman D. R. & Macpherson A. J. Interactions between the microbiota and the immune system. Science 336, 1268–1273 (2012).
- Turnbaugh P. J. et al. A core gut microbiome in obese and lean twins. Nature 457, 480–484 (2009).
- Ley R. E., Turnbaugh P. J., Klein S. & Gordon J. I. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023 (2006).
- Qin J. et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55–60 (2012).
- Donath M. Y. & Shoelson S. E. Type 2 diabetes as an inflammatory disease. Nature reviews. Immunology 11, 98–107 (2011).
- Pessin J. E. & Saltiel A. R. Signaling pathways in insulin action: molecular targets of insulin resistance. JCI 106, 165–169 (2000).
- DeFronzo R. A. & Tripathy D. Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes care, 32 Suppl 2, S157–163 (2009).
- Samuel V. T. & Shulman G. I. Mechanisms for insulin resistance: common threads and missing links. Cell 148, 852–871 (2012).
- Harding C., Heuser J. & Stahl P. Endocytosis and intracellular processing of transferrin and colloidal gold-transferrin in rat reticulocytes: demonstration of a pathway for receptor shedding. EJCB 35, 256–263 (1984).
- Pan B. T. & Johnstone R. M. Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell 33, 967–978 (1983).
- Bobrie A., Colombo M., Raposo G. & Thery C. Exosome secretion: molecular mechanisms and roles in immune responses. Traffic 12, 1659–1668 (2011).
- Mashburn L. M. & Whiteley M. Membrane vesicles traffic signals and facilitate group activities in a prokaryote. Nature 437, 422–425 (2005).
- Gyorgy B. et al. Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. CMLS 68, 2667–2688 (2011).
- Lee E. Y. et al. Global proteomic profiling of native outer membrane vesicles derived from Escherichia coli. Proteomics 7, 3143–3153 (2007).
- Lee E. Y. et al. Gram-positive bacteria produce membrane vesicles: proteomics-based characterization of Staphylococcus aureus-derived membrane vesicles. Proteomics 9, 5425–5436 (2009).
- Wu S. et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med 15, 1016–1022 (2009).
- Kim D. K. et al. EVpedia: an integrated database of high-throughput data for systemic analyses of extracellular vesicles. JEV 2, 20384 (2013).
- Kim M. R. et al. Staphylococcus aureus-derived extracellular vesicles induce neutrophilic pulmonary inflammation via both Th1 and Th17 cell responses. Allergy 67, 1271–1281 (2012).
- Kim O. S. et al. Introducing EzTaxon-e: a prokaryotic 16S rRNA gene sequence database with phylotypes that represent uncultured species. IJSEM 62, 716–721 (2012).
- Chun J. et al. EzTaxon: a web-based tool for the identification of prokaryotes based on 16S ribosomal RNA gene sequences. IJSEM 57, 2259–2261 (2007).
- Altschul S. F. et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. NAR 25, 3389–3402 (1997).
- Myers E. W. & Miller W. Optimal alignments in linear space. CABIOS 4, 11–17 (1988).
- Song P. et al. Emodin regulates glucose utilization by activating AMP-activated protein kinase. JBC 288, 5732–5742 (2013).
- Kim D. et al. CXCL12 secreted from adipose tissue recruits macrophages and induces insulin resistance in mice. Diabetologia 57, 1456–1465 (2014).
- Estrada D. E. et al. Stimulation of glucose uptake by the natural coenzyme alpha-lipoic acid/thioctic acid: participation of elements of the insulin signaling pathway. Diabetes 45, 1798–1804 (1996).
- Wang Q., Khayat Z., Kishi K., Ebina Y. & Klip A. GLUT4 translocation by insulin in intact muscle cells: detection by a fast and quantitative assay. FEBS letters 427, 193–197 (1998).
- Turnbaugh P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006).
- Cani P. D. et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761–1772 (2007).
- Cani P. D. et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57, 1470–1481 (2008).
- Qin J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010).
- Ley R. E. et al. Obesity alters gut microbial ecology. PNAS 102, 11070–11075 (2005).
- Furet J. P. et al. Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers. Diabetes 59, 3049–3057 (2010).
- Ghoshal S., Witta J., Zhong J., de Villiers W. & Eckhardt E. Chylomicrons promote intestinal absorption of lipopolysaccharides. JLR 50, 90–97 (2009).
- Erridge C., Attina T., Spickett C. M. & Webb D. J. A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation. AJCN 86, 1286–1292 (2007).
- Wei X. et al. Fatty acid synthase modulates intestinal barrier function through palmitoylation of mucin 2. Cell host & microbe 11, 140–152 (2012).
- Amar J. et al. Involvement of tissue bacteria in the onset of diabetes in humans: evidence for a concept. Diabetologia 54, 3055–3061 (2011).
Source: PubMed