The Intestinal Immune System in Obesity and Insulin Resistance
2016; Cell Press; Volume: 23; Issue: 3 Linguagem: Inglês
10.1016/j.cmet.2016.01.003
ISSN1932-7420
AutoresDaniel A. Winer, Helen Luck, Sue Tsai, Shawn Winer,
Tópico(s)Gut microbiota and health
ResumoObesity and insulin resistance are associated with chronic inflammation in metabolic tissues such as adipose tissue and the liver. Recently, growing evidence has implicated the intestinal immune system as an important contributor to metabolic disease. Obesity predisposes to altered intestinal immunity and is associated with changes to the gut microbiota, intestinal barrier function, gut-residing innate and adaptive immune cells, and oral tolerance to luminal antigens. Accordingly, the gut immune system may represent a novel therapeutic target for systemic inflammation in insulin resistance. This review discusses the emerging field of intestinal immunity in obesity-related insulin resistance and how it affects metabolic disease. Obesity and insulin resistance are associated with chronic inflammation in metabolic tissues such as adipose tissue and the liver. Recently, growing evidence has implicated the intestinal immune system as an important contributor to metabolic disease. Obesity predisposes to altered intestinal immunity and is associated with changes to the gut microbiota, intestinal barrier function, gut-residing innate and adaptive immune cells, and oral tolerance to luminal antigens. Accordingly, the gut immune system may represent a novel therapeutic target for systemic inflammation in insulin resistance. This review discusses the emerging field of intestinal immunity in obesity-related insulin resistance and how it affects metabolic disease. Obesity has reached epidemic proportions. The World Health Organization (WHO) estimates that over 1.9 billion people are overweight, of which 600 million are obese. Obesity is associated with numerous complications, including insulin resistance and type 2 diabetes, but also increased risks of cancer and cardiovascular and autoimmune diseases, among others. Obesity is associated with low-grade chronic inflammation, which may be the precipitating factor for many of its associated complications. Increased circulating levels of tumor necrosis factor α (TNF-α), interleukin-1 (IL-1), and IL-6 in obese humans and in diet-induced obese (DIO) mice contribute to the development of insulin resistance and subsequent type 2 diabetes (Hotamisligil et al., 1993Hotamisligil G.S. Shargill N.S. Spiegelman B.M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance.Science. 1993; 259: 87-91Crossref PubMed Google Scholar, Olefsky and Glass, 2010Olefsky J.M. Glass C.K. Macrophages, inflammation, and insulin resistance.Annu. Rev. Physiol. 2010; 72: 219-246Crossref PubMed Scopus (834) Google Scholar). 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Pomié C. Klopp P. Waget A. Charpentier J. Aloulou M. Giry A. Serino M. Stenman L. Lahtinen S. et al.The Gut Microbiota Regulates Intestinal CD4 T Cells Expressing RORγt and Controls Metabolic Disease.Cell Metab. 2015; 22: 100-112Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, Luck et al., 2015Luck H. Tsai S. Chung J. Clemente-Casares X. Ghazarian M. Revelo X.S. Lei H. Luk C.T. Shi S.Y. Surendra A. et al.Regulation of obesity-related insulin resistance with gut anti-inflammatory agents.Cell Metab. 2015; 21: 527-542Abstract Full Text Full Text PDF PubMed Google Scholar, Monteiro-Sepulveda et al., 2015Monteiro-Sepulveda M. Touch S. Mendes-Sá C. André S. Poitou C. Allatif O. Cotillard A. Fohrer-Ting H. Hubert E.L. Remark R. et al.Jejunal T Cell Inflammation in Human Obesity Correlates with Decreased Enterocyte Insulin Signaling.Cell Metab. 2015; 22: 113-124Abstract Full Text Full Text PDF PubMed Google Scholar). This review describes evidence for and against immune cell-mediated, low-grade intestinal inflammation as an emerging feature and potential driving force behind the development of obesity-associated insulin resistance. It also briefly examines the mechanisms, including dysbiosis, changes in intestinal permeability, and alterations in oral tolerance, by which the intestinal immune system may affect systemic inflammation and insulin resistance. Moreover, clinical implications regarding the design of low-toxicity, gut-specific therapies targeting the gut immune system are also described. The small and large intestines are home to over a trillion microorganisms consisting of hundreds of species. Increasing evidence links changes in intestinal bacteria to the development of obesity and glucose intolerance. Evidence for this notion stems from the initial observation that germ-free mice have reduced body fat and do not develop obesity or insulin resistance when placed on a high-fat diet (HFD) (Bäckhed et al., 2004Bäckhed F. Ding H. Wang T. Hooper L.V. Koh G.Y. Nagy A. Semenkovich C.F. Gordon J.I. The gut microbiota as an environmental factor that regulates fat storage.Proc. Natl. Acad. Sci. USA. 2004; 101: 15718-15723Crossref PubMed Scopus (1631) Google Scholar, Bäckhed et al., 2007Bäckhed F. Manchester J.K. Semenkovich C.F. Gordon J.I. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice.Proc. Natl. Acad. Sci. USA. 2007; 104: 979-984Crossref PubMed Scopus (745) Google Scholar). However, germ-free mice regain adiposity and develop insulin resistance and glucose intolerance 2 weeks after reconstitution with the gut microbiota of conventionally raised mice (Bäckhed et al., 2004Bäckhed F. Ding H. Wang T. Hooper L.V. Koh G.Y. Nagy A. Semenkovich C.F. Gordon J.I. The gut microbiota as an environmental factor that regulates fat storage.Proc. Natl. Acad. Sci. USA. 2004; 101: 15718-15723Crossref PubMed Scopus (1631) Google Scholar). This effect occurred even with reduced food intake, providing further evidence that gut bacteria are regulators of energy metabolism. Obesity and metabolic syndrome are associated with an altered gut microbiota, known as dysbiosis (Turnbaugh et al., 2006Turnbaugh P.J. Ley R.E. Mahowald M.A. Magrini V. Mardis E.R. Gordon J.I. An obesity-associated gut microbiome with increased capacity for energy harvest.Nature. 2006; 444: 1027-1031Crossref PubMed Scopus (2599) Google Scholar). In mice and humans, metagenomic analysis showed that most bacteria in the distal gut and feces belong to two main bacterial phyla, Bacteroidetes and Firmicutes (Gill et al., 2006Gill S.R. Pop M. Deboy R.T. Eckburg P.B. Turnbaugh P.J. Samuel B.S. Gordon J.I. Relman D.A. Fraser-Liggett C.M. Nelson K.E. 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Four weeks of continuous LPS infusion recapitulates many metabolic abnormalities that occur during HFD consumption, such as increased fasting glucose and insulin, increased liver and adipose tissue and body weight, and adipose tissue inflammation (Cani et al., 2007Cani P.D. Amar J. Iglesias M.A. Poggi M. Knauf C. Bastelica D. Neyrinck A.M. Fava F. Tuohy K.M. Chabo C. et al.Metabolic endotoxemia initiates obesity and insulin resistance.Diabetes. 2007; 56: 1761-1772Crossref PubMed Scopus (1281) Google Scholar). Bacterium-related leakage into blood and tissue, such as adipose tissue, can be detected as early as 1 week after starting a HFD and is dependent on the microbial pattern receptors NOD1 or CD14 (Amar et al., 2011aAmar J. Chabo C. Waget A. Klopp P. Vachoux C. Bermúdez-Humarán L.G. Smirnova N. Bergé M. Sulpice T. 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Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice.Diabetes. 2008; 57: 1470-1481Crossref PubMed Scopus (925) Google Scholar). Increased cytoplasmic sequestration of occludin has also been seen following HFD consumption in obesity-prone Sprague-Dawley rats (de La Serre et al., 2010de La Serre C.B. Ellis C.L. Lee J. Hartman A.L. Rutledge J.C. Raybould H.E. Propensity to high-fat diet-induced obesity in rats is associated with changes in the gut microbiota and gut inflammation.Am. J. Physiol. Gastrointest. Liver Physiol. 2010; 299: G440-G448Crossref PubMed Scopus (240) Google Scholar), and abnormal distribution of occludin and ZO-1 is seen in ob/ob mice (Brun et al., 2007Brun P. Castagliuolo I. Di Leo V. Buda A. Pinzani M. Palù G. Martines D. Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis.Am. J. Physiol. Gastrointest. 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