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Gastrointestinal Barrier Breakdown and Adipose Tissue Inflammation

  • Obesity Treatment (CM Apovian, Section Editor)
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Abstract

Purpose of Review

Obesity is a state of chronic inflammation. This review aims to summarize recent data supporting the role of the intestinal mucosal barrier and the microbiome in causing adipose tissue inflammation as well as metabolic factors that can affect the intestinal barrier.

Recent Findings

Obesity and its metabolic consequences, such as diabetes mellitus, are associated with disruption of the intestinal barrier function. Intestinal microbiota and diet play a key role in the maintenance of a healthy intestinal epithelium. Intestinal barrier dysfunction can lead to heightened inflammation, which in turn can further damage the intestinal barrier through the disruption of tight junction proteins.

Summary

Intestinal barrier breakdown is associated with adipose tissue inflammation in different disease states, such as obesity, diabetes mellitus, HIV, and inflammatory bowel disease. Future therapeutic strategies to ameliorate intestinal barrier function may help reduce inflammation in obesity and other chronic conditions of increased intestinal permeability.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Wells JM, Brummer RJ, Derrien M, MacDonald TT, Troost F, Cani PD, et al. Homeostasis of the gut barrier and potential biomarkers. Am J Physiol Gastrointest Liver Physiol. 2017;312(3):G171–G93.

    Article  Google Scholar 

  2. Tanoue T, Umesaki Y, Honda K. Immune responses to gut microbiota-commensals and pathogens. Gut Microbes. 2010;1(4):224–33.

    Article  Google Scholar 

  3. Sun M, He C, Cong Y, Liu Z. Regulatory immune cells in regulation of intestinal inflammatory response to microbiota. Mucosal Immunol. 2015 Sep;8(5):969–78.

    Article  CAS  Google Scholar 

  4. World Health Organization Global Health Observatory Data: https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight. Accessed 25 Feb 2019.

  5. Sahebekhtiari N, Saraswat M, Joenvaara S, Jokinen R, Lovric A, Kaye S, et al. Plasma proteomics analysis reveals dysregulation of complement proteins and inflammation in acquired obesity - a study on rare Bmi-discordant monozygotic twin pairs. Proteomics Clin Appl. 2019;27:e1800173.

    Article  Google Scholar 

  6. Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes. 2008;57(6):1470–81.

    Article  CAS  Google Scholar 

  7. Mayorga Reyes L, Gonzalez Vazquez R, Cruz Arroyo SM, Melendez Avalos A, Reyes Castillo PA, Chavaro Perez DA, et al. Correlation between diet and gut bacteria in a population of young adults. Int J Food Sci Nutr. 2016;67(4):470–8.

    Article  Google Scholar 

  8. •• Genser L, Aguanno D, Soula HA, Dong L, Trystram L, Assmann K, et al. Increased jejunal permeability in human obesity is revealed by a lipid challenge and is linked to inflammation and type 2 diabetes. J Pathol. 2018;246(2):217–30 The authors demonstrated that high-fat diet led to increased intestinal permeability in obese individuals. They report that obese patients had decreases in the tight junction proteins occludin and tricellulin and elevated levels of LBP and zonulin relative to lean controls.

    Article  CAS  Google Scholar 

  9. Campbell CL, Yu R, Li F, Zhou Q, Chen D, Qi C, et al. Modulation of fat metabolism and gut microbiota by resveratrol on high-fat diet-induced obese mice. Diabetes Metab Syndr Obes. 2019;12:97–107.

    Article  Google Scholar 

  10. Cotillard A, Kennedy SP, Kong LC, Prifti E, Pons N, Le Chatelier E, et al. Dietary intervention impact on gut microbial gene richness. Nature. 2013;500(7464):585–8.

    Article  CAS  Google Scholar 

  11. Singh RK, Chang HW, Yan D, Lee KM, Ucmak D, Wong K, et al. Influence of diet on the gut microbiome and implications for human health. J Transl Med. 2017;15(1):73.

    Article  Google Scholar 

  12. Okouchi R, E S, Yamamoto K, Ota T, Seki K, Imai M, et al. Simultaneous intake of Euglena gracilis and vegetables exerts synergistic anti-obesity and anti-inflammatory effects by modulating the gut microbiota in diet-induced obese mice. Nutrients. 2019;21:11(1).

    Google Scholar 

  13. Cani PD, Possemiers S, Van de Wiele T, Guiot Y, Everard A, Rottier O, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut. 2009;58(8):1091–103.

    Article  CAS  Google Scholar 

  14. Pendyala S, Walker JM, Holt PR. A high-fat diet is associated with endotoxemia that originates from the gut. Gastroenterology. 2012;142(5):1100–1 e2.

    Article  CAS  Google Scholar 

  15. Ghanim H, Abuaysheh S, Sia CL, Korzeniewski K, Chaudhuri A, Fernandez-Real JM, et al. Increase in plasma endotoxin concentrations and the expression of toll-like receptors and suppressor of cytokine signaling-3 in mononuclear cells after a high-fat, high-carbohydrate meal: implications for insulin resistance. Diabetes Care. 2009;32(12):2281–7.

    Article  CAS  Google Scholar 

  16. Wolf AM, Wolf D, Rumpold H, Enrich B, Tilg H. Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes. Biochem Biophys Res Commun. 2004;323(2):630–5.

    Article  CAS  Google Scholar 

  17. Zhao T, Hou M, Xia M, Wang Q, Zhu H, Xiao Y, et al. Globular adiponectin decreases leptin-induced tumor necrosis factor-alpha expression by murine macrophages: involvement of cAMP-PKA and MAPK pathways. Cell Immunol. 2005;238(1):19–30.

    Article  CAS  Google Scholar 

  18. Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med. 2009;15(8):914–20.

    Article  CAS  Google Scholar 

  19. Maioli TU, Goncalves JL, Miranda MC, Martins VD, Horta LS, Moreira TG, et al. High sugar and butter (HSB) diet induces obesity and metabolic syndrome with decrease in regulatory T cells in adipose tissue of mice. Inflamm Res. 2016;65(2):169–78.

    Article  CAS  Google Scholar 

  20. Meyer LK, Ciaraldi TP, Henry RR, Wittgrove AC, Phillips SA. Adipose tissue depot and cell size dependency of adiponectin synthesis and secretion in human obesity. Adipocyte. 2013 Oct 1;2(4):217–26.

    Article  CAS  Google Scholar 

  21. • Chang CC, Sia KC, Chang JF, Lin CM, Yang CM, Huang KY, et al. Lipopolysaccharide promoted proliferation and adipogenesis of preadipocytes through JAK/STAT and AMPK-regulated cPLA2 expression. Int J Med Sci. 2019;16(1):167–79 The authors propose a potential mechanism by which LPS stimulates preadipocyte proliferation and adipogenesis by activating JAK/STAT and AMPK pathways which in turn lead to an increase in cPLA2, an inflammatory mediator.

    Article  Google Scholar 

  22. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56(7):1761–72.

    Article  CAS  Google Scholar 

  23. Boutens L, Hooiveld GJ, Dhingra S, Cramer RA, Netea MG, Stienstra R. Unique metabolic activation of adipose tissue macrophages in obesity promotes inflammatory responses. Diabetologia. 2018;61(4):942–53.

    Article  CAS  Google Scholar 

  24. Al-Sadi R, Guo S, Ye D, Rawat M, Ma TY. TNF-alpha modulation of intestinal tight junction permeability is mediated by NIK/IKK-alpha axis activation of the canonical NF-kappaB pathway. Am J Pathol. 2016;186(5):1151–65.

    Article  CAS  Google Scholar 

  25. Engin A. The pathogenesis of obesity-associated adipose tissue inflammation. Adv Exp Med Biol. 2017;960:221–45.

    Article  CAS  Google Scholar 

  26. Larsen N, Vogensen FK, van den Berg FW, Nielsen DS, Andreasen AS, Pedersen BK, et al. Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLoS One. 2010;5(2):e9085.

    Article  Google Scholar 

  27. Zhang X, Shen D, Fang Z, Jie Z, Qiu X, Zhang C, et al. Human gut microbiota changes reveal the progression of glucose intolerance. PLoS One. 2013;8(8):e71108.

    Article  CAS  Google Scholar 

  28. • Forslund K, Hildebrand F, Nielsen T, Falony G, Le Chatelier E, Sunagawa S, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature. 2015;528(7581):262–6 This study elegantly reinforces the hypothesis that metformin’s therapeutic effects are mediated in part by increasing beneficial butyrate-producing bacteria in the intestinal microbiome.

    Article  CAS  Google Scholar 

  29. Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L, Stonebraker AC, et al. Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature. 2008;455(7216):1109–13.

    Article  CAS  Google Scholar 

  30. Burrows MP, Volchkov P, Kobayashi KS, Chervonsky AV. Microbiota regulates type 1 diabetes through toll-like receptors. Proc Natl Acad Sci U S A. 2015;112(32):9973–7.

    Article  CAS  Google Scholar 

  31. Pussinen PJ, Havulinna AS, Lehto M, Sundvall J, Salomaa V. Endotoxemia is associated with an increased risk of incident diabetes. Diabetes Care. 2011;34(2):392–7.

    Article  CAS  Google Scholar 

  32. Thaiss CA, Levy M, Grosheva I, Zheng D, Soffer E, Blacher E, et al. Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection. Science. 2018;359(6382):1376–83.

    Article  CAS  Google Scholar 

  33. Stephens JM, Lee J, Pilch PF. Tumor necrosis factor-alpha-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression without a loss of insulin receptor-mediated signal transduction. J Biol Chem. 1997;272(2):971–6.

    Article  CAS  Google Scholar 

  34. Hotamisligil GS, Budavari A, Murray D, Spiegelman BM. Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha. J Clin Invest. 1994;94(4):1543–9.

    Article  CAS  Google Scholar 

  35. Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol. 2011;29:415–45.

    Article  CAS  Google Scholar 

  36. Sabio G, Das M, Mora A, Zhang Z, Jun JY, Ko HJ, et al. A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science. 2008;322(5907):1539–43.

    Article  CAS  Google Scholar 

  37. Sandler NG, Douek DC. Microbial translocation in HIV infection: causes, consequences and treatment opportunities. Nat Rev Microbiol. 2012;10(9):655–66.

    Article  CAS  Google Scholar 

  38. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006;12(12):1365–71.

    Article  CAS  Google Scholar 

  39. Ridaura VK, Faith JJ, Rey FE, Cheng J, Duncan AE, Kau AL, et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science. 2013;341(6150):1241214.

    Article  Google Scholar 

  40. Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012;490(7418):55–60.

    Article  CAS  Google Scholar 

  41. Dillon SM, Kibbie J, Lee EJ, Guo K, Santiago ML, Austin GL, et al. Low abundance of colonic butyrate-producing bacteria in HIV infection is associated with microbial translocation and immune activation. AIDS. 2017;31(4):511–21.

    Article  CAS  Google Scholar 

  42. Zhang YZ, Li YY. Inflammatory bowel disease: pathogenesis. World J Gastroenterol. 2014;20(1):91–9.

    Article  Google Scholar 

  43. Heidarian F, Alebouyeh M, Shahrokh S, Balaii H, Zali MR. Altered fecal bacterial composition correlates with disease activity in inflammatory bowel disease and the extent of IL8 induction. Curr Res Transl Med 2019 23.

  44. Britton GJ, Contijoch EJ, Mogno I, Vennaro OH, Llewellyn SR, Ng R, et al. Microbiotas from humans with inflammatory bowel disease alter the balance of gut Th17 and RORgammat(+) regulatory T cells and exacerbate colitis in mice. Immunity. 2019;50(1):212–24 e4.

    Article  CAS  Google Scholar 

  45. Sartor RB. Mechanisms of disease: pathogenesis of Crohn’s disease and ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol. 2006;3(7):390–407.

    Article  CAS  Google Scholar 

  46. Rehman A, Sina C, Gavrilova O, Hasler R, Ott S, Baines JF, et al. Nod2 is essential for temporal development of intestinal microbial communities. Gut. 2011;60(10):1354–62.

    Article  CAS  Google Scholar 

  47. Strober W, Fuss I, Mannon P. The fundamental basis of inflammatory bowel disease. J Clin Invest. 2007;117(3):514–21.

    Article  CAS  Google Scholar 

  48. Karayiannakis AJ, Syrigos KN, Efstathiou J, Valizadeh A, Noda M, Playford RJ, et al. Expression of catenins and E-cadherin during epithelial restitution in inflammatory bowel disease. J Pathol. 1998;185(4):413–8.

    Article  CAS  Google Scholar 

  49. Jankowski JA, Bedford FK, Boulton RA, Cruickshank N, Hall C, Elder J, et al. Alterations in classical cadherins associated with progression in ulcerative and Crohn’s colitis. Lab Investig. 1998;78(9):1155–67.

    CAS  PubMed  Google Scholar 

  50. Kosovac K, Brenmoehl J, Holler E, Falk W, Schoelmerich J, Hausmann M, et al. Association of the NOD2 genotype with bacterial translocation via altered cell-cell contacts in Crohn’s disease patients. Inflamm Bowel Dis. 2010;16(8):1311–21.

    Article  Google Scholar 

  51. Jones GR, Bain CC, Fenton TM, Kelly A, Brown SL, Ivens AC, et al. Dynamics of Colon monocyte and macrophage activation during colitis. Front Immunol. 2018;9:2764.

    Article  Google Scholar 

  52. Chang J, Leong RW, Wasinger VC, Ip M, Yang M, Phan TG. Impaired intestinal permeability contributes to ongoing bowel symptoms in patients with inflammatory bowel disease and mucosal healing. Gastroenterology. 2017;153(3):723–31 e1.

    Article  Google Scholar 

  53. Steed H, Walsh S, Reynolds N. A brief report of the epidemiology of obesity in the inflammatory bowel disease population of Tayside, Scotland. Obes Facts. 2009;2(6):370–2.

    Article  Google Scholar 

  54. Uko V, Vortia E, Achkar JP, Karakas P, Fiocchi C, Worley S, et al. Impact of abdominal visceral adipose tissue on disease outcome in pediatric Crohn’s disease. Inflamm Bowel Dis. 2014;20(12):2286–91.

    Article  Google Scholar 

  55. Desreumaux P, Ernst O, Geboes K, Gambiez L, Berrebi D, Muller-Alouf H, et al. Inflammatory alterations in mesenteric adipose tissue in Crohn’s disease. Gastroenterology. 1999;117(1):73–81.

    Article  CAS  Google Scholar 

  56. Borley NR, Mortensen NJ, Jewell DP, Warren BF. The relationship between inflammatory and serosal connective tissue changes in ileal Crohn’s disease: evidence for a possible causative link. J Pathol. 2000;190(2):196–202.

    Article  CAS  Google Scholar 

  57. Peyrin-Biroulet L, Gonzalez F, Dubuquoy L, Rousseaux C, Dubuquoy C, Decourcelle C, et al. Mesenteric fat as a source of C reactive protein and as a target for bacterial translocation in Crohn’s disease. Gut. 2012;61(1):78–85.

    Article  CAS  Google Scholar 

  58. Asmuth DM, Ma ZM, Albanese A, Sandler NG, Devaraj S, Knight TH, et al. Oral serum-derived bovine immunoglobulin improves duodenal immune reconstitution and absorption function in patients with HIV enteropathy. AIDS. 2013;27(14):2207–17.

    Article  CAS  Google Scholar 

  59. Wild GE, Waschke KA, Bitton A, Thomson AB. The mechanisms of prednisone inhibition of inflammation in Crohn’s disease involve changes in intestinal permeability, mucosal TNFalpha production and nuclear factor kappa B expression. Aliment Pharmacol Ther. 2003;18(3):309–17.

    Article  CAS  Google Scholar 

  60. Suenaert P, Bulteel V, Lemmens L, Noman M, Geypens B, Van Assche G, et al. Anti-tumor necrosis factor treatment restores the gut barrier in Crohn’s disease. Am J Gastroenterol. 2002;97(8):2000–4.

    Article  CAS  Google Scholar 

  61. Roediger WE. Role of anaerobic bacteria in the metabolic welfare of the colonic mucosa in man. Gut. 1980;21(9):793–8.

    Article  CAS  Google Scholar 

  62. Donohoe DR, Garge N, Zhang X, Sun W, O’Connell TM, Bunger MK, et al. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab. 2011;13(5):517–26.

    Article  CAS  Google Scholar 

  63. Koffert JP, Mikkola K, Virtanen KA, Andersson AD, Faxius L, Hallsten K, et al. Metformin treatment significantly enhances intestinal glucose uptake in patients with type 2 diabetes: results from a randomized clinical trial. Diabetes Res Clin Pract. 2017;131:208–16.

    Article  CAS  Google Scholar 

  64. Zhou HY, Zhu H, Yao XM, Qian JP, Yang J, Pan XD, et al. Metformin regulates tight junction of intestinal epithelial cells via MLCK-MLC signaling pathway. Eur Rev Med Pharmacol Sci. 2017;21(22):5239–46.

    PubMed  Google Scholar 

  65. Deng J, Zeng L, Lai X, Li J, Liu L, Lin Q, et al. Metformin protects against intestinal barrier dysfunction via AMPKalpha1-dependent inhibition of JNK signalling activation. J Cell Mol Med. 2018;22(1):546–57.

    Article  CAS  Google Scholar 

  66. Kiss EA, Vonarbourg C, Kopfmann S, Hobeika E, Finke D, Esser C, et al. Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science. 2011;334(6062):1561–5.

    Article  CAS  Google Scholar 

  67. Caesar R, Tremaroli V, Kovatcheva-Datchary P, Cani PD, Backhed F. Crosstalk between gut microbiota and dietary lipids aggravates WAT inflammation through TLR signaling. Cell Metab. 2015;22(4):658–68.

    Article  CAS  Google Scholar 

  68. Cheru LT, Park EA, Saylor CF, Burdo TH, Fitch KV, Looby S, et al. I-FABP is higher in people with chronic HIV than elite controllers, related to sugar and fatty acid intake and inversely related to body fat in people with HIV. Open Forum Infect Dis. 2018;5(11):ofy288.

    Article  Google Scholar 

  69. Villar-Garcia J, Hernandez JJ, Guerri-Fernandez R, Gonzalez A, Lerma E, Guelar A, et al. Effect of probiotics (Saccharomyces boulardii) on microbial translocation and inflammation in HIV-treated patients: a double-blind, randomized, placebo-controlled trial. J Acquir Immune Defic Syndr. 2015;68(3):256–63.

    Article  Google Scholar 

  70. Kadooka Y, Sato M, Imaizumi K, Ogawa A, Ikuyama K, Akai Y, et al. Regulation of abdominal adiposity by probiotics (Lactobacillus gasseri SBT2055) in adults with obese tendencies in a randomized controlled trial. Eur J Clin Nutr. 2010;64(6):636–43.

    Article  CAS  Google Scholar 

  71. Jung SP, Lee KM, Kang JH, Yun SI, Park HO, Moon Y, et al. Effect of Lactobacillus gasseri BNR17 on overweight and obese adults: a randomized, double-blind clinical trial. Korean J Fam Med. 2013;34(2):80–9.

    Article  Google Scholar 

  72. Chung HJ, Yu JG, Lee IA, Liu MJ, Shen YF, Sharma SP, et al. Intestinal removal of free fatty acids from hosts by Lactobacilli for the treatment of obesity. FEBS Open Bio. 2016;6(1):64–76.

    Article  CAS  Google Scholar 

  73. Sharafedtinov KK, Plotnikova OA, Alexeeva RI, Sentsova TB, Songisepp E, Stsepetova J, et al. Hypocaloric diet supplemented with probiotic cheese improves body mass index and blood pressure indices of obese hypertensive patients--a randomized double-blind placebo-controlled pilot study. Nutr J. 2013;12:138.

    Article  Google Scholar 

  74. Bernini LJ, Simao AN, Alfieri DF, Lozovoy MA, Mari NL, de Souza CH, et al. Beneficial effects of Bifidobacterium lactis on lipid profile and cytokines in patients with metabolic syndrome: a randomized trial. Effects of probiotics on metabolic syndrome. Nutrition. 2016;32(6):716–9.

    Article  CAS  Google Scholar 

  75. Borgeraas H, Johnson LK, Skattebu J, Hertel JK, Hjelmesaeth J. Effects of probiotics on body weight, body mass index, fat mass and fat percentage in subjects with overweight or obesity: a systematic review and meta-analysis of randomized controlled trials. Obes Rev. 2018;19(2):219–32.

    Article  CAS  Google Scholar 

  76. Bates JM, Akerlund J, Mittge E, Guillemin K. Intestinal alkaline phosphatase detoxifies lipopolysaccharide and prevents inflammation in zebrafish in response to the gut microbiota. Cell Host Microbe. 2007;2(6):371–82.

    Article  CAS  Google Scholar 

  77. Malo MS. A high level of intestinal alkaline phosphatase is protective against type 2 diabetes mellitus irrespective of obesity. EBioMedicine. 2015;2(12):2016–23.

    Article  Google Scholar 

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Correspondence to Janet Lo.

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Lediya Cheru declares that she has no conflict of interest. Charles F. Saylor declares that he has no conflict of interest. Janet Lo received a donation of teduglutide and placebo from Shire for a NIH-funded clinical study and has served on a medical affairs advisory board for Gilead Sciences and as a consultant for ViiV Healthcare.

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Cheru, L., Saylor, C.F. & Lo, J. Gastrointestinal Barrier Breakdown and Adipose Tissue Inflammation. Curr Obes Rep 8, 165–174 (2019). https://doi.org/10.1007/s13679-019-00332-6

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