Diabetic gut microbiota dysbiosis as an inflammaging and immunosenescence condition that fosters progression of retinopathy and nephropathy

Biochimica et Biophysica Acta - Molecular Basis of Disease

Volumn 1865, Issue 7, 2019, Pages 1876-1897

  Fernandes, Rosa ^a   Viana, Sofia D ^a,b   Nunes, Sara ^a   Reis, Flávio ^a  

^a UNIVERSITY OF COIMBRA   (Portugal)

^b POLYTECHNIC INSTITUTE OF COIMBRA   (Portugal)

Author keywords

Diabetic nephropathy; Diabetic retinopathy; Gut microbiota; Immunosenescence; Inflammaging

Indexed keywords

UREMIC TOXIN;

DIABETIC NEPHROPATHY; DIABETIC PATIENT; DIABETIC RETINOPATHY; DYSBIOSIS; GASTROINTESTINAL TRACT; HUMAN; IMMUNOPHENOTYPING; IMMUNOSENESCENCE; INNATE IMMUNITY; INTESTINE FLORA; KIDNEY INJURY; NON INSULIN DEPENDENT DIABETES MELLITUS; PATHOPHYSIOLOGY; PRIORITY JOURNAL; REVIEW; AGING; ANIMAL; COMPLICATION; IMMUNITY; IMMUNOLOGY; INFLAMMATION; MICROBIOLOGY;

AGING; ANIMALS; DIABETES MELLITUS, TYPE 2; DIABETIC NEPHROPATHIES; DIABETIC RETINOPATHY; DYSBIOSIS; GASTROINTESTINAL MICROBIOME; HUMANS; IMMUNITY; INFLAMMATION;

EID: 85054463673     PISSN: 09254439     EISSN: 1879260X     Source Type: Journal    
DOI: 10.1016/j.bbadis.2018.09.032     Document Type: Review

References (417)

1. IDF, IDF Atlas. 8th edition, 2018.
2. N.C.D.R.F. Collaboration. Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants. Lancet 387 (2016), 1513–1530.
3. Ahsan, H., Diabetic retinopathy–biomolecules and multiple pathophysiology. Diabetol. Metab. Syndr. 9 (2015), 51–54.
4. Leasher, J.L., Bourne, R.R., Flaxman, S.R., Jonas, J.B., Keeffe, J., Naidoo, K., Pesudovs, K., Price, H., White, R.A., Wong, T.Y., Resnikoff, S., Taylor, H.R., S. Vision Loss Expert Group of the Global Burden of Disease, Global estimates on the number of people blind or visually impaired by diabetic retinopathy: a meta-analysis from 1990 to 2010. Diabetes Care 39 (2016), 1643–1649.
5. Forbes, J.M., Cooper, M.E., Mechanisms of diabetic complications. Physiol. Rev. 93 (2013), 137–188.
6. Rask-Madsen, C., King, G.L., Vascular complications of diabetes: mechanisms of injury and protective factors. Cell Metab. 17 (2013), 20–33.
7. Madonna, R., Balistreri, C.R., Geng, Y.J., De Caterina, R., Diabetic microangiopathy: pathogenetic insights and novel therapeutic approaches. Vasc. Pharmacol. 90 (2017), 1–7.
8. Roy, S., Kern, T.S., Song, B., Stuebe, C., Mechanistic insights into pathological changes in the diabetic retina: implications for targeting diabetic retinopathy. Am. J. Pathol. 187 (2017), 9–19.
9. Breyer, M.D., Kretzler, M., Novel avenues for drug discovery in diabetic kidney disease. Expert Opin. Drug Discovery 13 (2018), 65–74.
10. Mannucci, E., Dicembrini, I., Lauria, A., Pozzilli, P., Is glucose control important for prevention of cardiovascular disease in diabetes?. Diabetes Care 36:Suppl. 2 (2013), S259–S263.
11. Forbes, J.M., Fotheringham, A.K., Vascular complications in diabetes: old messages, new thoughts. Diabetologia 60 (2017), 2129–2138.
12. Burcelin, R., Gut microbiota and immune crosstalk in metabolic disease. Mol. Metab. 5 (2016), 771–781.
13. Tesch, G.H., Diabetic nephropathy - is this an immune disorder?. Clin. Sci. (Lond.) 131 (2017), 2183–2199.
14. Xu, H., Chen, M., Diabetic retinopathy and dysregulated innate immunity. Vis. Res. 139 (2017), 39–46.
15. Lozupone, C.A., Stombaugh, J.I., Gordon, J.I., Jansson, J.K., Knight, R., Diversity, stability and resilience of the human gut microbiota. Nature 489 (2012), 220–230.
16. Graf, D., Di Cagno, R., Fak, F., Flint, H.J., Nyman, M., Saarela, M., Watzl, B., Contribution of diet to the composition of the human gut microbiota. Microb. Ecol. Health Dis., 26, 2015, 26164.
17. Krishnan, S., Alden, N., Lee, K., Pathways and functions of gut microbiota metabolism impacting host physiology. Curr. Opin. Biotechnol. 36 (2015), 137–145.
18. Ascher, S., Reinhardt, C., The gut microbiota: an emerging risk factor for cardiovascular and cerebrovascular disease. Eur. J. Immunol. 48 (2018), 564–575.
19. Aron-Wisnewsky, J., Clement, K., The gut microbiome, diet, and links to cardiometabolic and chronic disorders. Nat. Rev. Nephrol. 12 (2016), 169–181.
20. Tang, W.H., Kitai, T., Hazen, S.L., Gut microbiota in cardiovascular health and disease. Circ. Res. 120 (2017), 1183–1196.
21. Karlamangla, A., Tinetti, M., Guralnik, J., Studenski, S., Wetle, T., Reuben, D., Comorbidity in older adults: nosology of impairment, diseases, and conditions. J. Gerontol. A Biol. Sci. Med. Sci. 62 (2007), 296–300.
22. Biagi, E., Candela, M., Fairweather-Tait, S., Franceschi, C., Brigidi, P., Aging of the human metaorganism: the microbial counterpart. Age (Dordr.) 34 (2012), 247–267.
23. Sabatino, A., Regolisti, G., Cosola, C., Gesualdo, L., Fiaccadori, E., Intestinal microbiota in type 2 diabetes and chronic kidney disease. Curr. Diab. Rep., 17, 2017, 16.
24. Franceschi, C., Bonafe, M., Valensin, S., Olivieri, F., De Luca, M., Ottaviani, E., De Benedictis, G., Inflamm-aging. An evolutionary perspective on immunosenescence. Ann. N. Y. Acad. Sci. 908 (2000), 244–254.
25. Shaw, A.C., Goldstein, D.R., Montgomery, R.R., Age-dependent dysregulation of innate immunity. Nat. Rev. Immunol. 13 (2013), 875–887.
26. Collino, S., Montoliu, I., Martin, F.P., Scherer, M., Mari, D., Salvioli, S., Bucci, L., Ostan, R., Monti, D., Biagi, E., Brigidi, P., Franceschi, C., Rezzi, S., Metabolic signatures of extreme longevity in northern Italian centenarians reveal a complex remodeling of lipids, amino acids, and gut microbiota metabolism. PLoS One, 8, 2013, e56564.
27. Stehle, J.R. Jr., Leng, X., Kitzman, D.W., Nicklas, B.J., Kritchevsky, S.B., High, K.P., Lipopolysaccharide-binding protein, a surrogate marker of microbial translocation, is associated with physical function in healthy older adults. J. Gerontol. A Biol. Sci. Med. Sci. 67 (2012), 1212–1218.
28. Sekirov, I., Russell, S.L., Antunes, L.C., Finlay, B.B., Gut microbiota in health and disease. Physiol. Rev. 90 (2010), 859–904.
29. C. Human Microbiome Project, Structure, function and diversity of the healthy human microbiome. Nature 486 (2012), 207–214.
30. Ley, R.E., Peterson, D.A., Gordon, J.I., Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 124 (2006), 837–848.
31. Eckburg, P.B., Bik, E.M., Bernstein, C.N., Purdom, E., Dethlefsen, L., Sargent, M., Gill, S.R., Nelson, K.E., Relman, D.A., Diversity of the human intestinal microbial flora. Science 308 (2005), 1635–1638.
32. Cox, M.J., Cookson, W.O., Moffatt, M.F., Sequencing the human microbiome in health and disease. Hum. Mol. Genet. 22 (2013), R88–R94.
33. Turnbaugh, P.J., Ley, R.E., Hamady, M., Fraser-Liggett, C.M., Knight, R., Gordon, J.I., The human microbiome project. Nature 449 (2007), 804–810.
34. Qin, J., Li, R., Raes, J., Arumugam, M., Burgdorf, K.S., Manichanh, C., Nielsen, T., Pons, N., Levenez, F., Yamada, T., Mende, D.R., Li, J., Xu, J., Li, S., Li, D., Cao, J., Wang, B., Liang, H., Zheng, H., Xie, Y., Tap, J., Lepage, P., Bertalan, M., Batto, J.M., Hansen, T., Le Paslier, D., Linneberg, A., Nielsen, H.B., Pelletier, E., Renault, P., Sicheritz-Ponten, T., Turner, K., Zhu, H., Yu, C., Li, S., Jian, M., Zhou, Y., Li, Y., Zhang, X., Li, S., Qin, N., Yang, H., Wang, J., Brunak, S., Dore, J., Guarner, F., Kristiansen, K., Pedersen, O., Parkhill, J., Weissenbach, J., Meta, H.I.T.C., Bork, P., Ehrlich, S.D., Wang, J., A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464 (2010), 59–65.
35. Mondot, S., Lepage, P., The human gut microbiome and its dysfunctions through the meta-omics prism. Ann. N. Y. Acad. Sci. 1372 (2016), 9–19.
36. Aguiar-Pulido, V., Huang, W., Suarez-Ulloa, V., Cickovski, T., Mathee, K., Narasimhan, G., Metagenomics, metatranscriptomics, and metabolomics approaches for microbiome analysis. Evol. Bioinformatics Online 12 (2016), 5–16.
37. Koboziev, I., Reinoso Webb, C., Furr, K.L., Grisham, M.B., Role of the enteric microbiota in intestinal homeostasis and inflammation. Free Radic. Biol. Med. 68 (2014), 122–133.
38. Aron-Wisnewsky, J., Dore, J., Clement, K., The importance of the gut microbiota after bariatric surgery. Nat. Rev. Gastroenterol. Hepatol. 9 (2012), 590–598.
39. Walker, A.W., Lawley, T.D., Therapeutic modulation of intestinal dysbiosis. Pharmacol. Res. 69 (2013), 75–86.
40. Brown, E.M., Sadarangani, M., Finlay, B.B., The role of the immune system in governing host-microbe interactions in the intestine. Nat. Immunol. 14 (2013), 660–667.
41. Li, H., Limenitakis, J.P., Fuhrer, T., Geuking, M.B., Lawson, M.A., Wyss, M., Brugiroux, S., Keller, I., Macpherson, J.A., Rupp, S., Stolp, B., Stein, J.V., Stecher, B., Sauer, U., McCoy, K.D., Macpherson, A.J., The outer mucus layer hosts a distinct intestinal microbial niche. Nat. Commun., 6, 2015, 8292.
42. Mizock, B.A., Probiotics. Dis. Mon. 61 (2015), 259–290.
43. Quigley, E.M., Prebiotics and probiotics; modifying and mining the microbiota. Pharmacol. Res. 61 (2010), 213–218.
44. Shulzhenko, N., Morgun, A., Hsiao, W., Battle, M., Yao, M., Gavrilova, O., Orandle, M., Mayer, L., Macpherson, A.J., McCoy, K.D., Fraser-Liggett, C., Matzinger, P., Crosstalk between B lymphocytes, microbiota and the intestinal epithelium governs immunity versus metabolism in the gut. Nat. Med. 17 (2011), 1585–1593.
45. Pagliari, D., Gambassi, G., Piccirillo, C.A., Cianci, R., The intricate link among gut “immunological niche,” microbiota, and xenobiotics in intestinal pathology. Mediat. Inflamm., 2017, 2017, 8390595.
46. Allaire, J.M., Crowley, S.M., Law, H.T., Chang, S.Y., Ko, H.J., Vallance, B.A., The intestinal epithelium: central coordinator of mucosal immunity. Trends Immunol. 39 (2018), 677–696.
47. Kurashima, Y., Kiyono, H., Mucosal ecological network of epithelium and immune cells for gut homeostasis and tissue healing. Annu. Rev. Immunol. 35 (2017), 119–147.
48. Davis, B.K., Philipson, C., Hontecillas, R., Eden, K., Bassaganya-Riera, J., Allen, I.C., Emerging significance of NLRs in inflammatory bowel disease. Inflamm. Bowel Dis. 20 (2014), 2412–2432.
49. Raman, K.G., Sappington, P.L., Yang, R., Levy, R.M., Prince, J.M., Liu, S., Watkins, S.K., Schmidt, A.M., Billiar, T.R., Fink, M.P., The role of RAGE in the pathogenesis of intestinal barrier dysfunction after hemorrhagic shock. Am. J. Physiol. Gastrointest. Liver Physiol. 291 (2006), G556–G565.
50. Lavelle, E.C., Murphy, C., O'Neill, L.A., Creagh, E.M., The role of TLRs, NLRs, and RLRs in mucosal innate immunity and homeostasis. Mucosal Immunol. 3 (2010), 17–28.
51. Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S., Medzhitov, R., Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118 (2004), 229–241.
52. Olszak, T., An, D., Zeissig, S., Vera, M.P., Richter, J., Franke, A., Glickman, J.N., Siebert, R., Baron, R.M., Kasper, D.L., Blumberg, R.S., Microbial exposure during early life has persistent effects on natural killer T cell function. Science 336 (2012), 489–493.
53. Konig, J., Wells, J., Cani, P.D., Garcia-Rodenas, C.L., MacDonald, T., Mercenier, A., Whyte, J., Troost, F., Brummer, R.J., Human intestinal barrier function in health and disease. Clin. Transl. Gastroenterol., 7, 2016, e196.
54. Takiishi, T., Fenero, C.I.M., Camara, N.O.S., Intestinal barrier and gut microbiota: shaping our immune responses throughout life. Tissue Barriers, 5, 2017, e1373208.
55. Robles Alonso, V., Guarner, F., Linking the gut microbiota to human health. Br. J. Nutr. 109:Suppl. 2 (2013), S21–S26.
56. Hooper, L.V., Macpherson, A.J., Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat. Rev. Immunol. 10 (2010), 159–169.
57. Okumura, R., Takeda, K., Maintenance of intestinal homeostasis by mucosal barriers. Inflamm. Regen., 38, 2018, 5.
58. Chung, H., Kasper, D.L., Microbiota-stimulated immune mechanisms to maintain gut homeostasis. Curr. Opin. Immunol. 22 (2010), 455–460.
59. Pelaseyed, T., Bergstrom, J.H., Gustafsson, J.K., Ermund, A., Birchenough, G.M., Schutte, A., van der Post, S., Svensson, F., Rodriguez-Pineiro, A.M., Nystrom, E.E., Wising, C., Johansson, M.E., Hansson, G.C., The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system. Immunol. Rev. 260 (2014), 8–20.
60. Derrien, M., van Passel, M.W., van de Bovenkamp, J.H., Schipper, R.G., de Vos, W.M., Dekker, J., Mucin-bacterial interactions in the human oral cavity and digestive tract. Gut Microbes 1 (2010), 254–268.
61. Dharmani, P., Srivastava, V., Kissoon-Singh, V., Chadee, K., Role of intestinal mucins in innate host defense mechanisms against pathogens. J. Innate Immun. 1 (2009), 123–135.
62. Birchenough, G.M., Johansson, M.E., Gustafsson, J.K., Bergstrom, J.H., Hansson, G.C., New developments in goblet cell mucus secretion and function. Mucosal Immunol. 8 (2015), 712–719.
63. Lu, P., Burger-van Paassen, N., van der Sluis, M., Witte-Bouma, J., Kerckaert, J.P., van Goudoever, J.B., Van Seuningen, I., Renes, I.B., Colonic gene expression patterns of mucin Muc2 knockout mice reveal various phases in colitis development. Inflamm. Bowel Dis. 17 (2011), 2047–2057.
64. Eri, R.D., Adams, R.J., Tran, T.V., Tong, H., Das, I., Roche, D.K., Oancea, I., Png, C.W., Jeffery, P.L., Radford-Smith, G.L., Cook, M.C., Florin, T.H., McGuckin, M.A., An intestinal epithelial defect conferring ER stress results in inflammation involving both innate and adaptive immunity. Mucosal Immunol. 4 (2011), 354–364.
65. Derrien, M., Vaughan, E.E., Plugge, C.M., de Vos, W.M., Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. Int. J. Syst. Evol. Microbiol. 54 (2004), 1469–1476.
66. Rho, J.H., Wright, D.P., Christie, D.L., Clinch, K., Furneaux, R.H., Roberton, A.M., A novel mechanism for desulfation of mucin: identification and cloning of a mucin-desulfating glycosidase (sulfoglycosidase) from Prevotella strain RS2. J. Bacteriol. 187 (2005), 1543–1551.
67. Huang, J.Y., Lee, S.M., Mazmanian, S.K., The human commensal Bacteroides fragilis binds intestinal mucin. Anaerobe 17 (2011), 137–141.
68. Celli, J.P., Turner, B.S., Afdhal, N.H., Keates, S., Ghiran, I., Kelly, C.P., Ewoldt, R.H., McKinley, G.H., So, P., Erramilli, S., Bansil, R., Helicobacter pylori moves through mucus by reducing mucin viscoelasticity. Proc. Natl. Acad. Sci. U. S. A. 106 (2009), 14321–14326.
69. Sicard, J.F., Le Bihan, G., Vogeleer, P., Jacques, M., Harel, J., Interactions of intestinal Bacteria with components of the intestinal mucus. Front. Cell. Infect. Microbiol., 7, 2017, 387.
70. Santaolalla, R., Abreu, M.T., Innate immunity in the small intestine. Curr. Opin. Gastroenterol. 28 (2012), 124–129.
71. Saleh, M., Trinchieri, G., Innate immune mechanisms of colitis and colitis-associated colorectal cancer. Nat. Rev. Immunol. 11 (2011), 9–20.
72. Marchiando, A.M., Graham, W.V., Turner, J.R., Epithelial barriers in homeostasis and disease. Annu. Rev. Pathol. 5 (2010), 119–144.
73. Laukoetter, M.G., Bruewer, M., Nusrat, A., Regulation of the intestinal epithelial barrier by the apical junctional complex. Curr. Opin. Gastroenterol. 22 (2006), 85–89.
74. Gupta, P., Andrew, H., Kirschner, B.S., Guandalini, S., Is lactobacillus GG helpful in children with Crohn's disease? Results of a preliminary, open-label study. J. Pediatr. Gastroenterol. Nutr. 31 (2000), 453–457.
75. Ewaschuk, J.B., Diaz, H., Meddings, L., Diederichs, B., Dmytrash, A., Backer, J., Looijer-van Langen, M., Madsen, K.L., Secreted bioactive factors from Bifidobacterium infantis enhance epithelial cell barrier function. Am. J. Physiol. Gastrointest. Liver Physiol. 295 (2008), G1025–G1034.
76. Cash, H.L., Whitham, C.V., Behrendt, C.L., Hooper, L.V., Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313 (2006), 1126–1130.
77. Tolhurst, G., Heffron, H., Lam, Y.S., Parker, H.E., Habib, A.M., Diakogiannaki, E., Cameron, J., Grosse, J., Reimann, F., Gribble, F.M., Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 61 (2012), 364–371.
78. Wikoff, W.R., Anfora, A.T., Liu, J., Schultz, P.G., Lesley, S.A., Peters, E.C., Siuzdak, G., Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc. Natl. Acad. Sci. U. S. A. 106 (2009), 3698–3703.
79. Evenepoel, P., Meijers, B.K., Bammens, B.R., Verbeke, K., Uremic toxins originating from colonic microbial metabolism. Kidney Int. Suppl., 2009, S12–S19.
80. Vanholder, R., De Smet, R., Glorieux, G., Argiles, A., Baurmeister, U., Brunet, P., Clark, W., Cohen, G., De Deyn, P.P., Deppisch, R., Descamps-Latscha, B., Henle, T., Jorres, A., Lemke, H.D., Massy, Z.A., Passlick-Deetjen, J., Rodriguez, M., Stegmayr, B., Stenvinkel, P., Tetta, C., Wanner, C., Zidek, W., G. European Uremic Toxin Work, Review on uremic toxins: classification, concentration, and interindividual variability. Kidney Int. 63 (2003), 1934–1943.
81. Koeth, R.A., Wang, Z., Levison, B.S., Buffa, J.A., Org, E., Sheehy, B.T., Britt, E.B., Fu, X., Wu, Y., Li, L., Smith, J.D., DiDonato, J.A., Chen, J., Li, H., Wu, G.D., Lewis, J.D., Warrier, M., Brown, J.M., Krauss, R.M., Tang, W.H., Bushman, F.D., Lusis, A.J., Hazen, S.L., Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19 (2013), 576–585.
82. Bennett, B.J., de Aguiar Vallim, T.Q., Wang, Z., Shih, D.M., Meng, Y., Gregory, J., Allayee, H., Lee, R., Graham, M., Crooke, R., Edwards, P.A., Hazen, S.L., Lusis, A.J., Trimethylamine‑N‑oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 17 (2013), 49–60.
83. Yamashita, T., Emoto, T., Sasaki, N., Hirata, K.I., Gut microbiota and coronary artery disease. Int. Heart J. 57 (2016), 663–671.
84. Zhu, Q., Gao, R., Zhang, Y., Pan, D., Zhu, Y., Zhang, X., Yang, R., Jiang, R., Xu, Y., Qin, H., Dysbiosis signatures of gut microbiota in coronary artery disease. Physiol. Genomics, 2018.
85. Sanchez-Alcoholado, L., Castellano-Castillo, D., Jordan-Martinez, L., Moreno-Indias, I., Cardila-Cruz, P., Elena, D., Munoz-Garcia, A.J., Queipo-Ortuno, M.I., Jimenez-Navarro, M., Role of gut microbiota on cardio-metabolic parameters and immunity in coronary artery disease patients with and without type-2 diabetes mellitus. Front. Microbiol., 8, 2017, 1936.
86. Mutsaers, H.A., Stribos, E.G., Glorieux, G., Vanholder, R., Olinga, P., Chronic kidney disease and fibrosis: the role of uremic retention solutes. Front. Med., 2, 2015, 60.
87. Meijers, B.K., Evenepoel, P., The gut-kidney axis: indoxyl sulfate, p-cresyl sulfate and CKD progression. Nephrol. Dial. Transplant. 26 (2011), 759–761.
88. Roberts, A.B., Gu, X., Buffa, J.A., Hurd, A.G., Wang, Z., Zhu, W., Gupta, N., Skye, S.M., Cody, D.B., Levison, B.S., Barrington, W.T., Russell, M.W., Reed, J.M., Duzan, A., Lang, J.M., Fu, X., Li, L., Myers, A.J., Rachakonda, S., DiDonato, J.A., Brown, J.M., Gogonea, V., Lusis, A.J., Garcia-Garcia, J.C., Hazen, S.L., Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential. Nat. Med. 24 (2018), 1407–1417.
89. Haissman, J.M., Knudsen, A., Hoel, H., Kjaer, A., Kristoffersen, U.S., Berge, R.K., Katzenstein, T.L., Svardal, A., Ueland, T., Aukrust, P., Lebech, A.M., Nielsen, S.D., Troseid, M., Microbiota-dependent marker TMAO is elevated in silent ischemia but is not associated with first-time myocardial infarction in HIV infection. J. Acquir. Immune Defic. Syndr. 71 (2016), 130–136.
90. Lam, V., Su, J., Koprowski, S., Hsu, A., Tweddell, J.S., Rafiee, P., Gross, G.J., Salzman, N.H., Baker, J.E., Intestinal microbiota determine severity of myocardial infarction in rats. FASEB J. 26 (2012), 1727–1735.
91. Battson, M.L., Lee, D.M., Jarrell, D.K., Hou, S., Ecton, K.E., Weir, T.L., Gentile, C.L., Suppression of gut dysbiosis reverses Western diet-induced vascular dysfunction. Am. J. Physiol. Endocrinol. Metab. 314 (2018), E468–E477.
92. Lin, L., Zhang, J., Role of intestinal microbiota and metabolites on gut homeostasis and human diseases. BMC Immunol., 18, 2017, 2.
93. Havenaar, R., Intestinal health functions of colonic microbial metabolites: a review. Benefic. Microbes 2 (2011), 103–114.
94. Zelante, T., Iannitti, R.G., Cunha, C., De Luca, A., Giovannini, G., Pieraccini, G., Zecchi, R., D'Angelo, C., Massi-Benedetti, C., Fallarino, F., Carvalho, A., Puccetti, P., Romani, L., Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin‑22. Immunity 39 (2013), 372–385.
95. Kinnebrew, M.A., Buffie, C.G., Diehl, G.E., Zenewicz, L.A., Leiner, I., Hohl, T.M., Flavell, R.A., Littman, D.R., Pamer, E.G., Interleukin 23 production by intestinal CD103(+)CD11b(+) dendritic cells in response to bacterial flagellin enhances mucosal innate immune defense. Immunity 36 (2012), 276–287.
96. Singh, N., Gurav, A., Sivaprakasam, S., Brady, E., Padia, R., Shi, H., Thangaraju, M., Prasad, P.D., Manicassamy, S., Munn, D.H., Lee, J.R., Offermanns, S., Ganapathy, V., Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40 (2014), 128–139.
97. Han, D., Walsh, M.C., Cejas, P.J., Dang, N.N., Kim, Y.F., Kim, J., Charrier-Hisamuddin, L., Chau, L., Zhang, Q., Bittinger, K., Bushman, F.D., Turka, L.A., Shen, H., Reizis, B., Defranco, A.L., Wu, G.D., Choi, Y., Dendritic cell expression of the signaling molecule TRAF6 is critical for gut microbiota-dependent immune tolerance. Immunity 38 (2013), 1211–1222.
98. Lundell, A.C., Bjornsson, V., Ljung, A., Ceder, M., Johansen, S., Lindhagen, G., Tornhage, C.J., Adlerberth, I., Wold, A.E., Rudin, A., Infant B cell memory differentiation and early gut bacterial colonization. J. Immunol. 188 (2012), 4315–4322.
99. Suzuki, K., Meek, B., Doi, Y., Muramatsu, M., Chiba, T., Honjo, T., Fagarasan, S., Aberrant expansion of segmented filamentous bacteria in IgA-deficient gut. Proc. Natl. Acad. Sci. U. S. A. 101 (2004), 1981–1986.
100. Hill, D.A., Artis, D., The influence of commensal bacteria-derived signals on basophil-associated allergic inflammation. Gut Microbes 4 (2013), 76–83.
101. Cahenzli, J., Koller, Y., Wyss, M., Geuking, M.B., McCoy, K.D., Intestinal microbial diversity during early-life colonization shapes long-term IgE levels. Cell Host Microbe 14 (2013), 559–570.
102. Rescigno, M., Intestinal microbiota and its effects on the immune system. Cell. Microbiol. 16 (2014), 1004–1013.
103. Ismail, A.S., Severson, K.M., Vaishnava, S., Behrendt, C.L., Yu, X., Benjamin, J.L., Ruhn, K.A., Hou, B., DeFranco, A.L., Yarovinsky, F., Hooper, L.V., Gammadelta intraepithelial lymphocytes are essential mediators of host-microbial homeostasis at the intestinal mucosal surface. Proc. Natl. Acad. Sci. U. S. A. 108 (2011), 8743–8748.
104. Ismail, A.S., Behrendt, C.L., Hooper, L.V., Reciprocal interactions between commensal bacteria and gamma delta intraepithelial lymphocytes during mucosal injury. J. Immunol. 182 (2009), 3047–3054.
105. Ivanov, I.I., Atarashi, K., Manel, N., Brodie, E.L., Shima, T., Karaoz, U., Wei, D., Goldfarb, K.C., Santee, C.A., Lynch, S.V., Tanoue, T., Imaoka, A., Itoh, K., Takeda, K., Umesaki, Y., Honda, K., Littman, D.R., Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139 (2009), 485–498.
106. Duan, J., Chung, H., Troy, E., Kasper, D.L., Microbial colonization drives expansion of IL-1 receptor 1-expressing and IL-17-producing gamma/delta T cells. Cell Host Microbe 7 (2010), 140–150.
107. Round, J.L., Mazmanian, S.K., The gut microbiota shapes intestinal immune responses during health and disease. Nat. Rev. Immunol. 9 (2009), 313–323.
108. Mazmanian, S.K., Liu, C.H., Tzianabos, A.O., Kasper, D.L., An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122 (2005), 107–118.
109. Sato, S., Kiyono, H., Fujihashi, K., Mucosal immunosenescence in the gastrointestinal tract: a mini-review. Gerontology 61 (2015), 336–342.
110. Belkaid, Y., Hand, T.W., Role of the microbiota in immunity and inflammation. Cell 157 (2014), 121–141.
111. Koleva, P.T., Kim, J.S., Scott, J.A., Kozyrskyj, A.L., Microbial programming of health and disease starts during fetal life. Birth Defects Res. C Embryo Today 105 (2015), 265–277.
112. DiGiulio, D.B., Romero, R., Amogan, H.P., Kusanovic, J.P., Bik, E.M., Gotsch, F., Kim, C.J., Erez, O., Edwin, S., Relman, D.A., Microbial prevalence, diversity and abundance in amniotic fluid during preterm labor: a molecular and culture-based investigation. PLoS One, 3, 2008, e3056.
113. Satokari, R., Gronroos, T., Laitinen, K., Salminen, S., Isolauri, E., Bifidobacterium and lactobacillus DNA in the human placenta. Lett. Appl. Microbiol. 48 (2009), 8–12.
114. Jimenez, E., Fernandez, L., Marin, M.L., Martin, R., Odriozola, J.M., Nueno-Palop, C., Narbad, A., Olivares, M., Xaus, J., Rodriguez, J.M., Isolation of commensal bacteria from umbilical cord blood of healthy neonates born by cesarean section. Curr. Microbiol. 51 (2005), 270–274.
115. Jimenez, E., Marin, M.L., Martin, R., Odriozola, J.M., Olivares, M., Xaus, J., Fernandez, L., Rodriguez, J.M., Is meconium from healthy newborns actually sterile?. Res. Microbiol. 159 (2008), 187–193.
116. Bailey, M.T., Lubach, G.R., Coe, C.L., Prenatal stress alters bacterial colonization of the gut in infant monkeys. J. Pediatr. Gastroenterol. Nutr. 38 (2004), 414–421.
117. Faa, G., Gerosa, C., Fanni, D., Nemolato, S., van Eyken, P., Fanos, V., Factors influencing the development of a personal tailored microbiota in the neonate, with particular emphasis on antibiotic therapy. J. Matern. Fetal Neonatal Med. 26:Suppl. 2 (2013), 35–43.
118. Azad, M.B., Konya, T., Maughan, H., Guttman, D.S., Field, C.J., Sears, M.R., Becker, A.B., Scott, J.A., Kozyrskyj, A.L., Infant gut microbiota and the hygiene hypothesis of allergic disease: impact of household pets and siblings on microbiota composition and diversity. Allergy, Asthma Clin. Immunol., 9, 2013, 15.
119. Icaza-Chavez, M.E., Gut microbiota in health and disease. Rev. Gastroenterol. Mex. 78 (2013), 240–248.
120. Arrieta, M.C., Stiemsma, L.T., Amenyogbe, N., Brown, E.M., Finlay, B., The intestinal microbiome in early life: health and disease. Front. Immunol., 5, 2014, 427.
121. Dominguez-Bello, M.G., Costello, E.K., Contreras, M., Magris, M., Hidalgo, G., Fierer, N., Knight, R., Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc. Natl. Acad. Sci. U. S. A. 107 (2010), 11971–11975.
122. Harmsen, H.J., Wildeboer-Veloo, A.C., Raangs, G.C., Wagendorp, A.A., Klijn, N., Bindels, J.G., Welling, G.W., Analysis of intestinal flora development in breast-fed and formula-fed infants by using molecular identification and detection methods. J. Pediatr. Gastroenterol. Nutr. 30 (2000), 61–67.
123. Penders, J., Vink, C., Driessen, C., London, N., Thijs, C., Stobberingh, E.E., Quantification of Bifidobacterium spp., Escherichia coli and Clostridium difficile in faecal samples of breast-fed and formula-fed infants by real-time PCR. FEMS Microbiol. Lett. 243 (2005), 141–147.
124. Bezirtzoglou, E., Tsiotsias, A., Welling, G.W., Microbiota profile in feces of breast- and formula-fed newborns by using fluorescence in situ hybridization (FISH). Anaerobe 17 (2011), 478–482.
125. Field, C.J., The immunological components of human milk and their effect on immune development in infants. J. Nutr. 135 (2005), 1–4.
126. Warner, D.M., George, C.R., Erythrocyte sedimentation rate and related factors in end-stage renal failure. Nephron, 57, 1991, 248.
127. Mariat, D., Firmesse, O., Levenez, F., Guimaraes, V., Sokol, H., Dore, J., Corthier, G., Furet, J.P., The Firmicutes/Bacteroidetes ratio of the human microbiota changes with age. BMC Microbiol., 9, 2009, 123.
128. Palmer, C., Bik, E.M., DiGiulio, D.B., Relman, D.A., Brown, P.O., Development of the human infant intestinal microbiota. PLoS Biol., 5, 2007, e177.
129. Biagi, E., Nylund, L., Candela, M., Ostan, R., Bucci, L., Pini, E., Nikkila, J., Monti, D., Satokari, R., Franceschi, C., Brigidi, P., De Vos, W., Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians. PLoS One, 5, 2010, e10667.
130. Meng, H., Zhang, Y., Zhao, L., Zhao, W., He, C., Honaker, C.F., Zhai, Z., Sun, Z., Siegel, P.B., Body weight selection affects quantitative genetic correlated responses in gut microbiota. PLoS One, 9, 2014, e89862.
131. Stewart, J.A., Chadwick, V.S., Murray, A., Investigations into the influence of host genetics on the predominant eubacteria in the faecal microflora of children. J. Med. Microbiol. 54 (2005), 1239–1242.
132. Turnbaugh, P.J., Hamady, M., Yatsunenko, T., Cantarel, B.L., Duncan, A., Ley, R.E., Sogin, M.L., Jones, W.J., Roe, B.A., Affourtit, J.P., Egholm, M., Henrissat, B., Heath, A.C., Knight, R., Gordon, J.I., A core gut microbiome in obese and lean twins. Nature 457 (2009), 480–484.
133. Kumar, M., Babaei, P., Ji, B., Nielsen, J., Human gut microbiota and healthy aging: recent developments and future prospective. Nutr. Health Aging 4 (2016), 3–16.
134. Vaiserman, A.M., Koliada, A.K., Marotta, F., Gut microbiota: a player in aging and a target for anti-aging intervention. Ageing Res. Rev. 35 (2017), 36–45.
135. Quercia, S., Candela, M., Giuliani, C., Turroni, S., Luiselli, D., Rampelli, S., Brigidi, P., Franceschi, C., Bacalini, M.G., Garagnani, P., Pirazzini, C., From lifetime to evolution: timescales of human gut microbiota adaptation. Front. Microbiol., 5, 2014, 587.
136. Leonardi, G.C., Accardi, G., Monastero, R., Nicoletti, F., Libra, M., Ageing: from inflammation to cancer. Immun. Ageing, 15, 2018, 1.
137. Kanasi, E., Ayilavarapu, S., Jones, J., The aging population: demographics and the biology of aging. Periodontol. 2000:72 (2016), 13–18.
138. Cesari, M., Calvani, R., Marzetti, E., Frailty in older persons. Clin. Geriatr. Med. 33 (2017), 293–303.
139. Ventura, M.T., Casciaro, M., Gangemi, S., Buquicchio, R., Immunosenescence in aging: between immune cells depletion and cytokines up-regulation. Clin. Mol. Allergy, 15, 2017, 21.
140. Newgard, C.B., Sharpless, N.E., Coming of age: molecular drivers of aging and therapeutic opportunities. J. Clin. Invest. 123 (2013), 946–950.
141. Atzmon, G., Rincon, M., Schechter, C.B., Shuldiner, A.R., Lipton, R.B., Bergman, A., Barzilai, N., Lipoprotein genotype and conserved pathway for exceptional longevity in humans. PLoS Biol., 4, 2006, e113.
142. Franceschi, C., Inflammaging as a major characteristic of old people: can it be prevented or cured?. Nutr. Rev. 65 (2007), S173–S176.
143. Franceschi, C., Garagnani, P., Morsiani, C., Conte, M., Santoro, A., Grignolio, A., Monti, D., Capri, M., Salvioli, S., The continuum of aging and age-related diseases: common mechanisms but different rates. Front. Med., 5, 2018, 61.
144. Bonafe, M., Olivieri, F., Cavallone, L., Giovagnetti, S., Mayegiani, F., Cardelli, M., Pieri, C., Marra, M., Antonicelli, R., Lisa, R., Rizzo, M.R., Paolisso, G., Monti, D., Franceschi, C., A gender–dependent genetic predisposition to produce high levels of IL-6 is detrimental for longevity. Eur. J. Immunol. 31 (2001), 2357–2361.
145. Gangemi, S., Basile, G., Monti, D., Merendino, R.A., Di Pasquale, G., Bisignano, U., Nicita-Mauro, V., Franceschi, C., Age-related modifications in circulating IL-15 levels in humans. Mediat. Inflamm. 2005 (2005), 245–247.
146. Monti, D., Ostan, R., Borelli, V., Castellani, G., Franceschi, C., Inflammaging and human longevity in the omics era. Mech. Ageing Dev. 165 (2017), 129–138.
147. Lu, J., Kishore, U., C1 complex: an adaptable proteolytic module for complement and non-complement functions. Front. Immunol., 8, 2017, 592.
148. Jose, S.S., Bendickova, K., Kepak, T., Krenova, Z., Fric, J., Chronic inflammation in immune aging: role of pattern recognition receptor crosstalk with the telomere complex?. Front. Immunol., 8, 2017, 1078.
149. Franceschi, C., Garagnani, P., Vitale, G., Capri, M., Salvioli, S., Inflammaging and 'Garb-aging'. Trends Endocrinol. Metab. 28 (2017), 199–212.
150. Coppe, J.P., Desprez, P.Y., Krtolica, A., Campisi, J., The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. 5 (2010), 99–118.
151. Appay, V., Sauce, D., Naive T cells: the crux of cellular immune aging?. Exp. Gerontol. 54 (2014), 90–93.
152. McElhaney, J.E., Meneilly, G.S., Beattie, B.L., Helgason, C.D., Lee, S.F., Devine, R.D., Bleackley, R.C., The effect of influenza vaccination on IL2 production in healthy elderly: implications for current vaccination practices. J. Gerontol. 47 (1992), M3–M8.
153. Powers, D.C., Belshe, R.B., Effect of age on cytotoxic T lymphocyte memory as well as serum and local antibody responses elicited by inactivated influenza virus vaccine. J. Infect. Dis. 167 (1993), 584–592.
154. van Deursen, J.M., The role of senescent cells in ageing. Nature 509 (2014), 439–446.
155. Franceschi, C., Salvioli, S., Garagnani, P., de Eguileor, M., Monti, D., Capri, M., Immunobiography and the heterogeneity of immune responses in the elderly: a focus on inflammaging and trained immunity. Front. Immunol., 8, 2017, 982.
156. Zhuang, Y., Lyga, J., Inflammaging in skin and other tissues - the roles of complement system and macrophage. Inflamm. Allergy Drug Targets 13 (2014), 153–161.
157. Dixit, V.D., Thymic fatness and approaches to enhance thymopoietic fitness in aging. Curr. Opin. Immunol. 22 (2010), 521–528.
158. Youm, Y.H., Kanneganti, T.D., Vandanmagsar, B., Zhu, X., Ravussin, A., Adijiang, A., Owen, J.S., Thomas, M.J., Francis, J., Parks, J.S., Dixit, V.D., The Nlrp3 inflammasome promotes age-related thymic demise and immunosenescence. Cell Rep. 1 (2012), 56–68.
159. Goronzy, J.J., Weyand, C.M., T cell development and receptor diversity during aging. Curr. Opin. Immunol. 17 (2005), 468–475.
160. Dorshkind, K., Montecino-Rodriguez, E., Signer, R.A., The ageing immune system: is it ever too old to become young again?. Nat. Rev. Immunol. 9 (2009), 57–62.
161. Maue, A.C., Yager, E.J., Swain, S.L., Woodland, D.L., Blackman, M.A., Haynes, L., T-cell immunosenescence: lessons learned from mouse models of aging. Trends Immunol. 30 (2009), 301–305.
162. Fietta, P., Delsante, G., The effector T helper cell triade. Riv. Biol. 102 (2009), 61–74.
163. Hoefig, K.P., Heissmeyer, V., Posttranscriptional regulation of T helper cell fate decisions. J. Cell Biol. 217 (2018), 2615–2631.
164. Ouyang, W., Kolls, J.K., Zheng, Y., The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 28 (2008), 454–467.
165. Schmitt, V., Rink, L., Uciechowski, P., The Th17/Treg balance is disturbed during aging. Exp. Gerontol. 48 (2013), 1379–1386.
166. Ouyang, X., Yang, Z., Zhang, R., Arnaboldi, P., Lu, G., Li, Q., Wang, W., Zhang, B., Cui, M., Zhang, H., Liang-Chen, J., Qin, L., Zheng, F., Huang, B., Xiong, H., Potentiation of Th17 cytokines in aging process contributes to the development of colitis. Cell. Immunol. 266 (2011), 208–217.
167. Franceschi, C., Valensin, S., Bonafe, M., Paolisso, G., Yashin, A.I., Monti, D., De Benedictis, G., The network and the remodeling theories of aging: historical background and new perspectives. Exp. Gerontol. 35 (2000), 879–896.
168. Yadav, S.K., Boppana, S., Ito, N., Mindur, J.E., Mathay, M.T., Patel, A., Dhib-Jalbut, S., Ito, K., Gut dysbiosis breaks immunological tolerance toward the central nervous system during young adulthood. Proc. Natl. Acad. Sci. U. S. A. 114 (2017), E9318–E9327.
169. Salminen, A., Kaarniranta, K., Kauppinen, A., Inflammaging: disturbed interplay between autophagy and inflammasomes. Aging (Albany NY) 4 (2012), 166–175.
170. Duewell, P., Kono, H., Rayner, K.J., Sirois, C.M., Vladimer, G., Bauernfeind, F.G., Abela, G.S., Franchi, L., Nunez, G., Schnurr, M., Espevik, T., Lien, E., Fitzgerald, K.A., Rock, K.L., Moore, K.J., Wright, S.D., Hornung, V., Latz, E., NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464 (2010), 1357–1361.
171. Hakimi, M., Peters, A., Becker, A., Bockler, D., Dihlmann, S., Inflammation-related induction of absent in melanoma 2 (AIM2) in vascular cells and atherosclerotic lesions suggests a role in vascular pathogenesis. J. Vasc. Surg. 59 (2014), 794–803.
172. Wu, X., Hakimi, M., Wortmann, M., Zhang, J., Bockler, D., Dihlmann, S., Gene expression of inflammasome components in peripheral blood mononuclear cells (PBMC) of vascular patients increases with age. Immun. Ageing, 12, 2015, 15.
173. Song, F., Ma, Y., Bai, X.Y., Chen, X., The expression changes of inflammasomes in the aging rat kidneys. J. Gerontol. A Biol. Sci. Med. Sci. 71 (2016), 747–756.
174. Kosmidou, C., Efstathiou, N.E., Hoang, M.V., Notomi, S., Konstantinou, E.K., Hirano, M., Takahashi, K., Maidana, D.E., Tsoka, P., Young, L., Gragoudas, E.S., Olsen, T.W., Morizane, Y., Miller, J.W., Vavvas, D.G., Issues with the specificity of immunological reagents for NLRP3: implications for age-related macular degeneration. Sci. Rep., 8, 2018, 461.
175. O'Toole, P.W., Jeffery, I.B., Gut microbiota and aging. Science 350 (2015), 1214–1215.
176. Ticinesi, A., Milani, C., Lauretani, F., Nouvenne, A., Mancabelli, L., Lugli, G.A., Turroni, F., Duranti, S., Mangifesta, M., Viappiani, A., Ferrario, C., Maggio, M., Ventura, M., Meschi, T., Gut microbiota composition is associated with polypharmacy in elderly hospitalized patients. Sci. Rep., 7, 2017, 11102.
177. Sansonetti, P.J., To be or not to be a pathogen: that is the mucosally relevant question. Mucosal Immunol. 4 (2011), 8–14.
178. Maloy, K.J., The Interleukin‑23/interleukin‑17 axis in intestinal inflammation. J. Intern. Med. 263 (2008), 584–590.
179. Man, A.L., Bertelli, E., Rentini, S., Regoli, M., Briars, G., Marini, M., Watson, A.J., Nicoletti, C., Age-associated modifications of intestinal permeability and innate immunity in human small intestine. Clin. Sci. (Lond.) 129 (2015), 515–527.
180. Buford, T.W., (Dis)trust your gut: the gut microbiome in age-related inflammation, health, and disease. Microbiome, 5, 2017, 80.
181. Fujihashi, K., Kiyono, H., Mucosal immunosenescence: new developments and vaccines to control infectious diseases. Trends Immunol. 30 (2009), 334–343.
182. Fujkuyama, Y., Tokuhara, D., Kataoka, K., Gilbert, R.S., McGhee, J.R., Yuki, Y., Kiyono, H., Fujihashi, K., Novel vaccine development strategies for inducing mucosal immunity. Expert Rev. Vaccines 11 (2012), 367–379.
183. Biagi, E., Franceschi, C., Rampelli, S., Severgnini, M., Ostan, R., Turroni, S., Consolandi, C., Quercia, S., Scurti, M., Monti, D., Capri, M., Brigidi, P., Candela, M., Gut microbiota and extreme longevity. Curr. Biol. 26 (2016), 1480–1485.
184. Kong, F., Hua, Y., Zeng, B., Ning, R., Li, Y., Zhao, J., Gut microbiota signatures of longevity. Curr. Biol. 26 (2016), R832–R833.
185. Gerli, R., Monti, D., Bistoni, O., Mazzone, A.M., Peri, G., Cossarizza, A., Di Gioacchino, M., Cesarotti, M.E., Doni, A., Mantovani, A., Franceschi, C., Paganelli, R., Chemokines, sTNF-Rs and sCD30 serum levels in healthy aged people and centenarians. Mech. Ageing Dev. 121 (2000), 37–46.
186. Genedani, S., Filaferro, M., Carone, C., Ostan, R., Bucci, L., Cevenini, E., Franceschi, C., Monti, D., Influence of f-MLP, ACTH(1-24) and CRH on in vitro chemotaxis of monocytes from centenarians. Neuroimmunomodulation 15 (2008), 285–289.
187. Meazza, C., Vitale, G., Pagani, S., Castaldi, D., Ogliari, G., Mari, D., Laarej, K., Tinelli, C., Bozzola, M., Common adipokine features of neonates and centenarians. J. Pediatr. Endocrinol. Metab. 24 (2011), 953–957.
188. Netea, M.G., Quintin, J., van der Meer, J.W., Trained immunity: a memory for innate host defense. Cell Host Microbe 9 (2011), 355–361.
189. Netea, M.G., Joosten, L.A., Latz, E., Mills, K.H., Natoli, G., Stunnenberg, H.G., O'Neill, L.A., Xavier, R.J., Trained immunity: A program of innate immune memory in health and disease. Science, 352, 2016, aaf1098.
190. Takeuchi, A., Dejima, T., Yamada, H., Shibata, K., Nakamura, R., Eto, M., Nakatani, T., Naito, S., Yoshikai, Y., IL-17 production by gammadelta T cells is important for the antitumor effect of Mycobacterium bovis bacillus Calmette-Guerin treatment against bladder cancer. Eur. J. Immunol. 41 (2011), 246–251.
191. Fowler, D.W., Copier, J., Wilson, N., Dalgleish, A.G., Bodman-Smith, M.D., Mycobacteria activate gammadelta T-cell anti-tumour responses via cytokines from type 1 myeloid dendritic cells: a mechanism of action for cancer immunotherapy. Cancer Immunol. Immunother. 61 (2012), 535–547.
192. Saeed, S., Quintin, J., Kerstens, H.H., Rao, N.A., Aghajanirefah, A., Matarese, F., Cheng, S.C., Ratter, J., Berentsen, K., van der Ent, M.A., Sharifi, N., Janssen-Megens, E.M., Ter Huurne, M., Mandoli, A., van Schaik, T., Ng, A., Burden, F., Downes, K., Frontini, M., Kumar, V., Giamarellos-Bourboulis, E.J., Ouwehand, W.H., van der Meer, J.W., Joosten, L.A., Wijmenga, C., Martens, J.H., Xavier, R.J., Logie, C., Netea, M.G., Stunnenberg, H.G., Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science, 345, 2014, 1251086.
193. Burgess, S.L., Buonomo, E., Carey, M., Cowardin, C., Naylor, C., Noor, Z., Wills-Karp, M., Petri, W.A. Jr., Bone marrow dendritic cells from mice with an altered microbiota provide interleukin 17A-dependent protection against Entamoeba histolytica colitis. MBio, 5, 2014, e01817.
194. Wojcik, M., Krawczyk, M., Wojcik, P., Cypryk, K., Wozniak, L.A., Molecular mechanisms underlying curcumin-mediated therapeutic effects in type 2 diabetes and Cancer. Oxidative Med. Cell. Longev., 2018, 2018, 9698258.
195. Sohail, M.U., Althani, A., Anwar, H., Rizzi, R., Marei, H.E., Role of the gastrointestinal tract microbiome in the pathophysiology of diabetes mellitus. J. Diabetes Res., 2017, 2017, 9631435.
196. Kakkar, R., Rising burden of diabetes-public health challenges and way out. Nepal J. Epidemiol. 6 (2016), 557–559.
197. Ibrahim, M., Tuomilehto, J., Aschner, P., Beseler, L., Cahn, A., Eckel, R.H., Fischl, A.H., Guthrie, G., Hill, J.O., Kumwenda, M., Leslie, R.D., Olson, D.E., Pozzilli, P., Weber, S.L., Umpierrez, G.E., Global status of diabetes prevention and prospects for action: A consensus statement. Diabetes Metab. Res. Rev., 2018, e3021.
198. Donath, M.Y., Shoelson, S.E., Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol. 11 (2011), 98–107.
199. Kelley, D.E., He, J., Menshikova, E.V., Ritov, V.B., Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51 (2002), 2944–2950.
200. Goldfine, A.B., Shoelson, S.E., Therapeutic approaches targeting inflammation for diabetes and associated cardiovascular risk. J. Clin. Invest. 127 (2017), 83–93.
201. Li, S.H., Szmitko, P.E., Weisel, R.D., Wang, C.H., Fedak, P.W., Li, R.K., Mickle, D.A., Verma, S., C-reactive protein upregulates complement-inhibitory factors in endothelial cells. Circulation 109 (2004), 833–836.
202. Masters, S.L., Latz, E., O'Neill, L.A., The inflammasome in atherosclerosis and type 2 diabetes. Sci. Transl. Med., 3, 2011, 81ps17.
203. Cevenini, E., Monti, D., Franceschi, C., Inflamm-ageing. Curr. Opin. Clin. Nutr. Metab. Care 16 (2013), 14–20.
204. Frasca, D., Blomberg, B.B., Paganelli, R., Aging, obesity, and inflammatory age-related diseases. Front. Immunol., 8, 2017, 1745.
205. Li, X., Watanabe, K., Kimura, I., Gut microbiota dysbiosis drives and implies novel therapeutic strategies for diabetes mellitus and related metabolic diseases. Front. Immunol., 8, 2017, 1882.
206. Fehervari, Z., Meta-inflammation and IRF3. Nat. Immunol., 17, 2016, 1015.
207. Rheinheimer, J., de Souza, B.M., Cardoso, N.S., Bauer, A.C., Crispim, D., Current role of the NLRP3 inflammasome on obesity and insulin resistance: a systematic review. Metabolism 74 (2017), 1–9.
208. Prattichizzo, F., De Nigris, V., La Sala, L., Procopio, A.D., Olivieri, F., Ceriello, A., “Inflammaging” as a druggable target: a senescence-associated secretory phenotype-centered view of type 2 diabetes. Oxidative Med. Cell. Longev., 2016, 2016, 1810327.
209. Palmer, A.K., Tchkonia, T., LeBrasseur, N.K., Chini, E.N., Xu, M., Kirkland, J.L., Cellular senescence in type 2 diabetes: a therapeutic opportunity. Diabetes 64 (2015), 2289–2298.
210. Prattichizzo, F., De Nigris, V., Spiga, R., Mancuso, E., La Sala, L., Antonicelli, R., Testa, R., Procopio, A.D., Olivieri, F., Ceriello, A., Inflammageing and metaflammation: the yin and yang of type 2 diabetes. Ageing Res. Rev. 41 (2018), 1–17.
211. Rea, I.M., Gibson, D.S., McGilligan, V., McNerlan, S.E., Alexander, H.D., Ross, O.A., Age and age-related diseases: role of inflammation triggers and cytokines. Front. Immunol., 9, 2018, 586.
212. Alizadeh, S., Mazloom, H., Sadeghi, A., Emamgholipour, S., Golestani, A., Noorbakhsh, F., Khoshniatnikoo, M., Meshkani, R., Evidence for the link between defective autophagy and inflammation in peripheral blood mononuclear cells of type 2 diabetic patients. J. Physiol. Biochem. 74 (2018), 369–379.
213. Verma, S., Li, S.H., Badiwala, M.V., Weisel, R.D., Fedak, P.W., Li, R.K., Dhillon, B., Mickle, D.A., Endothelin antagonism and interleukin-6 inhibition attenuate the proatherogenic effects of C-reactive protein. Circulation 105 (2002), 1890–1896.
214. Wang, C.H., Li, S.H., Weisel, R.D., Fedak, P.W., Dumont, A.S., Szmitko, P., Li, R.K., Mickle, D.A., Verma, S., C-reactive protein upregulates angiotensin type 1 receptors in vascular smooth muscle. Circulation 107 (2003), 1783–1790.
215. Mather, K.J., Verma, S., Anderson, T.J., Improved endothelial function with metformin in type 2 diabetes mellitus. J. Am. Coll. Cardiol. 37 (2001), 1344–1350.
216. Verma, S., Mathew, V., Farkouh, M.E., Targeting inflammation in the prevention and treatment of type 2 diabetes: insights from CANTOS. J. Am. Coll. Cardiol. 71 (2018), 2402–2404.
217. Pradhan, A.D., Manson, J.E., Rifai, N., Buring, J.E., Ridker, P.M., C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 286 (2001), 327–334.
218. Szmitko, P.E., Wang, C.H., Weisel, R.D., de Almeida, J.R., Anderson, T.J., Verma, S., New markers of inflammation and endothelial cell activation: part I. Circulation 108 (2003), 1917–1923.
219. Fulop, T., Dupuis, G., Witkowski, J.M., Larbi, A., The role of Immunosenescence in the development of age-related diseases. Rev. Investig. Clin. 68 (2016), 84–91.
220. Ceriello, A., The emerging challenge in diabetes: the "metabolic memory". Vasc. Pharmacol. 57 (2012), 133–138.
221. Donath, M.Y., Multiple benefits of targeting inflammation in the treatment of type 2 diabetes. Diabetologia 59 (2016), 679–682.
222. Li, S., Shin, H.J., Ding, E.L., van Dam, R.M., Adiponectin levels and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 302 (2009), 179–188.
223. Luotola, K., Pietila, A., Zeller, T., Moilanen, L., Kahonen, M., Nieminen, M.S., Kesaniemi, Y.A., Blankenberg, S., Jula, A., Perola, M., Salomaa, V., Health, F., Studies, Associations between interleukin-1 (IL-1) gene variations or IL-1 receptor antagonist levels and the development of type 2 diabetes. J. Intern. Med. 269 (2011), 322–332.
224. Herder, C., Zierer, A., Koenig, W., Roden, M., Meisinger, C., Thorand, B., Transforming growth factor-beta1 and incident type 2 diabetes: results from the MONICA/KORA case-cohort study, 1984-2002. Diabetes Care 32 (2009), 1921–1923.
225. Herder, C., Carstensen, M., Ouwens, D.M., Anti-inflammatory cytokines and risk of type 2 diabetes. Diabetes Obes. Metab. 15:Suppl. 3 (2013), 39–50.
226. Blandino, G., Inturri, R., Lazzara, F., Di Rosa, M., Malaguarnera, L., Impact of gut microbiota on diabetes mellitus. Diabete Metab. 42 (2016), 303–315.
227. Fei, N., Zhao, L., An opportunistic pathogen isolated from the gut of an obese human causes obesity in germfree mice. ISME J. 7 (2013), 880–884.
228. Le Chatelier, E., Nielsen, T., Qin, J., Prifti, E., Hildebrand, F., Falony, G., Almeida, M., Arumugam, M., Batto, J.M., Kennedy, S., Leonard, P., Li, J., Burgdorf, K., Grarup, N., Jorgensen, T., Brandslund, I., Nielsen, H.B., Juncker, A.S., Bertalan, M., Levenez, F., Pons, N., Rasmussen, S., Sunagawa, S., Tap, J., Tims, S., Zoetendal, E.G., Brunak, S., Clement, K., Dore, J., Kleerebezem, M., Kristiansen, K., Renault, P., Sicheritz-Ponten, T., de Vos, W.M., Zucker, J.D., Raes, J., Hansen, T., Meta, H.I.T.C., Bork, P., Wang, J., Ehrlich, S.D., Pedersen, O., Richness of human gut microbiome correlates with metabolic markers. Nature 500 (2013), 541–546.
229. Cani, P.D., Bibiloni, R., Knauf, C., Waget, A., Neyrinck, A.M., Delzenne, N.M., Burcelin, R., Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57 (2008), 1470–1481.
230. Gomes, J.M.G., Costa, J.A., Alfenas, R.C.G., Metabolic endotoxemia and diabetes mellitus: a systematic review. Metabolism 68 (2017), 133–144.
231. Wang, X., Ota, N., Manzanillo, P., Kates, L., Zavala-Solorio, J., Eidenschenk, C., Zhang, J., Lesch, J., Lee, W.P., Ross, J., Diehl, L., van Bruggen, N., Kolumam, G., Ouyang, W., Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes. Nature 514 (2014), 237–241.
232. Gulhane, M., Murray, L., Lourie, R., Tong, H., Sheng, Y.H., Wang, R., Kang, A., Schreiber, V., Wong, K.Y., Magor, G., Denman, S., Begun, J., Florin, T.H., Perkins, A., Cuiv, P.O., McGuckin, M.A., Hasnain, S.Z., High fat diets induce colonic epithelial cell stress and inflammation that is reversed by IL-22. Sci. Rep., 6, 2016, 28990.
233. Cook, D.N., Kang, H.S., Jetten, A.M., Retinoic Acid-related Orphan Receptors (RORs): regulatory functions in immunity, development, circadian rhythm, and metabolism. Nucl. Recept. Res., 2, 2015.
234. Cavallari, J.F., Denou, E., Foley, K.P., Khan, W.I., Schertzer, J.D., Different Th17 immunity in gut, liver, and adipose tissues during obesity: the role of diet, genetics, and microbes. Gut Microbes 7 (2016), 82–89.
235. Magalhaes, I., Pingris, K., Poitou, C., Bessoles, S., Venteclef, N., Kiaf, B., Beaudoin, L., Da Silva, J., Allatif, O., Rossjohn, J., Kjer-Nielsen, L., McCluskey, J., Ledoux, S., Genser, L., Torcivia, A., Soudais, C., Lantz, O., Boitard, C., Aron-Wisnewsky, J., Larger, E., Clement, K., Lehuen, A., Mucosal-associated invariant T cell alterations in obese and type 2 diabetic patients. J. Clin. Invest. 125 (2015), 1752–1762.
236. Marino, E., Richards, J.L., McLeod, K.H., Stanley, D., Yap, Y.A., Knight, J., McKenzie, C., Kranich, J., Oliveira, A.C., Rossello, F.J., Krishnamurthy, B., Nefzger, C.M., Macia, L., Thorburn, A., Baxter, A.G., Morahan, G., Wong, L.H., Polo, J.M., Moore, R.J., Lockett, T.J., Clarke, J.M., Topping, D.L., Harrison, L.C., Mackay, C.R., Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes. Nat. Immunol. 18 (2017), 552–562.
237. Tanaka, M., Masuda, S., Matsuo, Y., Sasaki, Y., Yamakage, H., Muranaka, K., Wada, H., Hasegawa, K., Tsukahara, T., Shimatsu, A., Satoh-Asahara, N., Hyperglycemia and inflammatory property of circulating monocytes are associated with inflammatory property of carotid plaques in patients undergoing carotid endarterectomy. J. Atheroscler. Thromb. 23 (2016), 1212–1221.
238. Kowluru, R.A., Effect of reinstitution of good glycemic control on retinal oxidative stress and nitrative stress in diabetic rats. Diabetes 52 (2003), 818–823.
239. Kowluru, R.A., Abbas, S.N., Odenbach, S., Reversal of hyperglycemia and diabetic nephropathy: effect of reinstitution of good metabolic control on oxidative stress in the kidney of diabetic rats. J. Diabetes Complicat. 18 (2004), 282–288.
240. Ceriello, A., Hypothesis: the "metabolic memory", the new challenge of diabetes. Diabetes Res. Clin. Pract. 86:Suppl. 1 (2009), S2–S6.
241. Rosca, M.G., Mustata, T.G., Kinter, M.T., Ozdemir, A.M., Kern, T.S., Szweda, L.I., Brownlee, M., Monnier, V.M., Weiss, M.F., Glycation of mitochondrial proteins from diabetic rat kidney is associated with excess superoxide formation. Am. J. Physiol. Ren. Physiol. 289 (2005), F420–F430.
242. Qing, S., Yuan, S., Yun, C., Hui, H., Mao, P., Wen, F., Ding, Y., Liu, Q., Serum miRNA biomarkers serve as a fingerprint for proliferative diabetic retinopathy. Cell. Physiol. Biochem. 34 (2014), 1733–1740.
243. McClelland, A.D., Herman-Edelstein, M., Komers, R., Jha, J.C., Winbanks, C.E., Hagiwara, S., Gregorevic, P., Kantharidis, P., Cooper, M.E., miR-21 promotes renal fibrosis in diabetic nephropathy by targeting PTEN and SMAD7. Clin. Sci. (Lond.) 129 (2015), 1237–1249.
244. Prattichizzo, F., Giuliani, A., De Nigris, V., Pujadas, G., Ceka, A., La Sala, L., Genovese, S., Testa, R., Procopio, A.D., Olivieri, F., Ceriello, A., Extracellular microRNAs and endothelial hyperglycaemic memory: a therapeutic opportunity?. Diabetes Obes. Metab. 18 (2016), 855–867.
245. Reddy, M.A., Natarajan, R., Epigenetic mechanisms in diabetic vascular complications. Cardiovasc. Res. 90 (2011), 421–429.
246. Reddy, M.A., Zhang, E., Natarajan, R., Epigenetic mechanisms in diabetic complications and metabolic memory. Diabetologia 58 (2015), 443–455.
247. Wegner, M., Neddermann, D., Piorunska-Stolzmann, M., Jagodzinski, P.P., Role of epigenetic mechanisms in the development of chronic complications of diabetes. Diabetes Res. Clin. Pract. 105 (2014), 164–175.
248. Pirola, L., Balcerczyk, A., Okabe, J., El-Osta, A., Epigenetic phenomena linked to diabetic complications. Nat. Rev. Endocrinol. 6 (2010), 665–675.
249. Remely, M., Aumueller, E., Jahn, D., Hippe, B., Brath, H., Haslberger, A.G., Microbiota and epigenetic regulation of inflammatory mediators in type 2 diabetes and obesity. Benefic. Microbes 5 (2014), 33–43.
250. Brasacchio, D., Okabe, J., Tikellis, C., Balcerczyk, A., George, P., Baker, E.K., Calkin, A.C., Brownlee, M., Cooper, M.E., El-Osta, A., Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail. Diabetes 58 (2009), 1229–1236.
251. Miao, F., Gonzalo, I.G., Lanting, L., Natarajan, R., In vivo chromatin remodeling events leading to inflammatory gene transcription under diabetic conditions. J. Biol. Chem. 279 (2004), 18091–18097.
252. Reddy, M.A., Natarajan, R., Role of epigenetic mechanisms in the vascular complications of diabetes. Subcell. Biochem. 61 (2013), 435–454.
253. Ting, D.S., Cheung, G.C., Wong, T.Y., Diabetic retinopathy: global prevalence, major risk factors, screening practices and public health challenges: a review. Clin. Exp. Ophthalmol. 44 (2016), 260–277.
254. Cheung, N., Mitchell, P., Wong, T.Y., Diabetic retinopathy. Lancet 376 (2010), 124–136.
255. Romero-Aroca, P., Navarro-Gil, R., Valls-Mateu, A., Sagarra-Alamo, R., Moreno-Ribas, A., Soler, N., Differences in incidence of diabetic retinopathy between type 1 and 2 diabetes mellitus: a nine-year follow-up study. Br. J. Ophthalmol. 101 (2017), 1346–1351.
256. Gardner, T.W., Abcouwer, S.F., Barber, A.J., Jackson, G.R., An integrated approach to diabetic retinopathy research. Arch. Ophthalmol. 129 (2011), 230–235.
257. Stitt, A.W., Curtis, T.M., Chen, M., Medina, R.J., McKay, G.J., Jenkins, A., Gardiner, T.A., Lyons, T.J., Hammes, H.P., Simo, R., Lois, N., The progress in understanding and treatment of diabetic retinopathy. Prog. Retin. Eye Res. 51 (2016), 156–186.
258. Lee, R., Wong, T.Y., Sabanayagam, C., Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss. Eye Vis. (Lond.), 2, 2015, 17.
259. U.P.D.S.U, Group, effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352 (1998), 854–865.
260. Engerman, R.L., Kern, T.S., Progression of incipient diabetic retinopathy during good glycemic control. Diabetes 36 (1987), 808–812.
261. Zong, H., Ward, M., Madden, A., Yong, P.H., Limb, G.A., Curtis, T.M., Stitt, A.W., Hyperglycaemia-induced pro-inflammatory responses by retinal Muller glia are regulated by the receptor for advanced glycation end-products (RAGE). Diabetologia 53 (2010), 2656–2666.
262. Antonetti, D.A., Barber, A.J., Bronson, S.K., Freeman, W.M., Gardner, T.W., Jefferson, L.S., Kester, M., Kimball, S.R., Krady, J.K., Lanoue, K.F., Norbury, C.C., Quinn, P.G., Sandirasegarane, L., Simpson, I.A., J.D.R.C. Group, Diabetic retinopathy: seeing beyond glucose-induced microvascular disease. Diabetes 55 (2006), 2401–2411.
263. Grigsby, J.G., Cardona, S.M., Pouw, C.E., Muniz, A., Mendiola, A.S., Tsin, A.T., Allen, D.M., Cardona, A.E., The role of microglia in diabetic retinopathy. J. Ophthalmol., 2014, 2014, 705783.
264. Krady, J.K., Basu, A., Allen, C.M., Xu, Y., LaNoue, K.F., Gardner, T.W., Levison, S.W., Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy. Diabetes 54 (2005), 1559–1565.
265. Cardoso, C.R.L., Leite, N.C., Dib, E., Salles, G.F., Predictors of development and progression of retinopathy in patients with type 2 diabetes: importance of blood pressure parameters. Sci. Rep., 7, 2017, 4867.
266. Qin, J., Li, Y., Cai, Z., Li, S., Zhu, J., Zhang, F., Liang, S., Zhang, W., Guan, Y., Shen, D., Peng, Y., Zhang, D., Jie, Z., Wu, W., Qin, Y., Xue, W., Li, J., Han, L., Lu, D., Wu, P., Dai, Y., Sun, X., Li, Z., Tang, A., Zhong, S., Li, X., Chen, W., Xu, R., Wang, M., Feng, Q., Gong, M., Yu, J., Zhang, Y., Zhang, M., Hansen, T., Sanchez, G., Raes, J., Falony, G., Okuda, S., Almeida, M., Lechatelier, E., Renault, P., Pons, N., Batto, J.M., Zhang, Z., Chen, H., Yang, R., Zheng, W., Li, S., Yang, H., Wang, J., Ehrlich, S.D., Nielsen, R., Pedersen, O., Kristiansen, K., Wang, J., A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490 (2012), 55–60.
267. Karlsson, F.H., Tremaroli, V., Nookaew, I., Bergstrom, G., Behre, C.J., Fagerberg, B., Nielsen, J., Backhed, F., Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 498 (2013), 99–103.
268. Griffin, J.L., Wang, X., Stanley, E., Does our gut microbiome predict cardiovascular risk? A review of the evidence from metabolomics. Circ. Cardiovasc. Genet. 8 (2015), 187–191.
269. Beli, E., Yan, Y., Moldovan, L., Vieira, C.P., Gao, R., Duan, Y., Prasad, R., Bhatwadekar, A., White, F.A., Townsend, S., Chan, L., Ryan, C.N., Morton, D., Moldovan, E.G., Chu, F.I., Oudit, G.Y., Derendorf, H., Adorini, L., Wang, X.X., Evans-Molina, C., Mirmira, R.G., Boulton, M.E., Yoder, M.C., Li, Q., Levi, M., Busik, J.V., Grant, M.B., Restructuring of the gut microbiome by intermittent fasting prevents retinopathy and prolongs survival in db/db mice. Diabetes 67 (2018), 1867–1879.
270. Egshatyan, L., Kashtanova, D., Popenko, A., Tkacheva, O., Tyakht, A., Alexeev, D., Karamnova, N., Kostryukova, E., Babenko, V., Vakhitova, M., Boytsov, S., Gut microbiota and diet in patients with different glucose tolerance. Endocr. Connect. 5 (2016), 1–9.
271. Allin, K.H., Nielsen, T., Pedersen, O., Mechanisms in endocrinology: gut microbiota in patients with type 2 diabetes mellitus. Eur. J. Endocrinol. 172 (2015), R167–R177.
272. Arora, T., Backhed, F., The gut microbiota and metabolic disease: current understanding and future perspectives. J. Intern. Med. 280 (2016), 339–349.
273. Markoulli, M., Flanagan, J., Tummanapalli, S.S., Wu, J., Willcox, M., The impact of diabetes on corneal nerve morphology and ocular surface integrity. Ocul. Surf. 16 (2018), 45–57.
274. Semeraro, F., Cancarini, A., dell'Omo, R., Rezzola, S., Romano, M.R., Costagliola, C., Diabetic retinopathy: vascular and inflammatory disease. J. Diabetes Res., 2015, 2015, 582060.
275. Powell, E.D., Field, R.A., Diabetic retinopathy and rheumatoid arthritis. Lancet 2 (1964), 17–18.
276. Brucklacher, R.M., Patel, K.M., Vanguilder, H.D., Bixler, G.V., Barber, A.J., Antonetti, D.A., Lin, C.M., Lanoue, K.F., Gardner, T.W., Bronson, S.K., Freeman, W.M., Whole genome assessment of the retinal response to diabetes reveals a progressive neurovascular inflammatory response. BMC Med. Genet., 1, 2008, 26.
277. Adamis, A.P., Berman, A.J., Immunological mechanisms in the pathogenesis of diabetic retinopathy. Semin. Immunopathol. 30 (2008), 65–84.
278. Kaul, K., Hodgkinson, A., Tarr, J.M., Kohner, E.M., Chibber, R., Is inflammation a common retinal-renal-nerve pathogenic link in diabetes?. Curr. Diabetes Rev. 6 (2010), 294–303.
279. Kern, T.S., Contributions of inflammatory processes to the development of the early stages of diabetic retinopathy. Exp. Diabetes Res., 2007, 2007, 95103.
280. Feng, S., Yu, H., Yu, Y., Geng, Y., Li, D., Yang, C., Lv, Q., Lu, L., Liu, T., Li, G., Yuan, L., Levels of inflammatory cytokines IL-1beta, IL-6, IL-8, IL-17A, and TNF-alpha in aqueous humour of patients with diabetic retinopathy. J. Diabetes Res., 2018, 2018, 8546423.
281. Tang, J., Kern, T.S., Inflammation in diabetic retinopathy. Prog. Retin. Eye Res. 30 (2011), 343–358.
282. Adamis, A.P., Is diabetic retinopathy an inflammatory disease?. Br. J. Ophthalmol. 86 (2002), 363–365.
283. Noda, K., Nakao, S., Ishida, S., Ishibashi, T., Leukocyte adhesion molecules in diabetic retinopathy. J. Ophthalmol., 2012, 2012, 279037.
284. Rangasamy, S., McGuire, P.G., Das, A., Diabetic retinopathy and inflammation: novel therapeutic targets. Middle East Afr. J. Ophthalmol. 19 (2012), 52–59.
285. Funatsu, H., Yamashita, H., Noma, H., Mimura, T., Nakamura, S., Sakata, K., Hori, S., Aqueous humor levels of cytokines are related to vitreous levels and progression of diabetic retinopathy in diabetic patients. Graefes Arch. Clin. Exp. Ophthalmol. 243 (2005), 3–8.
286. Demircan, N., Safran, B.G., Soylu, M., Ozcan, A.A., Sizmaz, S., Determination of vitreous interleukin-1 (IL-1) and tumour necrosis factor (TNF) levels in proliferative diabetic retinopathy. Eye (Lond.) 20 (2006), 1366–1369.
287. Abu El-Asrar, A.M., Struyf, S., Kangave, D., Geboes, K., Van Damme, J., Chemokines in proliferative diabetic retinopathy and proliferative vitreoretinopathy. Eur. Cytokine Netw. 17 (2006), 155–165.
288. Koskela, U.E., Kuusisto, S.M., Nissinen, A.E., Savolainen, M.J., Liinamaa, M.J., High vitreous concentration of IL-6 and IL-8, but not of adhesion molecules in relation to plasma concentrations in proliferative diabetic retinopathy. Ophthalmic Res. 49 (2013), 108–114.
289. Hernandez, C., Segura, R.M., Fonollosa, A., Carrasco, E., Francisco, G., Simo, R., Interleukin-8, monocyte chemoattractant protein-1 and IL-10 in the vitreous fluid of patients with proliferative diabetic retinopathy. Diabet. Med. 22 (2005), 719–722.
290. Hernandez, C., Ortega, F., Garcia-Ramirez, M., Villarroel, M., Casado, J., Garcia-Pascual, L., Fernandez-Real, J.M., Simo, R., Lipopolysaccharide-binding protein and soluble CD14 in the vitreous fluid of patients with proliferative diabetic retinopathy. Retina 30 (2010), 345–352.
291. Mudaliar, H., Pollock, C., Ma, J., Wu, H., Chadban, S., Panchapakesan, U., The role of TLR2 and 4-mediated inflammatory pathways in endothelial cells exposed to high glucose. PLoS One, 9, 2014, e108844.
292. Jiang, S., Chen, X., Expression of high-mobility group box 1 protein (HMGB1) and toll-like receptor 9 (TLR9) in retinas of diabetic rats. Med. Sci. Monit. 23 (2017), 3115–3122.
293. Schaaff, I., Hohmann, S., Zimmermann, F.K., Molecular analysis of the structural gene for yeast transaldolase. Eur. J. Biochem. 188 (1990), 597–603.
294. Sims, G.P., Rowe, D.C., Rietdijk, S.T., Herbst, R., Coyle, A.J., HMGB1 and RAGE in inflammation and cancer. Annu. Rev. Immunol. 28 (2010), 367–388.
295. van Beijnum, J.R., Buurman, W.A., Griffioen, A.W., Convergence and amplification of toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signaling pathways via high mobility group B1 (HMGB1). Angiogenesis 11 (2008), 91–99.
296. Takeuchi, M., Takino, J., Yamagishi, S., Involvement of the toxic AGEs (TAGE)-RAGE system in the pathogenesis of diabetic vascular complications: a novel therapeutic strategy. Curr. Drug Targets 11 (2010), 1468–1482.
297. Abu El-Asrar, A.M., Siddiquei, M.M., Nawaz, M.I., Geboes, K., Mohammad, G., The proinflammatory cytokine high-mobility group box-1 mediates retinal neuropathy induced by diabetes. Mediat. Inflamm., 2014, 2014, 746415.
298. Xu, W.Q., Wang, Y.S., The role of toll-like receptors in retinal ischemic diseases. Int. J. Ophthalmol. 9 (2016), 1343–1351.
299. Dandona, P., Aljada, A., Bandyopadhyay, A., Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol. 25 (2004), 4–7.
300. Jin, C., Flavell, R.A., Molecular mechanism of NLRP3 inflammasome activation. J. Clin. Immunol. 30 (2010), 628–631.
301. Schroder, K., Zhou, R., Tschopp, J., The NLRP3 inflammasome: a sensor for metabolic danger?. Science 327 (2010), 296–300.
302. Hoffman, H.M., Wanderer, A.A., Inflammasome and IL-1beta-mediated disorders. Curr Allergy Asthma Rep 10 (2010), 229–235.
303. Martinon, F., Burns, K., Tschopp, J., The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol. Cell 10 (2002), 417–426.
304. Agostini, L., Martinon, F., Burns, K., McDermott, M.F., Hawkins, P.N., Tschopp, J., NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 20 (2004), 319–325.
305. Doyle, S.L., Campbell, M., Ozaki, E., Salomon, R.G., Mori, A., Kenna, P.F., Farrar, G.J., Kiang, A.S., Humphries, M.M., Lavelle, E.C., O'Neill, L.A., Hollyfield, J.G., Humphries, P., NLRP3 has a protective role in age-related macular degeneration through the induction of IL-18 by drusen components. Nat. Med. 18 (2012), 791–798.
306. Loukovaara, S., Piippo, N., Kinnunen, K., Hytti, M., Kaarniranta, K., Kauppinen, A., NLRP3 inflammasome activation is associated with proliferative diabetic retinopathy. Acta Ophthalmol. 95 (2017), 803–808.
307. Hu, C., Ding, H., Li, Y., Pearson, J.A., Zhang, X., Flavell, R.A., Wong, F.S., Wen, L., NLRP3 deficiency protects from type 1 diabetes through the regulation of chemotaxis into the pancreatic islets. Proc. Natl. Acad. Sci. U. S. A. 112 (2015), 11318–11323.
308. Al-Shabrawey, M., Rojas, M., Sanders, T., Behzadian, A., El-Remessy, A., Bartoli, M., Parpia, A.K., Liou, G., Caldwell, R.B., Role of NADPH oxidase in retinal vascular inflammation. Invest. Ophthalmol. Vis. Sci. 49 (2008), 3239–3244.
309. El-Remessy, A.B., Al-Shabrawey, M., Platt, D.H., Bartoli, M., Behzadian, M.A., Ghaly, N., Tsai, N., Motamed, K., Caldwell, R.B., Peroxynitrite mediates VEGF's angiogenic signal and function via a nitration-independent mechanism in endothelial cells. FASEB J. 21 (2007), 2528–2539.
310. Zhong, Q., Mishra, M., Kowluru, R.A., Transcription factor Nrf2-mediated antioxidant defense system in the development of diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 54 (2013), 3941–3948.
311. Donato, A.J., Morgan, R.G., Walker, A.E., Lesniewski, L.A., Cellular and molecular biology of aging endothelial cells. J. Mol. Cell. Cardiol. 89 (2015), 122–135.
312. Sun, S., Cheng, B., Sun, P.G., Wu, X.H., Wu, Q.Q., He, P., RTEF-1 protects against oxidative damage induced by H2O2 in human umbilical vein endothelial cells through klotho activation. Exp. Biol. Med. (Maywood) 240 (2015), 1606–1613.
313. El Assar, M., Angulo, J., Vallejo, S., Peiro, C., Sanchez-Ferrer, C.F., Rodriguez-Manas, L., Mechanisms involved in the aging-induced vascular dysfunction. Front. Physiol., 3, 2012, 132.
314. Rodriguez-Manas, L., El-Assar, M., Vallejo, S., Lopez-Doriga, P., Solis, J., Petidier, R., Montes, M., Nevado, J., Castro, M., Gomez-Guerrero, C., Peiro, C., Sanchez-Ferrer, C.F., Endothelial dysfunction in aged humans is related with oxidative stress and vascular inflammation. Aging Cell 8 (2009), 226–238.
315. Zhong, W., Zou, G., Gu, J., Zhang, J., L-arginine attenuates high glucose-accelerated senescence in human umbilical vein endothelial cells. Diabetes Res. Clin. Pract. 89 (2010), 38–45.
316. Zhu, Y., Armstrong, J.L., Tchkonia, T., Kirkland, J.L., Cellular senescence and the senescent secretory phenotype in age-related chronic diseases. Curr. Opin. Clin. Nutr. Metab. Care 17 (2014), 324–328.
317. Brownlee, M., Biochemistry and molecular cell biology of diabetic complications. Nature 414 (2001), 813–820.
318. Lamoke, F., Shaw, S., Yuan, J., Ananth, S., Duncan, M., Martin, P., Bartoli, M., Increased oxidative and Nitrative stress accelerates aging of the retinal vasculature in the diabetic retina. PLoS One, 10, 2015, e0139664.
319. Oubaha, M., Miloudi, K., Dejda, A., Guber, V., Mawambo, G., Germain, M.A., Bourdel, G., Popovic, N., Rezende, F.A., Kaufman, R.J., Mallette, F.A., Sapieha, P., Senescence-associated secretory phenotype contributes to pathological angiogenesis in retinopathy. Sci. Transl. Med., 8, 2016, 362ra144.
320. Glassock, R.J., Warnock, D.G., Delanaye, P., The global burden of chronic kidney disease: estimates, variability and pitfalls. Nat. Rev. Nephrol. 13 (2017), 104–114.
321. Jha, V., Garcia-Garcia, G., Iseki, K., Li, Z., Naicker, S., Plattner, B., Saran, R., Wang, A.Y., Yang, C.W., Chronic kidney disease: global dimension and perspectives. Lancet 382 (2013), 260–272.
322. W.G.s.r.o.n. diseases, 2014.
323. Singh, D.K., Winocour, P., Farrington, K., Oxidative stress in early diabetic nephropathy: fueling the fire. Nat. Rev. Endocrinol. 7 (2011), 176–184.
324. Navarro-Gonzalez, J.F., Mora-Fernandez, C., Muros de Fuentes, M., Garcia-Perez, J., Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat. Rev. Nephrol. 7 (2011), 327–340.
325. Liu, Y., Cellular and molecular mechanisms of renal fibrosis. Nat. Rev. Nephrol. 7 (2011), 684–696.
326. Carrero, J.J., Stenvinkel, P., Persistent inflammation as a catalyst for other risk factors in chronic kidney disease: a hypothesis proposal. Clin. J. Am. Soc. Nephrol. 4:Suppl. 1 (2009), S49–S55.
327. Costa, E., Rocha, S., Rocha-Pereira, P., Castro, E., Reis, F., Teixeira, F., Miranda, V., Do Sameiro Faria, M., Loureiro, A., Quintanilha, A., Belo, L., Santos-Silva, A., Cross-talk between inflammation, coagulation/fibrinolysis and vascular access in hemodialysis patients. J. Vasc. Access 9 (2008), 248–253.
328. do Sameiro-Faria, M., Ribeiro, S., Costa, E., Mendonca, D., Teixeira, L., Rocha-Pereira, P., Fernandes, J., Nascimento, H., Kohlova, M., Reis, F., Amado, L., Bronze-da-Rocha, E., Miranda, V., Quintanilha, A., Belo, L., Santos-Silva, A., Risk factors for mortality in hemodialysis patients: two-year follow-up study. Dis. Markers 35 (2013), 791–798.
329. Johnson, A.M., Olefsky, J.M., The origins and drivers of insulin resistance. Cell 152 (2013), 673–684.
330. Kanbay, M., Onal, E.M., Afsar, B., Dagel, T., Yerlikaya, A., Covic, A., Vaziri, N.D., The crosstalk of gut microbiota and chronic kidney disease: role of inflammation, proteinuria, hypertension, and diabetes mellitus. Int. Urol. Nephrol. 50 (2018), 1453–1466.
331. Yang, T., Richards, E.M., Pepine, C.J., Raizada, M.K., The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease. Nat. Rev. Nephrol. 14 (2018), 442–456.
332. Evenepoel, P., Poesen, R., Meijers, B., The gut-kidney axis. Pediatr. Nephrol. 32 (2017), 2005–2014.
333. Khoury, T., Tzukert, K., Abel, R., Abu Rmeileh, A., Levi, R., Ilan, Y., The gut-kidney axis in chronic renal failure: a new potential target for therapy. Hemodial. Int. 21 (2017), 323–334.
334. Mahmoodpoor, F., Rahbar Saadat, Y., Barzegari, A., Ardalan, M., Zununi Vahed, S., The impact of gut microbiota on kidney function and pathogenesis. Biomed. Pharmacother. 93 (2017), 412–419.
335. Lewis, B., Mukewar, S., Lopez, R., Brzezinski, A., Hall, P., Shen, B., Frequency and risk factors of renal insufficiency in inflammatory bowel disease inpatients. Inflamm. Bowel Dis. 19 (2013), 1846–1851.
336. Casen, C., Vebo, H.C., Sekelja, M., Hegge, F.T., Karlsson, M.K., Ciemniejewska, E., Dzankovic, S., Froyland, C., Nestestog, R., Engstrand, L., Munkholm, P., Nielsen, O.H., Rogler, G., Simren, M., Ohman, L., Vatn, M.H., Rudi, K., Deviations in human gut microbiota: a novel diagnostic test for determining dysbiosis in patients with IBS or IBD. Aliment. Pharmacol. Ther. 42 (2015), 71–83.
337. Vaziri, N.D., Wong, J., Pahl, M., Piceno, Y.M., Yuan, J., DeSantis, T.Z., Ni, Z., Nguyen, T.H., Andersen, G.L., Chronic kidney disease alters intestinal microbial flora. Kidney Int. 83 (2013), 308–315.
338. Mafra, D., Fouque, D., Gut microbiota and inflammation in chronic kidney disease patients. Clin. Kidney J. 8 (2015), 332–334.
339. Coppo, R., The gut-kidney axis in IgA nephropathy: role of microbiota and diet on genetic predisposition. Pediatr. Nephrol. 33 (2018), 53–61.
340. Kau, A.L., Ahern, P.P., Griffin, N.W., Goodman, A.L., Gordon, J.I., Human nutrition, the gut microbiome and the immune system. Nature 474 (2011), 327–336.
341. David, L.A., Maurice, C.F., Carmody, R.N., Gootenberg, D.B., Button, J.E., Wolfe, B.E., Ling, A.V., Devlin, A.S., Varma, Y., Fischbach, M.A., Biddinger, S.B., Dutton, R.J., Turnbaugh, P.J., Diet rapidly and reproducibly alters the human gut microbiome. Nature 505 (2014), 559–563.
342. Bammens, B., Verbeke, K., Vanrenterghem, Y., Evenepoel, P., Evidence for impaired assimilation of protein in chronic renal failure. Kidney Int. 64 (2003), 2196–2203.
343. Mafra, D., Barros, A.F., Fouque, D., Dietary protein metabolism by gut microbiota and its consequences for chronic kidney disease patients. Future Microbiol 8 (2013), 1317–1323.
344. Nyangale, E.P., Mottram, D.S., Gibson, G.R., Gut microbial activity, implications for health and disease: the potential role of metabolite analysis. J. Proteome Res. 11 (2012), 5573–5585.
345. Bammens, B., Evenepoel, P., Verbeke, K., Vanrenterghem, Y., Impairment of small intestinal protein assimilation in patients with end-stage renal disease: extending the malnutrition-inflammation-atherosclerosis concept. Am. J. Clin. Nutr. 80 (2004), 1536–1543.
346. Vaziri, N.D., Zhao, Y.Y., Pahl, M.V., Altered intestinal microbial flora and impaired epithelial barrier structure and function in CKD: the nature, mechanisms, consequences and potential treatment. Nephrol. Dial. Transplant. 31 (2016), 737–746.
347. Barrios, C., Beaumont, M., Pallister, T., Villar, J., Goodrich, J.K., Clark, A., Pascual, J., Ley, R.E., Spector, T.D., Bell, J.T., Menni, C., Gut-microbiota-metabolite Axis in early renal function decline. PLoS One, 10, 2015, e0134311.
348. Jakobsson, H.E., Rodriguez-Pineiro, A.M., Schutte, A., Ermund, A., Boysen, P., Bemark, M., Sommer, F., Backhed, F., Hansson, G.C., Johansson, M.E., The composition of the gut microbiota shapes the colon mucus barrier. EMBO Rep. 16 (2015), 164–177.
349. Omenetti, S., Pizarro, T.T., The Treg/Th17 axis: a dynamic balance regulated by the gut microbiome. Front. Immunol., 6, 2015, 639.
350. Shi, K., Wang, F., Jiang, H., Liu, H., Wei, M., Wang, Z., Xie, L., Gut bacterial translocation may aggravate microinflammation in hemodialysis patients. Dig. Dis. Sci. 59 (2014), 2109–2117.
351. Poveda, J., Sanchez-Nino, M.D., Glorieux, G., Sanz, A.B., Egido, J., Vanholder, R., Ortiz, A., p-Cresyl sulphate has pro-inflammatory and cytotoxic actions on human proximal tubular epithelial cells. Nephrol. Dial. Transplant. 29 (2014), 56–64.
352. McIntyre, C.W., Harrison, L.E., Eldehni, M.T., Jefferies, H.J., Szeto, C.C., John, S.G., Sigrist, M.K., Burton, J.O., Hothi, D., Korsheed, S., Owen, P.J., Lai, K.B., Li, P.K., Circulating endotoxemia: a novel factor in systemic inflammation and cardiovascular disease in chronic kidney disease. Clin. J. Am. Soc. Nephrol. 6 (2011), 133–141.
353. Anders, H.J., Andersen, K., Stecher, B., The intestinal microbiota, a leaky gut, and abnormal immunity in kidney disease. Kidney Int. 83 (2013), 1010–1016.
354. Ramezani, A., Raj, D.S., The gut microbiome, kidney disease, and targeted interventions. J. Am. Soc. Nephrol. 25 (2014), 657–670.
355. Ramezani, A., Massy, Z.A., Meijers, B., Evenepoel, P., Vanholder, R., Raj, D.S., Role of the gut microbiome in uremia: a potential therapeutic target. Am. J. Kidney Dis. 67 (2016), 483–498.
356. Vaziri, N.D., Effect of synbiotic therapy on gut-derived uremic toxins and the intestinal microbiome in patients with CKD. Clin. J. Am. Soc. Nephrol. 11 (2016), 199–201.
357. Wu, I.W., Hsu, K.H., Lee, C.C., Sun, C.Y., Hsu, H.J., Tsai, C.J., Tzen, C.Y., Wang, Y.C., Lin, C.Y., Wu, M.S., p-Cresyl sulphate and indoxyl sulphate predict progression of chronic kidney disease. Nephrol. Dial. Transplant. 26 (2011), 938–947.
358. Satoh, M., Hayashi, H., Watanabe, M., Ueda, K., Yamato, H., Yoshioka, T., Motojima, M., Uremic toxins overload accelerates renal damage in a rat model of chronic renal failure. Nephron Exp. Nephrol. 95 (2003), e111–e118.
359. Miyazaki, T., Ise, M., Seo, H., Niwa, T., Indoxyl sulfate increases the gene expressions of TGF-beta 1, TIMP-1 and pro-alpha 1(I) collagen in uremic rat kidneys. Kidney Int. Suppl. 62 (1997), S15–S22.
360. Huang, S.T., Shu, K.H., Cheng, C.H., Wu, M.J., Yu, T.M., Chuang, Y.W., Chen, C.H., Serum total p-cresol and indoxyl sulfate correlated with stage of chronic kidney disease in renal transplant recipients. Transplant. Proc. 44 (2012), 621–624.
361. Lin, C.J., Chen, H.H., Pan, C.F., Chuang, C.K., Wang, T.J., Sun, F.J., Wu, C.J., p-Cresylsulfate and indoxyl sulfate level at different stages of chronic kidney disease. J. Clin. Lab. Anal. 25 (2011), 191–197.
362. Viaene, L., Annaert, P., de Loor, H., Poesen, R., Evenepoel, P., Meijers, B., Albumin is the main plasma binding protein for indoxyl sulfate and p-cresyl sulfate. Biopharm. Drug Dispos. 34 (2013), 165–175.
363. Borges, N.A., Barros, A.F., Nakao, L.S., Dolenga, C.J., Fouque, D., Mafra, D., Protein-bound uremic toxins from gut microbiota and inflammatory markers in chronic kidney disease. J. Ren. Nutr. 26 (2016), 396–400.
364. Ichii, O., Otsuka-Kanazawa, S., Nakamura, T., Ueno, M., Kon, Y., Chen, W., Rosenberg, A.Z., Kopp, J.B., Podocyte injury caused by indoxyl sulfate, a uremic toxin and aryl-hydrocarbon receptor ligand. PLoS One, 9, 2014, e108448.
365. Sun, C.Y., Chang, S.C., Wu, M.S., Uremic toxins induce kidney fibrosis by activating intrarenal renin-angiotensin-aldosterone system associated epithelial-to-mesenchymal transition. PLoS One, 7, 2012, e34026.
366. Sun, G., Yin, Z., Liu, N., Bian, X., Yu, R., Su, X., Zhang, B., Wang, Y., Gut microbial metabolite TMAO contributes to renal dysfunction in a mouse model of diet-induced obesity. Biochem. Biophys. Res. Commun. 493 (2017), 964–970.
367. Tang, W.H., Wang, Z., Kennedy, D.J., Wu, Y., Buffa, J.A., Agatisa-Boyle, B., Li, X.S., Levison, B.S., Hazen, S.L., Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ. Res. 116 (2015), 448–455.
368. Stubbs, J.R., House, J.A., Ocque, A.J., Zhang, S., Johnson, C., Kimber, C., Schmidt, K., Gupta, A., Wetmore, J.B., Nolin, T.D., Spertus, J.A., Yu, A.S., Serum trimethylamine-N-oxide is elevated in CKD and correlates with coronary atherosclerosis burden. J. Am. Soc. Nephrol. 27 (2016), 305–313.
369. Wada, J., Makino, H., Innate immunity in diabetes and diabetic nephropathy. Nat. Rev. Nephrol. 12 (2016), 13–26.
370. Keating, S.T., van Diepen, J.A., Riksen, N.P., El-Osta, A., Epigenetics in diabetic nephropathy, immunity and metabolism. Diabetologia 61 (2018), 6–20.
371. Garibotto, G., Carta, A., Picciotto, D., Viazzi, F., Verzola, D., Toll-like receptor-4 signaling mediates inflammation and tissue injury in diabetic nephropathy. J. Nephrol. 30 (2017), 719–727.
372. Mudaliar, H., Pollock, C., Panchapakesan, U., Role of toll-like receptors in diabetic nephropathy. Clin. Sci. (Lond.) 126 (2014), 685–694.
373. Verzola, D., Cappuccino, L., D'Amato, E., Villaggio, B., Gianiorio, F., Mij, M., Simonato, A., Viazzi, F., Salvidio, G., Garibotto, G., Enhanced glomerular toll-like receptor 4 expression and signaling in patients with type 2 diabetic nephropathy and microalbuminuria. Kidney Int. 86 (2014), 1229–1243.
374. Chow, F., Ozols, E., Nikolic-Paterson, D.J., Atkins, R.C., Tesch, G.H., Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury. Kidney Int. 65 (2004), 116–128.
375. Jialal, I., Major, A.M., Devaraj, S., Global toll-like receptor 4 knockout results in decreased renal inflammation, fibrosis and podocytopathy. J. Diabetes Complicat. 28 (2014), 755–761.
376. Devaraj, S., Tobias, P., Kasinath, B.S., Ramsamooj, R., Afify, A., Jialal, I., Knockout of toll-like receptor-2 attenuates both the proinflammatory state of diabetes and incipient diabetic nephropathy. Arterioscler. Thromb. Vasc. Biol. 31 (2011), 1796–1804.
377. Mudaliar, H., Pollock, C., Komala, M.G., Chadban, S., Wu, H., Panchapakesan, U., The role of toll-like receptor proteins (TLR) 2 and 4 in mediating inflammation in proximal tubules. Am. J. Physiol. Ren. Physiol. 305 (2013), F143–F154.
378. Lin, M., Yiu, W.H., Wu, H.J., Chan, L.Y., Leung, J.C., Au, W.S., Chan, K.W., Lai, K.N., Tang, S.C., Toll-like receptor 4 promotes tubular inflammation in diabetic nephropathy. J. Am. Soc. Nephrol. 23 (2012), 86–102.
379. Anders, H.J., Schlondorff, D., Toll-like receptors: emerging concepts in kidney disease. Curr. Opin. Nephrol. Hypertens. 16 (2007), 177–183.
380. Kaur, H., Chien, A., Jialal, I., Hyperglycemia induces toll like receptor 4 expression and activity in mouse mesangial cells: relevance to diabetic nephropathy. Am. J. Physiol. Ren. Physiol. 303 (2012), F1145–F1150.
381. Wu, C., Lv, C., Chen, F., Ma, X., Shao, Y., Wang, Q., The function of miR-199a-5p/klotho regulating TLR4/NF-kappaB p65/NGAL pathways in rat mesangial cells cultured with high glucose and the mechanism. Mol. Cell. Endocrinol. 417 (2015), 84–93.
382. Kuwabara, T., Mori, K., Mukoyama, M., Kasahara, M., Yokoi, H., Saito, Y., Ogawa, Y., Imamaki, H., Kawanishi, T., Ishii, A., Koga, K., Mori, K.P., Kato, Y., Sugawara, A., Nakao, K., Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by toll-like receptor 4 in mice. Diabetologia 55 (2012), 2256–2266.
383. Du, P., Fan, B., Han, H., Zhen, J., Shang, J., Wang, X., Li, X., Shi, W., Tang, W., Bao, C., Wang, Z., Zhang, Y., Zhang, B., Wei, X., Yi, F., NOD2 promotes renal injury by exacerbating inflammation and podocyte insulin resistance in diabetic nephropathy. Kidney Int. 84 (2013), 265–276.
384. Wang, C., Pan, Y., Zhang, Q.Y., Wang, F.M., Kong, L.D., Quercetin and allopurinol ameliorate kidney injury in STZ-treated rats with regulation of renal NLRP3 inflammasome activation and lipid accumulation. PLoS One, 7, 2012, e38285.
385. Chen, K., Zhang, J., Zhang, W., Zhang, J., Yang, J., Li, K., He, Y., ATP-P2X4 signaling mediates NLRP3 inflammasome activation: a novel pathway of diabetic nephropathy. Int. J. Biochem. Cell Biol. 45 (2013), 932–943.
386. Kim, S.M., Lee, S.H., Kim, Y.G., Kim, S.Y., Seo, J.W., Choi, Y.W., Kim, D.J., Jeong, K.H., Lee, T.W., Ihm, C.G., Won, K.Y., Moon, J.Y., Hyperuricemia-induced NLRP3 activation of macrophages contributes to the progression of diabetic nephropathy. Am. J. Physiol. Ren. Physiol. 308 (2015), F993–F1003.
387. Shahzad, K., Bock, F., Dong, W., Wang, H., Kopf, S., Kohli, S., Al-Dabet, M.M., Ranjan, S., Wolter, J., Wacker, C., Biemann, R., Stoyanov, S., Reymann, K., Soderkvist, P., Gross, O., Schwenger, V., Pahernik, S., Nawroth, P.P., Grone, H.J., Madhusudhan, T., Isermann, B., Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy. Kidney Int. 87 (2015), 74–84.
388. Nymark, M., Pussinen, P.J., Tuomainen, A.M., Forsblom, C., Groop, P.H., Lehto, M., FinnDiane Study, G., Serum lipopolysaccharide activity is associated with the progression of kidney disease in finnish patients with type 1 diabetes. Diabetes Care 32 (2009), 1689–1693.
389. Pussinen, P.J., Havulinna, A.S., Lehto, M., Sundvall, J., Salomaa, V., Endotoxemia is associated with an increased risk of incident diabetes. Diabetes Care 34 (2011), 392–397.
390. Verzola, D., Gandolfo, M.T., Ferrario, F., Rastaldi, M.P., Villaggio, B., Gianiorio, F., Giannoni, M., Rimoldi, L., Lauria, F., Miji, M., Deferrari, G., Garibotto, G., Apoptosis in the kidneys of patients with type II diabetic nephropathy. Kidney Int. 72 (2007), 1262–1272.
391. Verzola, D., Gandolfo, M.T., Gaetani, G., Ferraris, A., Mangerini, R., Ferrario, F., Villaggio, B., Gianiorio, F., Tosetti, F., Weiss, U., Traverso, P., Mji, M., Deferrari, G., Garibotto, G., Accelerated senescence in the kidneys of patients with type 2 diabetic nephropathy. Am. J. Physiol. Ren. Physiol. 295 (2008), F1563–F1573.
392. Verzola, D., Bertolotto, M.B., Villaggio, B., Ottonello, L., Dallegri, F., Salvatore, F., Berruti, V., Gandolfo, M.T., Garibotto, G., Deferrari, G., Oxidative stress mediates apoptotic changes induced by hyperglycemia in human tubular kidney cells. J. Am. Soc. Nephrol. 15:Suppl. 1 (2004), S85–S87.
393. Ding, G., Franki, N., Kapasi, A.A., Reddy, K., Gibbons, N., Singhal, P.C., Tubular cell senescence and expression of TGF-beta1 and p21(WAF1/CIP1) in tubulointerstitial fibrosis of aging rats. Exp. Mol. Pathol. 70 (2001), 43–53.
394. Melk, A., Schmidt, B.M., Takeuchi, O., Sawitzki, B., Rayner, D.C., Halloran, P.F., Expression of p16INK4a and other cell cycle regulator and senescence associated genes in aging human kidney. Kidney Int. 65 (2004), 510–520.
395. Ma, J., Rubin, B.K., Voynow, J.A., Mucins, mucus, and goblet cells. Chest 154 (2017), 169–176.
396. Roper, J., Yilmaz, O.H., Metabolic teamwork in the stem cell niche. Cell Metab. 25 (2017), 993–994.
397. Gerbe, F., Sidot, E., Smyth, D.J., Ohmoto, M., Matsumoto, I., Dardalhon, V., Cesses, P., Garnier, L., Pouzolles, M., Brulin, B., Bruschi, M., Harcus, Y., Zimmermann, V.S., Taylor, N., Maizels, R.M., Jay, P., Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature 529 (2016), 226–230.
398. Gribble, F.M., Reimann, F., Enteroendocrine cells: chemosensors in the intestinal epithelium. Annu. Rev. Physiol. 78 (2016), 277–299.
399. Gury-BenAri, M., Thaiss, C.A., Serafini, N., Winter, D.R., Giladi, A., Lara-Astiaso, D., Levy, M., Salame, T.M., Weiner, A., David, E., Shapiro, H., Dori-Bachash, M., Pevsner-Fischer, M., Lorenzo-Vivas, E., Keren-Shaul, H., Paul, F., Harmelin, A., Eberl, G., Itzkovitz, S., Tanay, A., Di Santo, J.P., Elinav, E., Amit, I., The Spectrum and regulatory landscape of intestinal innate lymphoid cells are shaped by the microbiome. Cell 166 (2016), 1231–1246 e1213.
400. Killig, M., Glatzer, T., Romagnani, C., Recognition strategies of group 3 innate lymphoid cells. Front. Immunol., 5, 2014, 142.
401. Brandtzaeg, P., Secretory IgA: designed for anti-microbial defense. Front. Immunol., 4, 2013, 222.
402. Mao, K., Baptista, A.P., Tamoutounour, S., Zhuang, L., Bouladoux, N., Martins, A.J., Huang, Y., Gerner, M.Y., Belkaid, Y., Germain, R.N., Innate and adaptive lymphocytes sequentially shape the gut microbiota and lipid metabolism. Nature 554 (2018), 255–259.
403. Tsiaoussis, G.I., Papaioannou, E.C., Kourea, E.P., Assimakopoulos, S.F., Theocharis, G.I., Petropoulos, M., Theopistos, V.I., Diamantopoulou, G.G., Lygerou, Z., Spiliopoulou, I., Thomopoulos, K.C., Expression of alpha-Defensins, CD20+ B‑lymphocytes, and intraepithelial CD3+ T‑lymphocytes in the intestinal mucosa of patients with liver cirrhosis: emerging mediators of intestinal barrier function. Dig. Dis. Sci., 2018.
404. Ghazarian, L., Caillat-Zucman, S., Houdouin, V., Mucosal-associated invariant T cell interactions with commensal and pathogenic bacteria: potential role in antimicrobial immunity in the child. Front. Immunol., 8, 2017, 1837.
405. Panea, C., Farkas, A.M., Goto, Y., Abdollahi-Roodsaz, S., Lee, C., Koscso, B., Gowda, K., Hohl, T.M., Bogunovic, M., Ivanov, II, intestinal monocyte-derived macrophages control commensal-specific Th17 responses. Cell Rep. 12 (2015), 1314–1324.
406. Sasaki, M., Ogasawara, N., Funaki, Y., Mizuno, M., Iida, A., Goto, C., Koikeda, S., Kasugai, K., Joh, T., Transglucosidase improves the gut microbiota profile of type 2 diabetes mellitus patients: a randomized double-blind, placebo-controlled study. BMC Gastroenterol., 13, 2013, 81.
407. Makivuokko, H., Tiihonen, K., Tynkkynen, S., Paulin, L., Rautonen, N., The effect of age and non-steroidal anti-inflammatory drugs on human intestinal microbiota composition. Br. J. Nutr. 103 (2010), 227–234.
408. Jackson, M.A., Jeffery, I.B., Beaumont, M., Bell, J.T., Clark, A.G., Ley, R.E., O'Toole, P.W., Spector, T.D., Steves, C.J., Signatures of early frailty in the gut microbiota. Genome Med., 8, 2016, 8.
409. Larsen, N., Vogensen, F.K., van den Berg, F.W., Nielsen, D.S., Andreasen, A.S., Pedersen, B.K., Al-Soud, W.A., Sorensen, S.J., Hansen, L.H., Jakobsen, M., Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLoS One, 5, 2010, e9085.
410. van Tongeren, S.P., Slaets, J.P., Harmsen, H.J., Welling, G.W., Fecal microbiota composition and frailty. Appl. Environ. Microbiol. 71 (2005), 6438–6442.
411. Zhang, X., Shen, D., Fang, Z., Jie, Z., Qiu, X., Zhang, C., Chen, Y., Ji, L., Human gut microbiota changes reveal the progression of glucose intolerance. PLoS One, 8, 2013, e71108.
412. Remely, M., Hippe, B., Zanner, J., Aumueller, E., Brath, H., Haslberger, A.G., Gut microbiota of obese, type 2 diabetic individuals is enriched in Faecalibacterium prausnitzii, Akkermansia muciniphila and Peptostreptococcus anaerobius after weight loss. Endocr Metab Immune Disord Drug Targets 16 (2016), 99–106.
413. Park, S.H., Kim, K.A., Ahn, Y.T., Jeong, J.J., Huh, C.S., Kim, D.H., Comparative analysis of gut microbiota in elderly people of urbanized towns and longevity villages. BMC Microbiol., 15, 2015, 49.
414. Pushpanathan, P., Srikanth, P., Seshadri, K.G., Selvarajan, S., Pitani, R.S., Kumar, T.D., Janarthanan, R., Gut microbiota in type 2 diabetes individuals and correlation with monocyte chemoattractant Protein1 and interferon gamma from patients attending a tertiary Care Centre in Chennai, India. Indian J. Endocrinol. Metab. 20 (2016), 523–530.
415. Wu, X., Ma, C., Han, L., Nawaz, M., Gao, F., Zhang, X., Yu, P., Zhao, C., Li, L., Zhou, A., Wang, J., Moore, J.E., Millar, B.C., Xu, J., Molecular characterisation of the faecal microbiota in patients with type II diabetes. Curr. Microbiol. 61 (2010), 69–78.
416. Bartosch, S., Fite, A., Macfarlane, G.T., McMurdo, M.E., Characterization of bacterial communities in feces from healthy elderly volunteers and hospitalized elderly patients by using real-time PCR and effects of antibiotic treatment on the fecal microbiota. Appl. Environ. Microbiol. 70 (2004), 3575–3581.
417. Collado, M.C., Derrien, M., Isolauri, E., de Vos, W.M., Salminen, S., Intestinal integrity and Akkermansia muciniphila, a mucin-degrading member of the intestinal microbiota present in infants, adults, and the elderly. Appl. Environ. Microbiol. 73 (2007), 7767–7770.