Immunometabolism of obesity and diabetes: Microbiota link compartmentalized immunity in the gut to metabolic tissue inflammation

Clinical Science

Volumn 129, Issue 12, 2015, Pages 1083-1096

  McPhee, Joseph B ^a   Schertzer, Jonathan D ^b  

^a RYERSON UNIVERSITY   (Canada)

^b MCMASTER UNIVERSITY   (Canada)

Author keywords

Antibiotics; Glucose; Insulin resistance; Metabolic inflammation; Microbiome

Indexed keywords

ADAPTIVE IMMUNITY; DIABETES MELLITUS; FAECALIBACTERIUM PRAUSNITZII; GLUCOSE HOMEOSTASIS; HUMAN; HYPERGLYCEMIA; IMMUNITY; IMMUNOMETABOLISM; INFLAMMATION; INNATE IMMUNITY; INSULIN RESISTANCE; INTESTINE FLORA; METABOLISM; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PRIORITY JOURNAL; REVIEW; TH17 CELL; TH22 CELL; ANIMAL; BACTERIUM; BLOOD; ENERGY METABOLISM; GLUCOSE BLOOD LEVEL; IMMUNOLOGY; INTESTINE; MICROBIOLOGY; MICROFLORA; MUCOSAL IMMUNITY; SIGNAL TRANSDUCTION;

AUTACOID; GLUCOSE BLOOD LEVEL; INSULIN;

ANIMALS; BACTERIA; BLOOD GLUCOSE; DIABETES MELLITUS, TYPE 2; ENERGY METABOLISM; HUMANS; IMMUNITY, MUCOSAL; INFLAMMATION; INFLAMMATION MEDIATORS; INSULIN; INTESTINES; MICROBIOTA; OBESITY; SIGNAL TRANSDUCTION;

EID: 84952021955     PISSN: 01435221     EISSN: 14708736     Source Type: Journal    
DOI: 10.1042/CS20150431     Document Type: Review

References (119)

1. Abusleme, L., Dupuy, A.K., Dutzan, N., Silva, N., Burleson, J.A., Strausbaugh, L.D., Gamonal, J. and Diaz, P.I. (2013) The subgingival microbiome in health and periodontitis and its relationship with community biomass and inflammation. ISME J. 7, 1016-1025
2. Alekseyenko, A.V., Perez-Perez, G.I., De Souza, A., Strober, B., Gao, Z., Bihan, M., Li, K., Methé, B.A. and Blaser, M.J. (2013) Community differentiation of the cutaneous microbiota in psoriasis. Microbiome 1, 31
3. Ravel, J., Brotman, R.M., Gajer, P., Ma, B., Nandy, M., Fadrosh, D.W., Sakamoto, J., Koenig, S.S., Fu, L., Zhou, X. et al. (2013) Daily temporal dynamics of vaginal microbiota before, during and after episodes of bacterial vaginosis. Microbiome 1, 29
4. Sekirov, I., Tam, N.M., Jogova, M., Robertson, M.L., Li, Y., Lupp, C. and Finlay, B.B. (2008) Antibiotic-induced perturbations of the intestinal microbiota alter host susceptibility to enteric infection. Infect. Immun. 76, 4726-4736
5. Sartor, R.B. (2008) Microbial influences in inflammatory bowel diseases. Gastroenterology 134, 577-594
6. 2-terminal kinase pathways in inflammation and origin of obesity and diabetes. Diabetes 54, S73-S78
7. Fullerton, M.D., Steinberg, G.R. and Schertzer, J.D. (2013) Immunometabolism of AMPK in insulin resistance and atherosclerosis. Mol. Cell. Endocrinol. 366, 224-234
8. Steinberg, G.R. and Schertzer, J.D. (2014) AMPK promotes macrophage fatty acid oxidative metabolism to mitigate inflammation: implications for diabetes and cardiovascular disease. Immunol. Cell Biol. 92, 340-345
9. Ehses, J.A., Lacraz, G., Giroix, M.-H., Schmidlin, F., Coulaud, J., Kassis, N., Irminger, J.-C., Kergoat, M., Portha, B., Homo-Delarche, F. et al. (2009) IL-1 antagonism reduces hyperglycemia and tissue inflammation in the type 2 diabetic GK rat. Proc. Natl. Acad. Sci. U.S.A. 106, 13998-14003
10. Weisberg, S.P., Hunter, D., Huber, R., Lemieux, J., Slaymaker, S., Vaddi, K., Charo, I., Leibel, R.L. and Ferrante, A.W. (2006) CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J. Clin. Invest. 116, 115-124
11. Winer, S., Paltser, S., Chan, G., Tsui, Y., Engleman, H., Winer, E., Dosch, D. and-M., H. (2009) Obesity predisposes to Th17 bias. Eur. J. Immunol. 39, 2629-2635
12. McLaughlin, T., Liu, L.-F., Lamendola, C., Shen, L., Morton, J., Rivas, H., Winer, D., Tolentino, L., Choi, O., Zhang, H. et al. (2014) T cell profile in adipose tissue is associated with insulin resistance and systemic inflammation in humans. Arterioscler. Thromb. Vasc. Biol. 34, 2637-2643
13. Fabbrini, E., Cella, M., McCartney, S.A., Fuchs, A., Abumrad, N.A., Pietka, T.A., Chen, Z., Finck, B.N., Han, D.H., Magkos, F. et al. (2013) Association between specific adipose tissue CD4+ T cell populations and insulin resistance in obese individuals. Gastroenterology 145, 366-374
14. Cipolletta, D. (2014) Adipose tissue-resident regulatory T cells: phenotypic specialization, functions and therapeutic potential. Immunology 142, 517-525
15. Chawla, A., Nguyen, K.D. and Goh, Y.P.S. (2011) Macrophage-mediated inflammation in metabolic disease. Nat. Rev. Immunol. 11, 738-749
16. Wernstedt Asterholm, I., Tao, C., Morley, T.S., Wang, Q.A., Delgado-Lopez, F., Wang, Z.V. and Scherer, P.E. (2014) Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling. Cell Metab. 20, 103-118
17. Round, J.L. and Mazmanian, S.K. (2009) The gut microbiota shapes intestinal immune responses during health and disease. Nat. Rev. Immunol. 9, 313-323
18. Carter, P.B. and Collins, F.M. (1974) The route of enteric infection in normal mice. J. Exp. Med. 139, 1189-1203
19. Collins, F.M. and Carter, P.B. (1978) Growth of salmonellae in orally infected germfree mice. Infect. Immun. 21, 41-47
20. Zachar, Z. and Savage, D.C. (1979) Microbial interference and colonization of the murine gastrointestinal tract by Listeria monocytogenes. Infect. Immun. 23, 168-174
21. Sonnenburg, J.L., Chen, C.T.L. and Gordon, J.I. (2006) Genomic and metabolic studies of the impact of probiotics on a model gut symbiont and host. PLoS Biol. 4, 2213-2226
22. Clevers, H.C. and Bevins, C.L. (2013) Paneth cells: maestros of the small intestinal crypts. Annu. Rev. Physiol. 75, 289-311
23. Pütsep, K., Axelsson, L.G., Boman, A., Midtvedt, T., Normark, S., Boman, H.G. and Andersson, M. (2000) Germ-free and colonized mice generate the same products from enteric prodefensins. J. Biol. Chem. 275, 40478-40482
24. Cash, H.L., Whitham, C.V., Behrendt, C.L. and Hooper, L.V. (2006) Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313, 1126-1130
25. Miki, T., Holsts, O. and Hardt, W.D. (2012) The bactericidal activity of the C-type lectin regIIIβ against gram-negative bacteria involves binding to lipid A. J. Biol. Chem. 287, 34844-34855
26. Peterson, L.W. and Artis, D. (2014) Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat. Rev. Immunol. 14, 141-153
27. Wang, X., Ota, N., Manzanillo, P., Kates, L., Zavala-Solorio, J., Eidenschenk, C., Zhang, J., Lesch, J., Lee, W.P., Ross, J. et al. (2014) Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes. Nature 514, 237-241
28. Korn, L.L., Thomas, H.L., Hubbeling, H.G., Spencer, S.P., Sinha, R., Simkins, H.M.A., Salzman, N.H., Bushman, F.D. and Laufer, T.M. (2014) Conventional CD4+ T cells regulate IL-22-producing intestinal innate lymphoid cells. Mucosal Immunol. 7, 1045-1057
29. Gordon, H.A., Bruckner-Kardoss, E. and Wostmann, B.S. (1966) Aging in germ-free mice: life tables and lesions observed at natural death. J. Gerontol. 21, 380-387
30. Bäckhed, F., Ding, H., Wang, T., Hooper, L.V., Koh, G.Y., Nagy, A., Semenkovich, C.F. and Gordon, J.I. (2004) The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl. Acad. Sci. U.S.A. 101, 15718-15723
31. Ridaura, V.K., Faith, J.J., Rey, F.E., Cheng, J., Duncan, A.E., Kau, A.L., Griffin, N.W., Lombard, V., Henrissat, B., Bain, J.R. et al. (2013) Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341, 1241214
32. Cani, P.D., Amar, J., Iglesias, M.A., Poggi, M., Knauf, C., Bastelica, D., Neyrinck, A.M., Fava, F., Tuohy, K.M., Chabo, C. et al. (2007) Metabolic endotoxemia initiated obesity and insulin resistance. Diabetes 56, 1761-1772
33. Henao-Mejia, J., Elinav, E., Jin, C., Hao, L., Mehal, W.Z., Strowig, T., Thaiss, C.A., Kau, A.L., Eisenbarth, S.C., Jurczak, M.J. et al. (2012) Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179-185
34. Vijay-Kumar, M., Aitken, J.D., Carvalho, F.A., Cullender, T.C., Mwangi, S., Srinivasan, S., Sitaraman, S.V., Knight, R., Ley, R.E. and Gewirtz, A.T. (2010) Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328, 228-231
35. Denou, E., Lolmède, K., Garidou, L., Pomie, C., Chabo, C., Lau, T.C., Fullerton, M.D., Nigro, G., Zakaroff-Girard, A., Luche, E. et al. (2015) Defective NOD 2 peptidoglycan sensing promotes diet-induced inflammation, dysbiosis, and insulin resistance. EMBO Mol. Med. 7, 259-274
36. Shi, H., Kokoeva, M.V., Inouye, K., Tzameli, I., Yin, H. and Flier, J.S. (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J. Clin. Invest. 116, 3015-3025
37. Turnbaugh, P.J., Ley, R.E., Mahowald, M.A., Magrini, V., Mardis, E.R. and Gordon, J.I. (2006) An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027-1031
38. Ley, R.E., Turnbaugh, P.J., Klein, S. and Gordon, J.I. (2006) Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022-1023
39. Le Chatelier, E., Nielsen, T., Qin, J., Prifti, E., Hildebrand, F., Falony, G., Almeida, M., Arumugam, M., Batto, J.-M., Kennedy, S. et al. (2013) Richness of human gut microbiome correlates with metabolic markers. Nature 500, 541-546
40. 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. et al. (2009) A core gut microbiome in obese and lean twins. Nature 457, 480-484
41. Corrodi, P., Wideman, P.A., Sutter, V.L., Drenick, E.J., Passaro, E. and Finegold, S.M. (1978) Bacterial flora of the small bowel before and after bypass procedure for morbid obesity. J. Infect. Dis. 137, 1-6
42. Bjørneklett, A., Viddal, K.O., Midtvedt, T. and Nygaard, K. (1981) Intestinal and gastric bypass: changes in intestinal microecology after surgical treatment of morbid obesity in man. Scand. J. Gastroenterol. 16, 681-687
43. Furet, J.P., Kong, L.C., Tap, J., Poitou, C., Basdevant, A., Bouillot, J.L., Mariat, D., Corthier, G., Doré, J., Henegar, C. et al. (2010) Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers. Diabetes 59, 3049-3057
44. Liou, A.P., Paziuk, M., Luevano, J.-M., Machineni, S., Turnbaugh, P.J. and Kaplan, L.M. (2013) Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity. Sci. Transl. Med. 5, 178ra41
45. 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. et al. (2014) Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559-563
46. Wu, G.D., Chen, J., Hoffmann, C., Bittinger, K., Chen, Y.-Y., Keilbaugh, S.A., Bewtra, M., Knights, D., Walters, W.A., Knight, R. et al. (2011) Linking long-term dietary patterns with gut microbial enterotypes. Science 334, 105-108
47. Cho, I., Yamanishi, S., Cox, L., Methé, B.A., Zavadil, J., Li, K., Gao, Z., Mahana, D., Raju, K., Teitler, I. et al. (2012) Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature 488, 621-626
48. Cox, L.M.M., Yamanishi, S., Sohn, J., Alekseyenko, A.V.V., Leung, J.M.M., Cho, I., Rogers, A.B.B., Kim, S.G.G., Li, H., Gao, Z. et al. (2014) Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell 158, 705-721
49. Hong, C.P., Yang, B.G., Kim, J.-H., Jang, M.S., Lee, E.-J., Jeun, E.J., Kim, C., Seoh, J.-Y. and Jang, M.H. (2013) High fat diet-induced obesity affects CD4+ T cell differentiation in the small intestine (P3176). J. Immunol. 190, 61.13
50. Garidou, L., Pomié, C., Klopp, P., Waget, A., Charpentier, J., Aloulou, M., Giry, A., Serino, M., Stenman, L., Lahtinen, S. et al. (2015) The gut microbiota regulates intestinal CD4 T cells expressing RORγ t and controls metabolic disease. Cell Metab 22, 100-112
51. Luck, H., Tsai, S., Chung, J., Clemente-Casares, X., Ghazarian, M., Revelo, X.S., Lei, H., Luk, C.T., Shi, S.Y., Surendra, A. et al. (2015) Regulation of obesity-related insulin resistance with gut anti-inflammatory agents. Cell Metab. 21, 527-542
52. Monk, J.M., Hou, T.Y., Turk, H.F., Weeks, B., Wu, C., McMurray, D.N. and Chapkin, F.S. (2012) Dietary n-3 polyunsaturated fatty acids (PUFA) decrease obesity-associated Th17 cell-mediated inflammation during colitis. PLoS One. 7, e49739
53. Kim, K.A., Gu, W., Lee, I.A., Joh, E.H. and Kim, D.H. (2012) High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS One. 7, e47713
54. Gagliani, N., Vesely, M.C.A., Iseppon, A., Brockmann, L., Xu, H., Palm, N.W., de Zoete, M.R., Licona-Limón, P., Paiva, R.S., Ching, T. et al. (2015) Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 523, 221-225
55. Vijay-Kumar, M., Aitken, J.J.D., Carvalho, F.A.F.F.A., Cullender, T.C., Mwangi, S., Srinivasan, S., Sitaraman, S.V., Knight, R., Ley, R.E. and Gewirtz, A.T. (2010) Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328, 228-231
56. Caricilli, A.M., Picardi, P.K., de Abreu, L.L., Ueno, M., Prada, P.O., Ropelle, E.R., Hirabara, S.M., Castoldi, Â., Vieira, P., Camara, N.O.S. et al. (2011) Gut microbiota is a key modulator of insulin resistance in TLR 2 knockout mice. PLoS Biol 9, e1001212
57. Chassaing, B., Ley, R.E. and Gewirtz, A.T. (2014) Intestinal epithelial cell Toll-like receptor 5 regulates the intestinal microbiota to prevent low-grade inflammation and metabolic syndrome in mice. Gastroenterology 147, 1363-1377
58. Pekkala, S., Munukka, E., Kong, L., Pöllänen, E., Autio, R., Roos, C., Wiklund, P., Fischer-Posovszky, P., Wabitsch, M., Alen, M. et al. (2015) Toll-like receptor 5 in obesity: the role of gut microbiota and adipose tissue inflammation. Obesity 23, 581-590
59. Chi, W., Dao, D., Lau, T.C., Henriksbo, B.D., Cavallari, J.F., Foley, K.P. and Schertzer, J.D. (2014) Bacterial peptidoglycan stimulates adipocyte lipolysis via NOD1. PLoS One 9, e97675
60. 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. et al. (2013) Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19, 576-585
61. Cuevas-Ramos, G., Petit, G., Marcq, C.R., Boury, I., Oswald, M., Nougayrède, E. and-P., J. (2010) Escherichia coli induces DNA damage in vivo and triggers genomic instability in mammalian cells. Proc. Natl. Acad. Sci. U.S.A. 107, 11537-11542
62. Bercik, P., Verdu, E.F., Foster, J.A., MacRi, J., Potter, M., Huang, X., Malinowski, P., Jackson, W., Blennerhassett, P., Neufeld, K.A. et al. (2010) Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice. Gastroenterology 139, 2102-2112
63. Reimann, H.A. (1965) Microbic phagocytosis by enteric epithelial cells. JAMA 192, 1130-1132
64. Davis, C.P. and Savage, D.C. (1974) Habitat, succession, attachment, and morphology of segmented, filamentous microbes indigenous to the murine gastrointestinal tract. Infect. Immun. 10, 948-956
65. Garland, C.D., Lee, A. and Dickson, M.R. (1982) Segmented filamentous bacteria in the rodent small intestine: their colonization of growing animals and possible role in host resistance to Salmonella. Microb. Ecol. 8, 181-190
66. Umesaki, Y., Setoyama, H., Matsumoto, S., Imaoka, A. and Itoh, K. (1999) Differential roles of segmented filamentous bacteria and clostridia in development of the intestinal immune system. Infect. Immun. 67, 3504-3511
67. Sczesnak, A., Segata, N., Qin, X., Gevers, D., Petrosino, J.F.F., Huttenhower, C., Littman, D.R.R. and Ivanov, I.I.I. (2011) The genome of Th17 cell-inducing segmented filamentous bacteria reveals extensive auxotrophy and adaptations to the intestinal environment. Cell Host Microbe 10, 260-272
68. Prakash, T., Oshima, K., Morita, H., Fukuda, S., Imaoka, A., Kumar, N., Sharma, V.K., Kim, S.-W., Takahashi, M., Saitou, N. et al. (2011) Complete genome sequences of rat and mouse segmented filamentous bacteria, a potent inducer of Th17 cell differentiation. Cell Host Microbe 10, 273-284
69. Thompson, C.L., Vier, R., Mikaelyan, A., Wienemann, T. and Brune, A. (2012) "Candidatus Arthromitus" revised: segmented filamentous bacteria in arthropod guts are members of Lachnospiraceae. Environ. Microbiol. 14, 1454-1465
70. Schnupf, P., Gaboriau-Routhiau, V., Gros, M., Friedman, R., Moya-Nilges, M., Nigro, G., Schnupf, P., Cerf-bensussan, N. and Sansonetti, P.J. (2015) Growth and host interaction of mouse segmented filamentous bacteria in vitro. Nature 520, 99-103
71. 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. et al. (2009) Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485-498
72. Brugman, S., Klatter, F.A., Visser, J.T.J., Wildeboer-Veloo, A.C.M., Harmsen, H.J.M., Rozing, J. and Bos, N.A. (2006) Antibiotic treatment partially protects against type 1 diabetes in the Bio-Breeding diabetes-prone rat: is the gut flora involved in the development of type 1 diabetes? Diabetologia 49, 2105-2108
73. Kriegel, M.A., Sefik, E., Hill, J.A., Wu, H.-J., Benoist, C. and Mathis, D. (2011) Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice. Proc. Natl. Acad. Sci. U.S.A. 108, 11548-11553
74. Hansen, C.H.F., Krych, L., Nielsen, D.S., Vogensen, F.K., Hansen, L.H., Sørensen, S.J., Buschard, K. and Hansen, a K. (2012) Early life treatment with vancomycin propagates Akkermansia muciniphila and reduces diabetes incidence in the NOD mouse. Diabetologia 55, 2285-2294
75. Ivanov, I.I., Frutos, R.D.L., Manel, N., Yoshinaga, K., Rifkin, D.B., Sartor, R.B., Finlay, B.B. and Littman, D.R. (2008) Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 4, 337-349
76. Ota, N., Wong, K., Valdez, P.A., Zheng, Y., Crellin, N.K., Diehl, L. and Ouyang, W. (2011) IL-22 bridges the lymphotoxin pathway with the maintenance of colonic lymphoid structures during infection with Citrobacter rodentium. Nat. Immunol. 12, 941-948
77. Yin, Y., Wang, Y., Zhu, L., Liu, W., Liao, N., Jiang, M., Zhu, B., Yu, H.D., Xiang, C. and Wang, X. (2013) Comparative analysis of the distribution of segmented filamentous bacteria in humans, mice and chickens. ISME J 7, 615-621
78. Ivanov, I.I. and Littman, D.R. (2010) Segmented filamentous bacteria take the stage. Mucosal Immunol. 3, 209-212
79. Harley, I.T.W., Giles, D.A., Pfluger, P.T., Burgess, S.L., Walters, S., Hembree, J., Raver, C., Rewerts, C.L., Downey, J., Flick, L.M. et al. (2013) Differential colonization with segmented filamentous bacteria and Lactobacillus murinus do not drive divergent development of diet-induced obesity in C57BL/6 mice. Mol. Metab. 2, 171-183
80. Upadhyay, V., Poroyko, V., Kim, T., Devkota, S., Fu, S., Liu, D., Tumanov, A.V., Koroleva, E.P., Deng, L., Nagler, C. et al. (2012) Lymphotoxin regulates commensal responses to enable diet-induced obesity. Nat. Immunol. 13, 947-953
81. Ostman, S., Rask, C., Wold, A.E., Hultkrantz, S. and Telemo, E. (2006) Impaired regulatory T cell function in germ-free mice. Eur. J. Immunol. 36, 2336-2346
82. Faith, J.J., Ahern, P.P., Ridaura, V.K., Cheng, J. and Gordon, J.I. (2014) Identifying gut microbe-host phenotype relationships using combinatorial communities in gnotobiotic mice. Sci. Transl. Med. 6, 220ra11
83. reg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500, 232-236
84. Odegaard, J.I., Ricardo-Gonzalez, R.R., Eagle, A.R., Vats, D., Morel, C.R., Goforth, M.H., Subramanian, V., Mukundan, L., Ferrante, A.W. and Chawla, A. (2008) Alternative (M2) activation of Kupffer cells by PPARδ ameliorates obesity-induced insulin resistance. Cell Metab 7, 496-507
85. Kang, K., Reilly, K., Karabacak, S.M., Gangl, V., Fitzgerald, M.R., Hatano, K., Lee, B. and-H., C. (2008) Adipocyte-derived Th2 cytokines and myeloid PPARδ regulate macrophage polarization and insulin sensitivity. Cell Metab 7, 485-495
86. Sokol, H., Pigneur, B., Watterlot, L., Lakhdari, O., Bermúdez-Humarán, L.G., Gratadoux, J.-J., Blugeon, S., Bridonneau, C., Furet, J.-P., Corthier, G. et al. (2008) Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc. Natl. Acad. Sci. U.S.A. 105, 16731-16736
87. Zhang, M., Qiu, X., Zhang, H., Yang, X., Hong, N., Yang, Y., Chen, H. and Yu, C. (2014) Faecalibacterium prausnitzii inhibits interleukin-17 to ameliorate colorectal colitis in rats. PLoS One 9, e109146
88. Qiu, X., Zhang, M., Yang, X., Hong, N. and Yu, C. (2013) Faecalibacterium prausnitzii upregulates regulatory T cells and anti-inflammatory cytokines in treating TNBS-induced colitis. J. Crohns Colitis 7, e558-e568
89. Hua, Y., Shen, J., Song, Y., Xing, Y. and Ye, X. (2013) Interleukin-10-592C/A, -819C/T and-1082A/G polymorphisms with risk of Type 2 diabetes mellitus: a HuGE review and meta-analysis. PLoS One 8, e66568
90. Saxena, M., Srivastava, N. and Banerjee, M. (2013) Association of IL-6, TNF-α and IL-10 gene polymorphisms with type 2 diabetes mellitus. Mol. Biol. Rep. 40, 6271-6279
91. Bai, H., Jing, D., Guo, A. and Yin, S. (2014) Association between interleukin 10 gene polymorphisms and risk of type 2 diabetes mellitus in a Chinese population. J. Int. Med. Res. 42, 702-710
92. Quevrain, E., Maubert, M.A., Michon, C., Chain, F., Marquant, R., Tailhades, J., Miquel, S., Carlier, L., Bermudez-Humaran, L.G., Pigneur, B. et al. (2015) Identification of an anti-inflammatory protein from Faecalibacterium prausnitzii, a commensal bacterium deficient in Crohn's disease. Gut
93. Qin, J., Li, Y., Cai, Z., Li, S., Zhu, J., Zhang, F., Liang, S., Zhang, W., Guan, Y., Shen, D. et al. (2012) A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55-60
94. Karlsson, F.H., Tremaroli, V., Nookaew, I., Bergström, G., Behre, C.J., Fagerberg, B., Nielsen, J. and Bäckhed, F. (2013) Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 498, 99-103
95. Vrieze, A., Van Nood, E., Holleman, F., Salojärvi, J., Kootte, R.S., Bartelsman, J.F.W.M., Dallinga-Thie, G.M., Ackermans, M.T., Serlie, M.J., Oozeer, R. et al. (2012) Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 143, 913-916
96. Koren, O., Goodrich, J.K., Cullender, T.C., Spor, A., Laitinen, K., Bäckhed, H.K., Gonzalez, A., Werner, J.J., Angenent, L.T., Knight, R. et al. (2012) Host remodeling of the gut microbiome and metabolic changes during pregnancy. Cell 150, 470-480
97. Lin, H.V., Frassetto, A., Kowalik, E.J., Nawrocki, A.R., Lu, M.M., Kosinski, J.R., Hubert, J.A., Szeto, D., Yao, X., Forrest, G. et al. (2012) Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms. PLoS One. 7, 1-9
98. McGuckin, M.A., Lindén, S.K., Sutton, P. and Florin, T.H. (2011) Mucin dynamics and enteric pathogens. Nat. Rev. Microbiol. 9, 265-278
99. Derrien, M., Vaughan, E.E., Plugge, C.M. and de Vos, W.M. (2004) Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. Int. J. Syst. Evol. Microbiol. 54, 1469-1476
100. Reunanen, J., Kainulainen, V., Huuskonen, L., Ottman, N., Belzer, C., Huhtinen, H., de Vos, W.M. and Satokari, R. (2015) Akkermansia muciniphila adheres to enterocytes and strengthens the integrity of epithelial cell layer. Appl. Environ. Microbiol. 81, 3655-3662
101. Van Passel, M.W.J., Kant, R., Zoetendal, E.G., Plugge, C.M., Derrien, M., Malfatti, S.A., Chain, P.S.G., Woyke, T., Palva, A., de Vos, W.M. et al. (2011) The genome of Akkermansia muciniphila, a dedicated intestinal mucin degrader, and its use in exploring intestinal metagenomes. PLoS One 6, e16876
102. Shin, N.-R., Lee, J.-C., Lee, H.-Y., Kim, M.-S., Whon, T.W., Lee, M.-S. and Bae, J.-W. (2014) An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 63, 727-735
103. Everard, A., Belzer, C., Geurts, L., Ouwerkerk, J.P., Druart, C., Bindels, L.B., Guiot, Y., Derrien, M., Muccioli, G.G., Delzenne, N.M. et al. (2013) Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc. Natl. Acad. Sci. U.S.A. 110, 9066-9071
104. Karlsson, C.L.J., Önnerfält, J., Xu, J., Molin, G., Ahrné, S. and Thorngren-Jerneck, K. (2012) The microbiota of the gut in preschool children with normal and excessive body weight. Obesity 20, 2257-2261
105. Ellekilde, M., Krych, L., Hansen, C.H.F., Hufeldt, M.R., Dahl, K., Hansen, L.H., Sørensen, S.J., Vogensen, F.K., Nielsen, D.S. and Hansen, A.K. (2014) Characterization of the gut microbiota in leptin deficient obese mice: correlation to inflammatory and diabetic parameters. Res. Vet. Sci. 96, 241-250
106. Everard, A., Lazarevic, V., Derrien, M., Girard, M., Muccioli, G.M., Neyrinck, A.M., Possemiers, S., Van Holle, A., François, P., De Vos, W.M. et al. (2011) Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice. Diabetes 60, 2775-2786
107. Anhê, F.F., Roy, D., Pilon, G., Dudonné, S., Matamoros, S., Varin, T.V., Garofalo, C., Moine, Q., Desjardins, Y., Levy, E. et al. (2014) A polyphenol-rich cranberry extract protects from diet-induced obesity, insulin resistance and intestinal inflammation in association with increased Akkermansia spp. population in the gut microbiota of mice. Gut 64, 872-883
108. Derrien, M., Van Baarlen, P., Hooiveld, G., Norin, E., Müller, M. and de Vos, W.M. (2011) Modulation of mucosal immune response, tolerance, and proliferation in mice colonized by the mucin-degrader Akkermansia muciniphila. Front. Microbiol. 2, 1-14
109. Stienstra, R., Mandard, S., Patsouris, D., Maass, C., Kersten, S. and Müller, M. (2007) Peroxisome proliferator-activated receptor a protects against obesity-induced hepatic inflammation. Endocrinology 148, 2753-2763
110. Guerre-Millo, M., Gervois, M., Raspé, P., Madsen, E., Poulain, L., Derudas, P., Herbert, B., -M., J., Winegar, J., Willson, D.A., Fruchart, T.M., -C., J. et al. (2000) Peroxisome proliferator-activated receptor α activators improve insulin sensitivity and reduce adiposity. J. Biol. Chem. 275, 16638-16642
111. Lukovac, S., Belzer, C., Pellis, L., Keijser, B.J., de Vos, W.M., Montijn, R.C. and Roeselers, G. (2014) Differential modulation by Akkermansia muciniphila and Faecalibacterium prausnitzii of host peripheral lipid metabolism and histone acetylation in mouse gut organoids. MBio 5, e01438-14
112. Maslowski, K.M., Vieira, A.T., Ng, A., Kranich, J., Sierro, F., Yu, D., Schilter, H.C., Rolph, M.S., Mackay, F., Artis, D. et al. (2009) Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461, 1282-1286
113. Alex, S., Lange, K., Amolo, T., Grinstead, J.S., Haakonsson, A.K., Szalowska, E., Koppen, A., Mudde, K., Haenen, D., Al-Lahham, S. et al. (2013) Short-chain fatty acids stimulate angiopoietin-like 4 synthesis in human colon adenocarcinoma cells by activating peroxisome proliferator-activated receptor γ. Mol. Cell. Biol. 33, 1303-1316
114. Wen, L., Ley, R.E., Volchkov, P.Y., Stranges, P.B., Avanesyan, L., Stonebraker, A.C., Hu, C., Wong, F.S., Szot, G.L., Bluestone, J.A. et al. (2008) Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature 455, 1109-1113
115. King, C. and Sarvetnick, N. (2011) The incidence of type-1 diabetes in NOD mice is modulated by restricted flora not germ-free conditions. PLoS One 6, e17049
116. Mattila, E., Uusitalo-Seppälä, R., Wuorela, M., Lehtola, L., Nurmi, H., Ristikankare, M., Moilanen, V., Salminen, K., Seppälä, M., Mattila, P.S. et al. (2012) Fecal transplantation, through colonoscopy, is effective therapy for recurrent Clostridium difficile infection. Gastroenterology 142, 490-496
117. Ahern, P.P., Faith, J.J. and Gordon, J.I. (2014) Mining the human gut microbiota for effector strains that shape the immune system. Immunity 40, 815-823
118. Bermúdez-Humarán, L.G., Nouaille, S., Zilberfarb, V., Corthier, G., Gruss, A., Langella, P. and Issad, T. (2007) Effects of intranasal administration of a leptin-secreting Lactococcus lactis recombinant on food intake, body weight, and immune response of mice. Appl. Environ. Microbiol. 73, 5300-5307
119. Amar, J., Chabo, C., Waget, A., Klopp, P., Vachoux, C., Bermúdez-Humarán, L.G., Smirnova, N., Bergé, M., Sulpice, T., Lahtinen, S. et al. (2011) Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: molecular mechanisms and probiotic treatment. EMBO Mol. Med. 3, 559-572