Sex Effects at the Ramparts: Nutrient- and Microbe-Mediated Regulation of the Immune-Metabolic Interface

  • Nyrie Israelian
  • Jayne S. Danska
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1043)


The relationships between dietary compounds, derivative metabolites, and host metabolism and immunity are controlled by diverse molecular mechanisms. Essential contributions to these dynamics come from the community of microbes (the microbiome) inhabiting the human digestive tract. The composition and function of the microbiome are shaped by available nutrients, and reciprocally, these organisms produce an as yet poorly defined repertoire of molecules that communicate with the epithelial barrier and the mucosal immune system. We present evidence that diet-derived vitamins and lipids regulate immunity and metabolic function and highlight the diverse mechanisms through which these effects are impacted by sex. We discuss exciting new data emerging from studies using high-throughput sequencing technology, specialized mouse models, and bio-specimens, and clinical data from human subjects that have begun to reveal the complexity of these interactions. Also profiled in this chapter are the striking sex differences in pathways by which dietary nutrients and gut microbes modify metabolism, immunity, and immune- and inflammation-mediated diseases. Although the incidence, severity, and therapeutic responses of many autoimmune diseases differ by sex, the molecular mechanisms of these effects remain poorly understood.


  1. Abou-Raya, A., Abou-Raya, S., & Helmii, M. (2013). The effect of vitamin D supplementation on inflammatory and hemostatic markers and disease activity in patients with systemic lupus erythematosus: a randomized placebo-controlled trial. The Journal of Rheumatology, 40, 265–272.CrossRefPubMedGoogle Scholar
  2. Adorini, L. (2002). Immunomodulatory effects of vitamin D receptor ligands in autoimmune diseases. International Immunopharmacology, 2, 1017–1028.CrossRefPubMedGoogle Scholar
  3. Adorini, L., & Penna, G. (2008). Control of autoimmune diseases by the vitamin D endocrine system. Nature Clinical Practice. Rheumatology, 4, 404–412.CrossRefPubMedGoogle Scholar
  4. Ahmadian, M., Suh, J. M., Hah, N., Liddle, C., Atkins, A. R., Downes, M., & Evans, R. M. (2013). PPARgamma signaling and metabolism: The good, the bad and the future. Nature Medicine, 19, 557–566.CrossRefPubMedGoogle Scholar
  5. Alharbi, F. M. (2015). Update in vitamin D and multiple sclerosis. Neurosciences (Riyadh), 20, 329–335.CrossRefGoogle Scholar
  6. Allie, S. R., Zhang, W., Tsai, C. Y., Noelle, R. J., & Usherwood, E. J. (2013). Critical role for all-trans retinoic acid for optimal effector and effector memory CD8 T cell differentiation. Journal of Immunology, 190, 2178–2187.CrossRefGoogle Scholar
  7. Amisten, S., Mohammad Al-Amily, I., Soni, A., Hawkes, R., Atanes, P., Persaud, S. J., Rorsman, P., & Salehi, A. (2017). Anti-diabetic action of all-trans retinoic acid and the orphan G protein coupled receptor GPRC5C in pancreatic beta-cells. Endocrine Journal, 64, 325–338.CrossRefPubMedGoogle Scholar
  8. Assa, A., Vong, L., Pinnell, L. J., Avitzur, N., Johnson-Henry, K. C., & Sherman, P. M. (2014). Vitamin D deficiency promotes epithelial barrier dysfunction and intestinal inflammation. The Journal of Infectious Diseases, 210, 1296–1305.CrossRefPubMedGoogle Scholar
  9. Azuma, Y. T., Nishiyama, K., Matsuo, Y., Kuwamura, M., Morioka, A., Nakajima, H., & Takeuchi, T. (2010). PPARalpha contributes to colonic protection in mice with DSS-induced colitis. International Immunopharmacology, 10, 1261–1267.CrossRefPubMedGoogle Scholar
  10. Backhed, F., Manchester, J. K., Semenkovich, C. F., & Gordon, J. I. (2007). Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proceedings of the National Academy of Sciences of the United States of America, 104, 979–984.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Bakdash, G., Vogelpoel, L. T., van Capel, T. M., Kapsenberg, M. L., & de Jong, E. C. (2015). Retinoic acid primes human dendritic cells to induce gut-homing, IL-10-producing regulatory T cells. Mucosal Immunology, 8, 265–278.CrossRefPubMedGoogle Scholar
  12. Barbachano, A., Fernandez-Barral, A., Ferrer-Mayorga, G., Costales-Carrera, A., Larriba, M. J., & Munoz, A. (2017). The endocrine vitamin D system in the gut. Molecular and Cellular Endocrinology, 453, 79–87.CrossRefPubMedGoogle Scholar
  13. Bashir, M., Prietl, B., Tauschmann, M., Mautner, S. I., Kump, P. K., Treiber, G., Wurm, P., Gorkiewicz, G., Hogenauer, C., & Pieber, T. R. (2016). Effects of high doses of vitamin D3 on mucosa-associated gut microbiome vary between regions of the human gastrointestinal tract. European Journal of Nutrition, 55, 1479–1489.CrossRefPubMedGoogle Scholar
  14. Bebo, B. F., Jr., Zelinka-Vincent, E., Adamus, G., Amundson, D., Vandenbark, A. A., & Offner, H. (1998). Gonadal hormones influence the immune response to PLP 139-151 and the clinical course of relapsing experimental autoimmune encephalomyelitis. Journal of Neuroimmunology, 84, 122–130.CrossRefPubMedGoogle Scholar
  15. Belkaid, Y., & Hand, T. W. (2014). Role of the microbiota in immunity and inflammation. Cell, 157, 121–141.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Bensinger, S. J., Bradley, M. N., Joseph, S. B., Zelcer, N., Janssen, E. M., Hausner, M. A., Shih, R., Parks, J. S., Edwards, P. A., Jamieson, B. D., & Tontonoz, P. (2008). LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell, 134, 97–111.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Bergstrom, K. S., Kissoon-Singh, V., Gibson, D. L., Ma, C., Montero, M., Sham, H. P., Ryz, N., Huang, T., Velcich, A., Finlay, B. B., Chadee, K., & Vallance, B. A. (2010). Muc2 protects against lethal infectious colitis by disassociating pathogenic and commensal bacteria from the colonic mucosa. PLoS Pathogens, 6, e1000902.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Blanton, L. V., Charbonneau, M. R., Salih, T., Barratt, M. J., Venkatesh, S., Ilkaveya, O., Subramanian, S., Manary, M. J., Trehan, I., Jorgensen, J. M., Fan, Y. M., Henrissat, B., Leyn, S. A., Rodionov, D. A., Osterman, A. L., Maleta, K. M., Newgard, C. B., Ashorn, P., Dewey, K. G., & Gordon, J. I. (2016). Gut bacteria that prevent growth impairments transmitted by microbiota from malnourished children. Science, 351, aad3311.CrossRefPubMedGoogle Scholar
  19. Bogdanou, D., Penna-Martinez, M., Filmann, N., Chung, T. L., Moran-Auth, Y., Wehrle, J., Cappel, C., Huenecke, S., Herrmann, E., Koehl, U., & Badenhoop, K. (2017). T-lymphocyte and glycemic status after vitamin D treatment in type 1 diabetes: A randomized controlled trial with sequential crossover. Diabetes/Metabolism Research and Reviews, 33, e2865.Google Scholar
  20. Bollrath, J., & Powrie, F. M. (2013). Controlling the frontier: Regulatory T-cells and intestinal homeostasis. Seminars in Immunology, 25, 352–357.CrossRefPubMedGoogle Scholar
  21. Bono, M. R., Tejon, G., Flores-Santibanez, F., Fernandez, D., Rosemblatt, M., & Sauma, D. (2016). Retinoic acid as a modulator of T cell immunity. Nutrients, 8, 349.CrossRefPubMedCentralGoogle Scholar
  22. Borba, V. Z., Vieira, J. G., Kasamatsu, T., Radominski, S. C., Sato, E. I., & Lazaretti-Castro, M. (2009). Vitamin D deficiency in patients with active systemic lupus erythematosus. Osteoporosis International, 20, 427–433.CrossRefPubMedGoogle Scholar
  23. Boucher, B. J. (2011). Vitamin D insufficiency and diabetes risks. Current Drug Targets, 12, 61–87.CrossRefPubMedGoogle Scholar
  24. Brucklacher-Waldert, V., Carr, E. J., Linterman, M. A., & Veldhoen, M. (2014). Cellular plasticity of CD4+ T cells in the intestine. Frontiers in Immunology, 5, 488.CrossRefPubMedPubMedCentralGoogle Scholar
  25. Buckley, J. D., & Howe, P. R. (2009). Anti-obesity effects of long-chain omega-3 polyunsaturated fatty acids. Obesity Reviews, 10, 648–659.CrossRefPubMedGoogle Scholar
  26. Caesar, R., Reigstad, C. S., Backhed, H. K., Reinhardt, C., Ketonen, M., Lunden, G. O., Cani, P. D., & Backhed, F. (2012). Gut-derived lipopolysaccharide augments adipose macrophage accumulation but is not essential for impaired glucose or insulin tolerance in mice. Gut, 61, 1701–1707.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Caesar, R., Tremaroli, V., Kovatcheva-Datchary, P., Cani, P. D., & Backhed, F. (2015). Crosstalk between gut microbiota and dietary lipids aggravates WAT inflammation through TLR signaling. Cell Metabolism, 22, 658–668.CrossRefPubMedPubMedCentralGoogle Scholar
  28. Calder, P. C. (2006). n-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. The American Journal of Clinical Nutrition, 83, 1505S–1519S.CrossRefPubMedGoogle Scholar
  29. Cani, P. D., Bibiloni, R., Knauf, C., Waget, A., Neyrinck, A. M., Delzenne, N. M., & Burcelin, R. (2008). Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes, 57, 1470–1481.CrossRefPubMedGoogle Scholar
  30. Cantarel, B. L., Waubant, E., Chehoud, C., Kuczynski, J., Desantis, T. Z., Warrington, J., Venkatesan, A., Fraser, C. M., & Mowry, E. M. (2015). Gut microbiota in multiple sclerosis: Possible influence of immunomodulators. Journal of Investigative Medicine, 63, 729–734.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Caramaschi, P., Dalla Gassa, A., Ruzzenente, O., Volpe, A., Ravagnani, V., Tinazzi, I., Barausse, G., Bambara, L. M., & Biasi, D. (2010). Very low levels of vitamin D in systemic sclerosis patients. Clinical Rheumatology, 29, 1419–1425.CrossRefPubMedGoogle Scholar
  32. Case, L. K., Wall, E. H., Dragon, J. A., Saligrama, N., Krementsov, D. N., Moussawi, M., Zachary, J. F., Huber, S. A., Blankenhorn, E. P., & Teuscher, C. (2013). The Y chromosome as a regulatory element shaping immune cell transcriptomes and susceptibility to autoimmune disease. Genome Research, 23, 1474–1485.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Chambers, E. S., & Hawrylowicz, C. M. (2011). The impact of vitamin D on regulatory T cells. Current Allergy and Asthma Reports, 11, 29–36.CrossRefPubMedGoogle Scholar
  34. Chen, T., Tibbitt, C. A., Feng, X., Stark, J. M., Rohrbeck, L., Rausch, L., Sedimbi, S. K., Karlsson, M. C. I., Lambrecht, B. N., Karlsson Hedestam, G. B., Hendriks, R. W., Chambers, B. J., Nylen, S., & Coquet, J. M. (2017). PPAR-gamma promotes type 2 immune responses in allergy and nematode infection. Sci Immunol, 2, eaal5196.CrossRefPubMedGoogle Scholar
  35. Chien, C. Y., Yuan, T. A., Cho, C. H., Chang, F. P., Mao, W. Y., Wu, R. R., Lee, H. S., & Shen, C. N. (2016). All-trans retinoic acid ameliorates glycemic control in diabetic mice via modulating pancreatic islet production of vascular endothelial growth factor-A. Biochemical and Biophysical Research Communications, 477, 874–880.CrossRefPubMedGoogle Scholar
  36. Chinetti-Gbaguidi, G., & Staels, B. (2017). PPARbeta in macrophages and atherosclerosis. Biochimie, 136, 59–64.CrossRefPubMedGoogle Scholar
  37. Christian, P., West, K. P., Jr., Khatry, S. K., Leclerq, S. C., Kimbrough-Pradhan, E., Katz, J., & Shrestha, S. R. (2001). Maternal night blindness increases risk of mortality in the first 6 months of life among infants in Nepal. The Journal of Nutrition, 131, 1510–1512.CrossRefPubMedGoogle Scholar
  38. Cipolletta, D., Feuerer, M., Li, A., Kamei, N., Lee, J., Shoelson, S. E., Benoist, C., & Mathis, D. (2012). PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature, 486, 549–553.CrossRefPubMedPubMedCentralGoogle Scholar
  39. Clark, A., & Mach, N. (2016). Role of vitamin D in the hygiene hypothesis: The interplay between vitamin D, vitamin D receptors, gut microbiota, and immune response. Frontiers in Immunology, 7, 627.CrossRefPubMedPubMedCentralGoogle Scholar
  40. Clark, R. B., Bishop-Bailey, D., Estrada-Hernandez, T., Hla, T., Puddington, L., & Padula, S. J. (2000). The nuclear receptor PPAR gamma and immunoregulation: PPAR gamma mediates inhibition of helper T cell responses. Journal of Immunology, 164, 1364–1371.CrossRefGoogle Scholar
  41. Coombes, J. L., Siddiqui, K. R., Arancibia-Carcamo, C. V., Hall, J., Sun, C. M., Belkaid, Y., & Powrie, F. (2007). A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. The Journal of Experimental Medicine, 204, 1757–1764.CrossRefPubMedPubMedCentralGoogle Scholar
  42. Cui, G., Qin, X., Wu, L., Zhang, Y., Sheng, X., Yu, Q., Sheng, H., Xi, B., Zhang, J. Z., & Zang, Y. Q. (2011). Liver X receptor (LXR) mediates negative regulation of mouse and human Th17 differentiation. The Journal of Clinical Investigation, 121, 658–670.CrossRefPubMedPubMedCentralGoogle Scholar
  43. Cutolo, M. (2013). Further emergent evidence for the vitamin D endocrine system involvement in autoimmune rheumatic disease risk and prognosis. Annals of the Rheumatic Diseases, 72, 473–475.CrossRefPubMedGoogle Scholar
  44. Czarnewski, P., Das, S., Parigi, S. M., & Villablanca, E. J. (2017). Retinoic acid and its role in modulating intestinal innate immunity. Nutrients, 9, 68.CrossRefPubMedCentralGoogle Scholar
  45. D’aquila, T., Hung, Y. H., Carreiro, A., & Buhman, K. K. (2016). Recent discoveries on absorption of dietary fat: Presence, synthesis, and metabolism of cytoplasmic lipid droplets within enterocytes. Biochimica et Biophysica Acta, 1861, 730–747.CrossRefPubMedPubMedCentralGoogle Scholar
  46. Dakshinamurti, K. (2015). Vitamins and their derivatives in the prevention and treatment of metabolic syndrome diseases (diabetes). Canadian Journal of Physiology and Pharmacology, 93, 355–362.CrossRefPubMedGoogle Scholar
  47. Dankers, W., Colin, E. M., van Hamburg, J. P., & Lubberts, E. (2016). Vitamin D in autoimmunity: Molecular mechanisms and therapeutic potential. Frontiers in Immunology, 7, 697.PubMedGoogle Scholar
  48. Dimitrov, V., & White, J. H. (2017). Vitamin D signaling in intestinal innate immunity and homeostasis. Molecular and Cellular Endocrinology, 453, 68–78.CrossRefPubMedGoogle Scholar
  49. Ding, S., Chi, M. M., Scull, B. P., Rigby, R., Schwerbrock, N. M., Magness, S., Jobin, C., & Lund, P. K. (2010). High-fat diet: Bacteria interactions promote intestinal inflammation which precedes and correlates with obesity and insulin resistance in mouse. PLoS One, 5, e12191.CrossRefPubMedPubMedCentralGoogle Scholar
  50. Dominianni, C., Sinha, R., Goedert, J. J., Pei, Z., Yang, L., Hayes, R. B., & Ahn, J. (2015). Sex, body mass index, and dietary fiber intake influence the human gut microbiome. PLoS One, 10, e0124599.CrossRefPubMedPubMedCentralGoogle Scholar
  51. Dorak, M. T., & Karpuzoglu, E. (2012). Gender differences in cancer susceptibility: An inadequately addressed issue. Frontiers in Genetics, 3, 268.CrossRefPubMedPubMedCentralGoogle Scholar
  52. Dubrac, S., Elentner, A., Schoonjans, K., Auwerx, J., & Schmuth, M. (2011). Lack of IL-2 in PPAR-alpha-deficient mice triggers allergic contact dermatitis by affecting regulatory T cells. European Journal of Immunology, 41, 1980–1991.CrossRefPubMedGoogle Scholar
  53. Duester, G. (2008). Retinoic acid synthesis and signaling during early organogenesis. Cell, 134, 921–931.CrossRefPubMedPubMedCentralGoogle Scholar
  54. Dunn, S. E., Ousman, S. S., Sobel, R. A., Zuniga, L., Baranzini, S. E., Youssef, S., Crowell, A., Loh, J., Oksenberg, J., & Steinman, L. (2007). Peroxisome proliferator-activated receptor (PPAR)alpha expression in T cells mediates gender differences in development of T cell-mediated autoimmunity. The Journal of Experimental Medicine, 204, 321–330.CrossRefPubMedPubMedCentralGoogle Scholar
  55. Durmus, B., Altay, Z., Baysal, O., & Ersoy, Y. (2012). Does vitamin D affect disease severity in patients with ankylosing spondylitis? Chinese Medical Journal, 125, 2511–2515.PubMedGoogle Scholar
  56. Erten, S., Sahin, A., Altunoglu, A., Gemcioglu, E., & Koca, C. (2015). Comparison of plasma vitamin D levels in patients with Sjogren’s syndrome and healthy subjects. International Journal of Rheumatic Diseases, 18, 70–75.CrossRefPubMedGoogle Scholar
  57. Feskens, E. J., Virtanen, S. M., Rasanen, L., Tuomilehto, J., Stengard, J., Pekkanen, J., Nissinen, A., & Kromhout, D. (1995). Dietary factors determining diabetes and impaired glucose tolerance. A 20-year follow-up of the Finnish and Dutch cohorts of the Seven Countries Study. Diabetes Care, 18, 1104–1112.CrossRefPubMedGoogle Scholar
  58. Flachs, P., Rossmeisl, M., & Kopecky, J. (2014). The effect of n-3 fatty acids on glucose homeostasis and insulin sensitivity. Physiological Research, 63(Suppl 1), S93–118.PubMedGoogle Scholar
  59. Fujimoto, W. Y., Hershon, K., Kinyoun, J., Stolov, W., Weinberg, C., Ishiwata, K., Kajinuma, H., Kanazawa, Y., & Kuzuya, N. (1983). Type II diabetes mellitus in Seattle and Tokyo. The Tohoku Journal of Experimental Medicine, 141(Suppl), 133–139.CrossRefPubMedGoogle Scholar
  60. Garcia-Irigoyen, O., & Moschetta, A. (2017). A novel protective role for FXR against inflammasome activation and endotoxemia. Cell Metabolism, 25, 763–764.CrossRefPubMedGoogle Scholar
  61. Gimeno, R. E. (2007). Fatty acid transport proteins. Current Opinion in Lipidology, 18, 271–276.CrossRefPubMedGoogle Scholar
  62. Giulietti, A., van Etten, E., Overbergh, L., Stoffels, K., Bouillon, R., & Mathieu, C. (2007). Monocytes from type 2 diabetic patients have a pro-inflammatory profile. 1,25-Dihydroxyvitamin D(3) works as anti-inflammatory. Diabetes Research and Clinical Practice, 77, 47–57.CrossRefPubMedGoogle Scholar
  63. Gocke, A. R., Hussain, R. Z., Yang, Y., Peng, H., Weiner, J., Ben, L. H., Drew, P. D., Stuve, O., Lovett-Racke, A. E., & Racke, M. K. (2009). Transcriptional modulation of the immune response by peroxisome proliferator-activated receptor-{alpha} agonists in autoimmune disease. Journal of Immunology, 182, 4479–4487.CrossRefGoogle Scholar
  64. Golden, L. C., & Voskuhl, R. (2017). The importance of studying sex differences in disease: The example of multiple sclerosis. Journal of Neuroscience Research, 95, 633–643.CrossRefPubMedPubMedCentralGoogle Scholar
  65. Gorman, S., Kuritzky, L. A., Judge, M. A., Dixon, K. M., Mcglade, J. P., Mason, R. S., Finlay-Jones, J. J., & Hart, P. H. (2007). Topically applied 1,25-dihydroxyvitamin D3 enhances the suppressive activity of CD4+CD25+ cells in the draining lymph nodes. Journal of Immunology, 179, 6273–6283.CrossRefGoogle Scholar
  66. Gross, B., Pawlak, M., Lefebvre, P., & Staels, B. (2017). PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD. Nature Reviews. Endocrinology, 13, 36–49.CrossRefPubMedGoogle Scholar
  67. Gushchina, L. V., Yasmeen, R., & Ziouzenkova, O. (2013). Moderate vitamin A supplementation in obese mice regulates tissue factor and cytokine production in a sex-specific manner. Archives of Biochemistry and Biophysics, 539, 239–247.CrossRefPubMedGoogle Scholar
  68. Hagenau, T., Vest, R., Gissel, T. N., Poulsen, C. S., Erlandsen, M., Mosekilde, L., & Vestergaard, P. (2009). Global vitamin D levels in relation to age, gender, skin pigmentation and latitude: An ecologic meta-regression analysis. Osteoporosis International, 20, 133–140.CrossRefPubMedGoogle Scholar
  69. Hall, J. A., Cannons, J. L., Grainger, J. R., dos Santos, L. M., Hand, T. W., Naik, S., Wohlfert, E. A., Chou, D. B., Oldenhove, G., Robinson, M., Grigg, M. E., Kastenmayer, R., Schwartzberg, P. L., & Belkaid, Y. (2011). Essential role for retinoic acid in the promotion of CD4(+) T cell effector responses via retinoic acid receptor alpha. Immunity, 34, 435–447.CrossRefPubMedPubMedCentralGoogle Scholar
  70. Hao, H., Cao, L., Jiang, C., Che, Y., Zhang, S., Takahashi, S., Wang, G., & Gonzalez, F. J. (2017). Farnesoid X receptor regulation of the NLRP3 inflammasome underlies cholestasis-associated sepsis. Cell Metabolism, 25, 856–867. e5.CrossRefPubMedGoogle Scholar
  71. Haro, C., Rangel-Zuniga, O. A., Alcala-Diaz, J. F., Gomez-Delgado, F., Perez-Martinez, P., Delgado-Lista, J., Quintana-Navarro, G. M., Landa, B. B., Navas-Cortes, J. A., Tena-Sempere, M., Clemente, J. C., Lopez-Miranda, J., Perez-Jimenez, F., & Camargo, A. (2016). Intestinal microbiota is influenced by gender and body mass index. PLoS One, 11, e0154090.CrossRefPubMedPubMedCentralGoogle Scholar
  72. Harrison, E. H. (2005). Mechanisms of digestion and absorption of dietary vitamin A. Annual Review of Nutrition, 25, 87–103.CrossRefPubMedGoogle Scholar
  73. Heller, J. J., Qiu, J., & Zhou, L. (2011). Nuclear receptors take center stage in Th17 cell-mediated autoimmunity. The Journal of Clinical Investigation, 121, 519–521.CrossRefPubMedPubMedCentralGoogle Scholar
  74. Hibberd, M. C., Wu, M., Rodionov, D. A., Li, X., Cheng, J., Griffin, N. W., Barratt, M. J., Giannone, R. J., Hettich, R. L., Osterman, A. L., & Gordon, J. I. (2017). The effects of micronutrient deficiencies on bacterial species from the human gut microbiota. Science Translational Medicine, 9, eaal4069.CrossRefPubMedPubMedCentralGoogle Scholar
  75. Hichami, A., Yessoufou, A., Ghiringhelli, F., Salvadori, F., Moutairou, K., Zwetyenga, N., & Khan, N. A. (2016). Peroxisome proliferator-activated receptor alpha deficiency impairs regulatory T cell functions: Possible application in the inhibition of melanoma tumor growth in mice. Biochimie, 131, 1–10.CrossRefPubMedGoogle Scholar
  76. Hildebrandt, M. A., Hoffmann, C., Sherrill-Mix, S. A., Keilbaugh, S. A., Hamady, M., Chen, Y. Y., Knight, R., Ahima, R. S., Bushman, F., & Wu, G. D. (2009). High-fat diet determines the composition of the murine gut microbiome independently of obesity. Gastroenterology, 137(1716–24), e1–e2.Google Scholar
  77. Hirasawa, A., Tsumaya, K., Awaji, T., Katsuma, S., Adachi, T., Yamada, M., Sugimoto, Y., Miyazaki, S., & Tsujimoto, G. (2005). Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nature Medicine, 11, 90–94.CrossRefPubMedGoogle Scholar
  78. Hontecillas, R., & Bassaganya-Riera, J. (2007). Peroxisome proliferator-activated receptor gamma is required for regulatory CD4+ T cell-mediated protection against colitis. Journal of Immunology, 178, 2940–2949.CrossRefGoogle Scholar
  79. Hotamisligil, G. S., & Bernlohr, D. A. (2015). Metabolic functions of FABPs – mechanisms and therapeutic implications. Nature Reviews Endocrinology, 11, 592–605.CrossRefPubMedPubMedCentralGoogle Scholar
  80. Hussain, M. M. (2014). Intestinal lipid absorption and lipoprotein formation. Current Opinion in Lipidology, 25, 200–206.CrossRefPubMedPubMedCentralGoogle Scholar
  81. International Multiple Sclerosis Genetics, C, Wellcome Trust Case Control, C, Sawcer, S., Hellenthal, G., Pirinen, M., Spencer, C. C., Patsopoulos, N. A., Moutsianas, L., Dilthey, A., Su, Z., Freeman, C., Hunt, S. E., Edkins, S., Gray, E., Booth, D. R., Potter, S. C., Goris, A., Band, G., Oturai, A. B., Strange, A., Saarela, J., Bellenguez, C., Fontaine, B., Gillman, M., Hemmer, B., Gwilliam, R., Zipp, F., Jayakumar, A., Martin, R., Leslie, S., Hawkins, S., Giannoulatou, E., D’Alfonso, S., Blackburn, H., Martinelli Boneschi, F., Liddle, J., Harbo, H. F., Perez, M. L., Spurkland, A., Waller, M. J., Mycko, M. P., Ricketts, M., Comabella, M., Hammond, N., Kockum, I., Mccann, O. T., Ban, M., Whittaker, P., Kemppinen, A., Weston, P., Hawkins, C., Widaa, S., Zajicek, J., Dronov, S., Robertson, N., Bumpstead, S. J., Barcellos, L. F., Ravindrarajah, R., Abraham, R., Alfredsson, L., Ardlie, K., Aubin, C., Baker, A., Baker, K., Baranzini, S. E., Bergamaschi, L., Bergamaschi, R., Bernstein, A., Berthele, A., Boggild, M., Bradfield, J. P., Brassat, D., Broadley, S. A., Buck, D., Butzkueven, H., Capra, R., Carroll, W. M., Cavalla, P., Celius, E. G., Cepok, S., Chiavacci, R., Clerget-Darpoux, F., Clysters, K., Comi, G., Cossburn, M., Cournu-Rebeix, I., Cox, M. B., Cozen, W., Cree, B. A., Cross, A. H., Cusi, D., Daly, M. J., Davis, E., de Bakker, P. I., Debouverie, M., D’Hooghe, M. B., Dixon, K., Dobosi, R., Dubois, B., Ellinghaus, D., et al. (2011). Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature, 476, 214–219.CrossRefGoogle Scholar
  82. Italiani, P., & Boraschi, D. (2014). From monocytes to M1/M2 macrophages: Phenotypical vs. functional differentiation. Frontiers in Immunology, 5, 514.CrossRefPubMedPubMedCentralGoogle Scholar
  83. Iwata, M., Hirakiyama, A., Eshima, Y., Kagechika, H., Kato, C., & Song, S. Y. (2004). Retinoic acid imprints gut-homing specificity on T cells. Immunity, 21, 527–538.CrossRefPubMedGoogle Scholar
  84. Jaensson-Gyllenback, E., Kotarsky, K., Zapata, F., Persson, E. K., Gundersen, T. E., Blomhoff, R., & Agace, W. W. (2011). Bile retinoids imprint intestinal CD103+ dendritic cells with the ability to generate gut-tropic T cells. Mucosal Immunology, 4, 438–447.CrossRefPubMedPubMedCentralGoogle Scholar
  85. Jafari, T., Fallah, A. A., & Azadbakht, L. (2013). Role of dietary n-3 polyunsaturated fatty acids in type 2 diabetes: A review of epidemiological and clinical studies. Maturitas, 74, 303–308.CrossRefPubMedGoogle Scholar
  86. Janowski, B. A., Grogan, M. J., Jones, S. A., Wisely, G. B., Kliewer, S. A., Corey, E. J., & Mangelsdorf, D. J. (1999). Structural requirements of ligands for the oxysterol liver X receptors LXRalpha and LXRbeta. Proceedings of the National Academy of Sciences of the United States of America, 96, 266–271.CrossRefPubMedPubMedCentralGoogle Scholar
  87. Jeffery, L. E., Burke, F., Mura, M., Zheng, Y., Qureshi, O. S., Hewison, M., Walker, L. S., Lammas, D. A., Raza, K., & Sansom, D. M. (2009). 1,25-Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. Journal of Immunology, 183, 5458–5467.CrossRefGoogle Scholar
  88. Johnson, L. K., Hofso, D., Aasheim, E. T., Tanbo, T., Holven, K. B., Andersen, L. F., Roislien, J., & Hjelmesaeth, J. (2012). Impact of gender on vitamin D deficiency in morbidly obese patients: A cross-sectional study. European Journal of Clinical Nutrition, 66, 83–90.CrossRefPubMedGoogle Scholar
  89. Joseph, S. B., Castrillo, A., Laffitte, B. A., Mangelsdorf, D. J., & Tontonoz, P. (2003). Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nature Medicine, 9, 213–219.CrossRefPubMedGoogle Scholar
  90. Jungert, A., & Neuhauser-Berthold, M. (2015). Sex-specific determinants of serum 25-hydroxyvitamin D3 concentrations in an elderly German cohort: A cross-sectional study. Nutrition & Metabolism (London), 12, 2.CrossRefGoogle Scholar
  91. Kamen, D. L., Cooper, G. S., Bouali, H., Shaftman, S. R., Hollis, B. W., & Gilkeson, G. S. (2006). Vitamin D deficiency in systemic lupus erythematosus. Autoimmunity Reviews, 5, 114–117.CrossRefPubMedGoogle Scholar
  92. Kang, M. K., Yoon, Y. E., Yang, J. Y., Kwon, K. B., Park, J. W., & Jhee, E. C. (2004). Protective effect of retinoic acid on interleukin-1 beta-induced cytotoxicity of pancreatic beta-cells. Mechanisms of Ageing and Development, 125, 483–490.CrossRefPubMedGoogle Scholar
  93. Kang, S. G., Lim, H. W., Andrisani, O. M., Broxmeyer, H. E., & Kim, C. H. (2007). Vitamin A metabolites induce gut-homing FoxP3+ regulatory T cells. Journal of Immunology, 179, 3724–3733.CrossRefGoogle Scholar
  94. Kawate, R., Yamakido, M., Nishimoto, Y., Bennett, P. H., Hamman, R. F., & Knowler, W. C. (1979). Diabetes mellitus and its vascular complications in Japanese migrants on the Island of Hawaii. Diabetes Care, 2, 161–170.CrossRefPubMedGoogle Scholar
  95. Keller, A., Angquist, L., Jacobsen, R., Vaag, A., & Heitmann, B. L. (2017). A retrospective analysis of a societal experiment among the Danish population suggests that exposure to extra doses of vitamin A during fetal development may lower type 2 diabetes mellitus (T2DM) risk later in life. The British Journal of Nutrition, 117, 731–736.CrossRefPubMedGoogle Scholar
  96. Kennedy, A., Martinez, K., Chuang, C. C., Lapoint, K., & Mcintosh, M. (2009). Saturated fatty acid-mediated inflammation and insulin resistance in adipose tissue: Mechanisms of action and implications. The Journal of Nutrition, 139, 1–4.CrossRefPubMedGoogle Scholar
  97. Kidani, Y., & Bensinger, S. J. (2012). Liver X receptor and peroxisome proliferator-activated receptor as integrators of lipid homeostasis and immunity. Immunological Reviews, 249, 72–83.CrossRefPubMedPubMedCentralGoogle Scholar
  98. Klein, S. L., & Flanagan, K. L. (2016). Sex differences in immune responses. Nature Reviews Immunology, 16, 626–638.CrossRefPubMedGoogle Scholar
  99. Klotz, L., Dani, I., Edenhofer, F., Nolden, L., Evert, B., Paul, B., Kolanus, W., Klockgether, T., Knolle, P., & Diehl, L. (2007). Peroxisome proliferator-activated receptor gamma control of dendritic cell function contributes to development of CD4+ T cell anergy. Journal of Immunology, 178, 2122–2131.CrossRefGoogle Scholar
  100. Konieczna, P., Ferstl, R., Ziegler, M., Frei, R., Nehrbass, D., Lauener, R. P., Akdis, C. A., & O’Mahony, L. (2013). Immunomodulation by Bifidobacterium infantis 35624 in the murine lamina propria requires retinoic acid-dependent and independent mechanisms. PLoS One, 8, e62617.CrossRefPubMedPubMedCentralGoogle Scholar
  101. Kos, K., Wong, S., Tan, B. K., Kerrigan, D., Randeva, H. S., Pinkney, J. H., & Wilding, J. P. (2011). Human RBP4 adipose tissue expression is gender specific and influenced by leptin. Clinical Endocrinology, 74, 197–205.CrossRefPubMedGoogle Scholar
  102. Kovats, S. (2015). Estrogen receptors regulate innate immune cells and signaling pathways. Cellular Immunology, 294, 63–69.CrossRefPubMedPubMedCentralGoogle Scholar
  103. Kragt, J., van Amerongen, B., Killestein, J., Dijkstra, C., Uitdehaag, B., Polman, C., & Lips, P. (2009). Higher levels of 25-hydroxyvitamin D are associated with a lower incidence of multiple sclerosis only in women. Multiple Sclerosis, 15, 9–15.CrossRefPubMedGoogle Scholar
  104. Kumar, S., Sandell, L. L., Trainor, P. A., Koentgen, F., & Duester, G. (2012). Alcohol and aldehyde dehydrogenases: retinoid metabolic effects in mouse knockout models. Biochimica et Biophysica Acta, 1821, 198–205.CrossRefPubMedGoogle Scholar
  105. van de Laar, F. A., van de Lisdonk, E. H., Lucassen, P. L., Tigchelaar, J. M., Meyboom, S., Mulder, J., van den Hoogen, H. J., Rutten, G. E., & van Weel, C. (2004). Fat intake in patients newly diagnosed with type 2 diabetes: A 4-year follow-up study in general practice. The British Journal of General Practice, 54, 177–182.PubMedPubMedCentralGoogle Scholar
  106. Lackey, D. E., & Olefsky, J. M. (2016). Regulation of metabolism by the innate immune system. Nature Reviews. Endocrinology, 12, 15–28.CrossRefPubMedGoogle Scholar
  107. Lagishetty, V., Misharin, A. V., Liu, N. Q., Lisse, T. S., Chun, R. F., Ouyang, Y., Mclachlan, S. M., Adams, J. S., & Hewison, M. (2010). Vitamin D deficiency in mice impairs colonic antibacterial activity and predisposes to colitis. Endocrinology, 151, 2423–2432.CrossRefPubMedPubMedCentralGoogle Scholar
  108. Lagunova, Z., Porojnicu, A. C., Lindberg, F., Hexeberg, S., & Moan, J. (2009). The dependency of vitamin D status on body mass index, gender, age and season. Anticancer Research, 29, 3713–3720.PubMedGoogle Scholar
  109. Lalia, A. Z., & Lanza, I. R. (2016). Insulin-sensitizing effects of omega-3 fatty acids: Lost in translation? Nutrients, 8, 329.CrossRefPubMedCentralGoogle Scholar
  110. Lampen, A., Meyer, S., Arnhold, T., & Nau, H. (2000). Metabolism of vitamin A and its active metabolite all-trans-retinoic acid in small intestinal enterocytes. The Journal of Pharmacology and Experimental Therapeutics, 295, 979–985.PubMedGoogle Scholar
  111. Lamping, K. G., Nuno, D. W., Coppey, L. J., Holmes, A. J., Hu, S., Oltman, C. L., Norris, A. W., & Yorek, M. A. (2013). Modification of high saturated fat diet with n-3 polyunsaturated fat improves glucose intolerance and vascular dysfunction. Diabetes, Obesity & Metabolism, 15, 144–152.CrossRefGoogle Scholar
  112. Larange, A., & Cheroutre, H. (2016). Retinoic acid and retinoic acid receptors as pleiotropic modulators of the immune system. Annual Review of Immunology, 34, 369–394.CrossRefPubMedGoogle Scholar
  113. Lee, H., & Ko, G. (2016). Antiviral effect of vitamin A on norovirus infection via modulation of the gut microbiome. Scientific Reports, 6, 25835.CrossRefPubMedPubMedCentralGoogle Scholar
  114. Lee, C. H., Chawla, A., Urbiztondo, N., Liao, D., Boisvert, W. A., Evans, R. M., & Curtiss, L. K. (2003). Transcriptional repression of atherogenic inflammation: Modulation by PPARdelta. Science, 302, 453–457.CrossRefPubMedGoogle Scholar
  115. Lee, J. W., Bajwa, P. J., Carson, M. J., Jeske, D. R., Cong, Y., Elson, C. O., Lytle, C., & Straus, D. S. (2007). Fenofibrate represses interleukin-17 and interferon-gamma expression and improves colitis in interleukin-10-deficient mice. Gastroenterology, 133, 108–123.CrossRefPubMedGoogle Scholar
  116. Lei, J., Hasegawa, H., Matsumoto, T., & Yasukawa, M. (2010). Peroxisome proliferator-activated receptor alpha and gamma agonists together with TGF-beta convert human CD4+CD25- T cells into functional Foxp3+ regulatory T cells. Journal of Immunology, 185, 7186–7198.CrossRefGoogle Scholar
  117. Li, X. H., Kakkad, B., & Ong, D. E. (2004). Estrogen directly induces expression of retinoic acid biosynthetic enzymes, compartmentalized between the epithelium and underlying stromal cells in rat uterus. Endocrinology, 145, 4756–4762.CrossRefPubMedGoogle Scholar
  118. Libert, C., Dejager, L., & Pinheiro, I. (2010). The X chromosome in immune functions: When a chromosome makes the difference. Nature Reviews. Immunology, 10, 594–604.CrossRefPubMedGoogle Scholar
  119. Lindstrom, J., Peltonen, M., Eriksson, J. G., Louheranta, A., Fogelholm, M., Uusitupa, M., & Tuomilehto, J. (2006). High-fibre, low-fat diet predicts long-term weight loss and decreased type 2 diabetes risk: The Finnish Diabetes Prevention Study. Diabetologia, 49, 912–920.CrossRefPubMedGoogle Scholar
  120. Lucas, R. M., Gorman, S., Geldenhuys, S., & Hart, P. H. (2014). Vitamin D and immunity. F1000Prime Rep, 6, 118.CrossRefPubMedPubMedCentralGoogle Scholar
  121. Makishima, M., Okamoto, A. Y., Repa, J. J., Tu, H., Learned, R. M., Luk, A., Hull, M. V., Lustig, K. D., Mangelsdorf, D. J., & Shan, B. (1999). Identification of a nuclear receptor for bile acids. Science, 284, 1362–1365.CrossRefPubMedGoogle Scholar
  122. Mantis, N. J., Rol, N., & Corthesy, B. (2011). Secretory IgA’s complex roles in immunity and mucosal homeostasis in the gut. Mucosal Immunology, 4, 603–611.CrossRefPubMedPubMedCentralGoogle Scholar
  123. Markle, J. G., Frank, D. N., Mortin-Toth, S., Robertson, C. E., Feazel, L. M., Rolle-Kampczyk, U., von Bergen, M., Mccoy, K. D., Macpherson, A. J., & Danska, J. S. (2013). Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science, 339, 1084–1088.CrossRefPubMedGoogle Scholar
  124. Marshall, J. A., Hamman, R. F., & Baxter, J. (1991). High-fat, low-carbohydrate diet and the etiology of non-insulin-dependent diabetes mellitus: The San Luis Valley Diabetes Study. American Journal of Epidemiology, 134, 590–603.CrossRefPubMedGoogle Scholar
  125. Martinez, F. O., Helming, L., & Gordon, S. (2009). Alternative activation of macrophages: An immunologic functional perspective. Annual Review of Immunology, 27, 451–483.CrossRefPubMedGoogle Scholar
  126. Marx, N., Kehrle, B., Kohlhammer, K., Grub, M., Koenig, W., Hombach, V., Libby, P., & Plutzky, J. (2002). PPAR activators as antiinflammatory mediators in human T lymphocytes: Implications for atherosclerosis and transplantation-associated arteriosclerosis. Circulation Research, 90, 703–710.CrossRefPubMedPubMedCentralGoogle Scholar
  127. Maslowski, K. M., & Mackay, C. R. (2011). Diet, gut microbiota and immune responses. Nature Immunology, 12, 5–9.CrossRefPubMedGoogle Scholar
  128. Matalonga, J., Glaria, E., Bresque, M., Escande, C., Carbo, J. M., Kiefer, K., Vicente, R., Leon, T. E., Beceiro, S., Pascual-Garcia, M., Serret, J., Sanjurjo, L., Moron-Ros, S., Riera, A., Paytubi, S., Juarez, A., Sotillo, F., Lindbom, L., Caelles, C., Sarrias, M. R., Sancho, J., Castrillo, A., Chini, E. N., & Valledor, A. F. (2017). The nuclear receptor LXR limits bacterial infection of host macrophages through a mechanism that impacts cellular NAD metabolism. Cell Reports, 18, 1241–1255.CrossRefPubMedGoogle Scholar
  129. Mauvais-Jarvis, F. (2015). Sex differences in metabolic homeostasis, diabetes, and obesity. Biology of Sex Differences, 6, 14.CrossRefPubMedPubMedCentralGoogle Scholar
  130. Mccullough, M. L., Weinstein, S. J., Freedman, D. M., Helzlsouer, K., Flanders, W. D., Koenig, K., Kolonel, L., Laden, F., Le Marchand, L., Purdue, M., Snyder, K., Stevens, V. L., Stolzenberg-Solomon, R., Virtamo, J., Yang, G., Yu, K., Zheng, W., Albanes, D., Ashby, J., Bertrand, K., Cai, H., Chen, Y., Gallicchio, L., Giovannucci, E., Jacobs, E. J., Hankinson, S. E., Hartge, P., Hartmuller, V., Harvey, C., Hayes, R. B., Horst, R. L., & Shu, X. O. (2010). Correlates of circulating 25-hydroxyvitamin D: Cohort consortium vitamin D pooling project of rarer cancers. American Journal of Epidemiology, 172, 21–35.CrossRefPubMedPubMedCentralGoogle Scholar
  131. Meeker, S., Seamons, A., Maggio-Price, L., & Paik, J. (2016). Protective links between vitamin D, inflammatory bowel disease and colon cancer. World Journal of Gastroenterology, 22, 933–948.CrossRefPubMedPubMedCentralGoogle Scholar
  132. Meerza, D., Iqbal, S., Zaheer, S., & Naseem, I. (2016). Retinoids have therapeutic action in type 2 diabetes. Nutrition, 32, 898–903.CrossRefPubMedGoogle Scholar
  133. Mielcarz, D. W., & Kasper, L. H. (2015). The gut microbiome in multiple sclerosis. Current Treatment Options in Neurology, 17, 344.CrossRefPubMedGoogle Scholar
  134. Mohr, S. B., Garland, C. F., Gorham, E. D., & Garland, F. C. (2008). The association between ultraviolet B irradiance, vitamin D status and incidence rates of type 1 diabetes in 51 regions worldwide. Diabetologia, 51, 1391–1398.CrossRefPubMedGoogle Scholar
  135. Mokry, L. E., Ross, S., Ahmad, O. S., Forgetta, V., Smith, G. D., Goltzman, D., Leong, A., Greenwood, C. M., Thanassoulis, G., & Richards, J. B. (2015). Vitamin D and risk of multiple sclerosis: A Mendelian randomization study. PLoS Medicine, 12, e1001866.CrossRefPubMedPubMedCentralGoogle Scholar
  136. Mora, J. R., Iwata, M., Eksteen, B., Song, S. Y., Junt, T., Senman, B., Otipoby, K. L., Yokota, A., Takeuchi, H., Ricciardi-Castagnoli, P., Rajewsky, K., Adams, D. H., & von Andrian, U. H. (2006). Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science, 314, 1157–1160.CrossRefPubMedGoogle Scholar
  137. Mucida, D., Park, Y., Kim, G., Turovskaya, O., Scott, I., Kronenberg, M., & Cheroutre, H. (2007). Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science, 317, 256–260.CrossRefPubMedGoogle Scholar
  138. Muehleisen, B., & Gallo, R. L. (2013). Vitamin D in allergic disease: Shedding light on a complex problem. The Journal of Allergy and Clinical Immunology, 131, 324–329.CrossRefPubMedGoogle Scholar
  139. Nashold, F. E., Spach, K. M., Spanier, J. A., & Hayes, C. E. (2009). Estrogen controls vitamin D3-mediated resistance to experimental autoimmune encephalomyelitis by controlling vitamin D3 metabolism and receptor expression. Journal of Immunology, 183, 3672–3681.CrossRefGoogle Scholar
  140. Nasri, H., Behradmanesh, S., Maghsoudi, A. R., Ahmadi, A., Nasri, P., & Rafieian-Kopaei, M. (2014). Efficacy of supplementary vitamin D on improvement of glycemic parameters in patients with type 2 diabetes mellitus; a randomized double blind clinical trial. Journal of Renal Injury Prevention, 3, 31–34.PubMedGoogle Scholar
  141. Neve, A., Corrado, A., & Cantatore, F. P. (2014). Immunomodulatory effects of vitamin D in peripheral blood monocyte-derived macrophages from patients with rheumatoid arthritis. Clinical and Experimental Medicine, 14, 275–283.CrossRefPubMedGoogle Scholar
  142. Ngo, S. T., Steyn, F. J., & Mccombe, P. A. (2014). Gender differences in autoimmune disease. Frontiers in Neuroendocrinology, 35, 347–369.CrossRefPubMedGoogle Scholar
  143. Oh, D. Y., Talukdar, S., Bae, E. J., Imamura, T., Morinaga, H., Fan, W., Li, P., Lu, W. J., Watkins, S. M., & Olefsky, J. M. (2010). GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell, 142, 687–698.CrossRefPubMedPubMedCentralGoogle Scholar
  144. Ooi, J. H., Li, Y., Rogers, C. J., & Cantorna, M. T. (2013). Vitamin D regulates the gut microbiome and protects mice from dextran sodium sulfate-induced colitis. The Journal of Nutrition, 143, 1679–1686.CrossRefPubMedPubMedCentralGoogle Scholar
  145. Pantazi, E., Marks, E., Stolarczyk, E., Lycke, N., Noelle, R. J., & Elgueta, R. (2015). Cutting edge: Retinoic acid signaling in B cells is essential for oral immunization and microflora composition. Journal of Immunology, 195, 1368–1371.CrossRefGoogle Scholar
  146. Park, H. J., & Choi, J. M. (2017). Sex-specific regulation of immune responses by PPARs. Experimental & Molecular Medicine, 49, e364.CrossRefGoogle Scholar
  147. Park, H. J., Kim, D. H., Choi, J. Y., Kim, W. J., Kim, J. Y., Senejani, A. G., Hwang, S. S., Kim, L. K., Tobiasova, Z., Lee, G. R., Craft, J., Bothwell, A. L., & Choi, J. M. (2014). PPARgamma negatively regulates T cell activation to prevent follicular helper T cells and germinal center formation. PLoS One, 9, e99127.CrossRefPubMedPubMedCentralGoogle Scholar
  148. Park, H. J., Park, H. S., Lee, J. U., Bothwell, A. L., & Choi, J. M. (2016). Gender-specific differences in PPARgamma regulation of follicular helper T cell responses with estrogen. Scientific Reports, 6, 28495.CrossRefPubMedPubMedCentralGoogle Scholar
  149. Pascual-Garcia, M., & Valledor, A. F. (2012). Biological roles of liver X receptors in immune cells. Archivum Immunologiae et Therapiae Experimentalis (Warsz), 60, 235–249.CrossRefGoogle Scholar
  150. Paun, A., Yau, C., & Danska, J. S. (2017). The influence of the microbiome on Type 1 diabetes. Journal of Immunology, 198, 590–595.CrossRefGoogle Scholar
  151. Penna, G., Roncari, A., Amuchastegui, S., Daniel, K. C., Berti, E., Colonna, M., & Adorini, L. (2005). Expression of the inhibitory receptor ILT3 on dendritic cells is dispensable for induction of CD4+Foxp3+ regulatory T cells by 1,25-dihydroxyvitamin D3. Blood, 106, 3490–3497.CrossRefPubMedGoogle Scholar
  152. Petrosino, J. M., Disilvestro, D., & Ziouzenkova, O. (2014). Aldehyde dehydrogenase 1A1: Friend or foe to female metabolism? Nutrients, 6, 950–973.CrossRefPubMedPubMedCentralGoogle Scholar
  153. Pierrot-Deseilligny, C., & Souberbielle, J. C. (2017). Vitamin D and multiple sclerosis: An update. Multiple Sclerosis and Related Disorders, 14, 35–45.CrossRefPubMedGoogle Scholar
  154. Pilon, C., Rebellato, A., Urbanet, R., Guzzardo, V., Cappellesso, R., Sasano, H., Fassina, A., & Fallo, F. (2015). Methylation status of vitamin D receptor gene promoter in benign and malignant adrenal tumors. International Journal of Endocrinology, 2015, 375349.CrossRefPubMedPubMedCentralGoogle Scholar
  155. Pino-Lagos, K., Guo, Y., Brown, C., Alexander, M. P., Elgueta, R., Bennett, K. A., de Vries, V., Nowak, E., Blomhoff, R., Sockanathan, S., Chandraratna, R. A., Dmitrovsky, E., & Noelle, R. J. (2011). A retinoic acid-dependent checkpoint in the development of CD4+ T cell-mediated immunity. The Journal of Experimental Medicine, 208, 1767–1775.CrossRefPubMedPubMedCentralGoogle Scholar
  156. Pourcet, B., Gage, M. C., Leon, T. E., Waddington, K. E., Pello, O. M., Steffensen, K. R., Castrillo, A., Valledor, A. F., & Pineda-Torra, I. (2016). The nuclear receptor LXR modulates interleukin-18 levels in macrophages through multiple mechanisms. Scientific Reports, 6, 25481.CrossRefPubMedPubMedCentralGoogle Scholar
  157. Rabot, S., Membrez, M., Bruneau, A., Gerard, P., Harach, T., Moser, M., Raymond, F., Mansourian, R., & Chou, C. J. (2010). Germ-free C57BL/6J mice are resistant to high-fat-diet-induced insulin resistance and have altered cholesterol metabolism. The FASEB Journal, 24, 4948–4959.CrossRefPubMedGoogle Scholar
  158. Ramasamy, A., Trabzuni, D., Forabosco, P., Smith, C., Walker, R., Dillman, A., Sveinbjornsdottir, S., North American Brain Expression Consortium, U. K. B. E. C, Hardy, J., Weale, M. E., & Ryten, M. (2014). Genetic evidence for a pathogenic role for the vitamin D3 metabolizing enzyme CYP24A1 in multiple sclerosis. Multiple Sclerosis and Related Disorders, 3, 211–219.CrossRefPubMedPubMedCentralGoogle Scholar
  159. Reichert, B., Yasmeen, R., Jeyakumar, S. M., Yang, F., Thomou, T., Alder, H., Duester, G., Maiseyeu, A., Mihai, G., Harrison, E. H., Rajagopalan, S., Kirkland, J. L., & Ziouzenkova, O. (2011). Concerted action of aldehyde dehydrogenases influences depot-specific fat formation. Molecular Endocrinology, 25, 799–809.CrossRefPubMedPubMedCentralGoogle Scholar
  160. Rhead, B., Baarnhielm, M., Gianfrancesco, M., Mok, A., Shao, X., Quach, H., Shen, L., Schaefer, C., Link, J., Gyllenberg, A., Hedstrom, A. K., Olsson, T., Hillert, J., Kockum, I., Glymour, M. M., Alfredsson, L., & Barcellos, L. F. (2016). Mendelian randomization shows a causal effect of low vitamin D on multiple sclerosis risk. Neurology Genetics, 2, e97.CrossRefPubMedPubMedCentralGoogle Scholar
  161. Rhee, E. J., & Plutzky, J. (2012). Retinoid metabolism and diabetes mellitus. Diabetes and Metabolism Journal, 36, 167–180.CrossRefPubMedPubMedCentralGoogle Scholar
  162. da Rocha, L. F., Jr., Rego, M. J., Cavalcanti, M. B., Pereira, M. C., Pitta, M. G., de Oliveira, P. S., Goncalves, S. M., Duarte, A. L., de Lima, C., Pitta Ida, R., & Pitta, M. G. (2013). Synthesis of a novel thiazolidinedione and evaluation of its modulatory effect on IFN- gamma, IL-6, IL-17A, and IL-22 production in PBMCs from rheumatoid arthritis patients. BioMed Research International, 2013, 926060.CrossRefGoogle Scholar
  163. Rochette-Egly, C., & Germain, P. (2009). Dynamic and combinatorial control of gene expression by nuclear retinoic acid receptors (RARs). Nuclear Receptor Signaling, 7, e005.PubMedPubMedCentralGoogle Scholar
  164. di Rosa, M., Malaguarnera, M., Nicoletti, F., & Malaguarnera, L. (2011). Vitamin D3: A helpful immuno-modulator. Immunology, 134, 123–139.CrossRefPubMedPubMedCentralGoogle Scholar
  165. Round, J. L., & Mazmanian, S. K. (2009). The gut microbiota shapes intestinal immune responses during health and disease. Nature Reviews Immunology, 9, 313–323.CrossRefPubMedPubMedCentralGoogle Scholar
  166. Rowland, I., Gibson, G., Heinken, A., Scott, K., Swann, J., Thiele, I., & Tuohy, K. (2017). Gut microbiota functions: Metabolism of nutrients and other food components. European Journal of Nutrition, 1–24.Google Scholar
  167. Rubtsova, K., Marrack, P., & Rubtsov, A. V. (2015). Sexual dimorphism in autoimmunity. The Journal of Clinical Investigation, 125, 2187–2193.CrossRefPubMedPubMedCentralGoogle Scholar
  168. Schaible, U. E., & Kaufmann, S. H. (2007). Malnutrition and infection: Complex mechanisms and global impacts. PLoS Medicine, 4, e115.CrossRefPubMedPubMedCentralGoogle Scholar
  169. Schwingshackl, L., & Hoffmann, G. (2012). Monounsaturated fatty acids and risk of cardiovascular disease: Synopsis of the evidence available from systematic reviews and meta-analyses. Nutrients, 4, 1989–2007.CrossRefPubMedPubMedCentralGoogle Scholar
  170. Shen, W., Wolf, P. G., Carbonero, F., Zhong, W., Reid, T., Gaskins, H. R., & Mcintosh, M. K. (2014). Intestinal and systemic inflammatory responses are positively associated with sulfidogenic bacteria abundance in high-fat-fed male C57BL/6J mice. The Journal of Nutrition, 144, 1181–1187.CrossRefPubMedGoogle Scholar
  171. Sommer, A. (2008). Vitamin a deficiency and clinical disease: An historical overview. The Journal of Nutrition, 138, 1835–1839.CrossRefPubMedGoogle Scholar
  172. Sonnenburg, J. L., & Backhed, F. (2016). Diet-microbiota interactions as moderators of human metabolism. Nature, 535, 56–64.CrossRefPubMedGoogle Scholar
  173. Spach, K. M., & Hayes, C. E. (2005). Vitamin D3 confers protection from autoimmune encephalomyelitis only in female mice. Journal of Immunology, 175, 4119–4126.CrossRefGoogle Scholar
  174. Stern, M. P., Gonzalez, C., Mitchell, B. D., Villalpando, E., Haffner, S. M., & Hazuda, H. P. (1992). Genetic and environmental determinants of type II diabetes in Mexico City and San Antonio. Diabetes, 41, 484–492.CrossRefPubMedGoogle Scholar
  175. Straus, D. S., & Glass, C. K. (2007). Anti-inflammatory actions of PPAR ligands: New insights on cellular and molecular mechanisms. Trends in Immunology, 28, 551–558.CrossRefPubMedGoogle Scholar
  176. Su, D., Nie, Y., Zhu, A., Chen, Z., Wu, P., Zhang, L., Luo, M., Sun, Q., Cai, L., Lai, Y., Xiao, Z., Duan, Z., Zheng, S., Wu, G., Hu, R., Tsukamoto, H., Lugea, A., Liu, Z., Pandol, S. J., & Han, Y. P. (2016). Vitamin D signaling through induction of paneth cell defensins maintains gut microbiota and improves metabolic disorders and hepatic steatosis in animal models. Frontiers in Physiology, 7, 498.CrossRefPubMedPubMedCentralGoogle Scholar
  177. Subramanian, S., Huq, S., Yatsunenko, T., Haque, R., Mahfuz, M., Alam, M. A., Benezra, A., Destefano, J., Meier, M. F., Muegge, B. D., Barratt, M. J., Vanarendonk, L. G., Zhang, Q., Province, M. A., Petri, W. A., Jr., Ahmed, T., & Gordon, J. I. (2014). Persistent gut microbiota immaturity in malnourished Bangladeshi children. Nature, 510, 417–421.CrossRefPubMedPubMedCentralGoogle Scholar
  178. Sun, L., Qi, Q., Zong, G., Ye, X., Li, H., Liu, X., Zheng, H., Hu, F. B., Liu, Y., & Lin, X. (2014). Elevated plasma retinol-binding protein 4 is associated with increased risk of type 2 diabetes in middle-aged and elderly Chinese adults. The Journal of Nutrition, 144, 722–728.CrossRefPubMedGoogle Scholar
  179. Tavera-Mendoza, L. E., & White, J. H. (2007). Cell defenses and the sunshine vitamin. Scientific American, 297, 62–65. 68–70, 72.CrossRefPubMedGoogle Scholar
  180. Thorburn, A. N., Macia, L., & Mackay, C. R. (2014). Diet, metabolites, and “western-lifestyle” inflammatory diseases. Immunity, 40, 833–842.CrossRefPubMedGoogle Scholar
  181. Tontonoz, P., & Spiegelman, B. M. (2008). Fat and beyond: The diverse biology of PPARgamma. Annual Review of Biochemistry, 77, 289–312.CrossRefPubMedGoogle Scholar
  182. Trasino, S. E., & Gudas, L. J. (2015). Vitamin A: A missing link in diabetes? Diabetes Management (London), 5, 359–367.CrossRefGoogle Scholar
  183. Trasino, S. E., Harrison, E. H., & Wang, T. T. (2007). Androgen regulation of aldehyde dehydrogenase 1A3 (ALDH1A3) in the androgen-responsive human prostate cancer cell line LNCaP. Experimental Biology and Medicine (Maywood, N.J.), 232, 762–771.Google Scholar
  184. Trigunaite, A., Dimo, J., & Jorgensen, T. N. (2015). Suppressive effects of androgens on the immune system. Cellular Immunology, 294, 87–94.CrossRefPubMedGoogle Scholar
  185. Tsunehara, C. H., Leonetti, D. L., & Fujimoto, W. Y. (1990). Diet of second-generation Japanese-American men with and without non-insulin-dependent diabetes. The American Journal of Clinical Nutrition, 52, 731–738.CrossRefPubMedGoogle Scholar
  186. Turnbaugh, P. J., Backhed, F., Fulton, L., & Gordon, J. I. (2008). Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host & Microbe, 3, 213–223.CrossRefGoogle Scholar
  187. Turnbaugh, P. J., Ridaura, V. K., Faith, J. J., Rey, F. E., Knight, R., & Gordon, J. I. (2009). The effect of diet on the human gut microbiome: A metagenomic analysis in humanized gnotobiotic mice. Science Translational Medicine, 1, 6ra14.CrossRefPubMedPubMedCentralGoogle Scholar
  188. Vacca, A., Cormier, C., Piras, M., Mathieu, A., Kahan, A., & Allanore, Y. (2009). Vitamin D deficiency and insufficiency in 2 independent cohorts of patients with systemic sclerosis. The Journal of Rheumatology, 36, 1924–1929.CrossRefPubMedGoogle Scholar
  189. Van der Aar, A. M., Sibiryak, D. S., Bakdash, G., van Capel, T. M., van der Kleij, H. P., Opstelten, D. J., Teunissen, M. B., Kapsenberg, M. L., & de Jong, E. C. (2011). Vitamin D3 targets epidermal and dermal dendritic cells for induction of distinct regulatory T cells. The Journal of Allergy and Clinical Immunology, 127(1532–40), e7.Google Scholar
  190. Varga, T., Czimmerer, Z., & Nagy, L. (2011). PPARs are a unique set of fatty acid regulated transcription factors controlling both lipid metabolism and inflammation. Biochimica et Biophysica Acta, 1812, 1007–1022.CrossRefPubMedPubMedCentralGoogle Scholar
  191. Vasile, M., Corinaldesi, C., Antinozzi, C., & Crescioli, C. (2017). Vitamin D in autoimmune rheumatic diseases: A view inside gender differences. Pharmacological Research, 117, 228–241.CrossRefPubMedGoogle Scholar
  192. Vavassori, P., Mencarelli, A., Renga, B., Distrutti, E., & Fiorucci, S. (2009). The bile acid receptor FXR is a modulator of intestinal innate immunity. Journal of Immunology, 183, 6251–6261.CrossRefGoogle Scholar
  193. Veldhoen, M., & Brucklacher-Waldert, V. (2012). Dietary influences on intestinal immunity. Nature reviews. Immunology, 12, 696–708.PubMedGoogle Scholar
  194. Wahli, W., & Michalik, L. (2012). PPARs at the crossroads of lipid signaling and inflammation. Trends in Endocrinology and Metabolism, 23, 351–363.CrossRefPubMedGoogle Scholar
  195. Wang, X., Sperkova, Z., & Napoli, J. L. (2001). Analysis of mouse retinal dehydrogenase type 2 promoter and expression. Genomics, 74, 245–250.CrossRefPubMedGoogle Scholar
  196. Wang, S., Villablanca, E. J., de Calisto, J., Gomes, D. C., Nguyen, D. D., Mizoguchi, E., Kagan, J. C., Reinecker, H. C., Hacohen, N., Nagler, C., Xavier, R. J., Rossi-Bergmann, B., Chen, Y. B., Blomhoff, R., Snapper, S. B., & Mora, J. R. (2011). MyD88-dependent TLR1/2 signals educate dendritic cells with gut-specific imprinting properties. Journal of Immunology, 187, 141–150.CrossRefGoogle Scholar
  197. West, K. P., Jr., & Mehra, S. (2010). Vitamin A intake and status in populations facing economic stress. The Journal of Nutrition, 140, 201S–207S.CrossRefPubMedGoogle Scholar
  198. Wimalawansa, S. J. (2016). Associations of vitamin D with insulin resistance, obesity, type 2 diabetes, and metabolic syndrome. The Journal of Steroid Biochemistry and Molecular Biology, S0960-0760, 30253–30259.Google Scholar
  199. Wortsman, J., Matsuoka, L. Y., Chen, T. C., Lu, Z., & Holick, M. F. (2000). Decreased bioavailability of vitamin D in obesity. The American Journal of Clinical Nutrition, 72, 690–693.CrossRefPubMedGoogle Scholar
  200. Xu, J., Wagoner, G., Douglas, J. C., & Drew, P. D. (2009). Liver X receptor agonist regulation of Th17 lymphocyte function in autoimmunity. Journal of Leukocyte Biology, 86, 401–409.CrossRefPubMedPubMedCentralGoogle Scholar
  201. Yan, Y., Jiang, W., Spinetti, T., Tardivel, A., Castillo, R., Bourquin, C., Guarda, G., Tian, Z., Tschopp, J., & Zhou, R. (2013). Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. Immunity, 38, 1154–1163.CrossRefPubMedGoogle Scholar
  202. Yang, X. Y., Wang, L. H., Chen, T., Hodge, D. R., Resau, J. H., Dasilva, L., & Farrar, W. L. (2000). Activation of human T lymphocytes is inhibited by peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. PPARgamma co-association with transcription factor NFAT. Journal of Biological Chemistry, 275, 4541–4544.CrossRefPubMedGoogle Scholar
  203. Yasmeen, R., Reichert, B., Deiuliis, J., Yang, F., Lynch, A., Meyers, J., Sharlach, M., Shin, S., Volz, K. S., Green, K. B., Lee, K., Alder, H., Duester, G., Zechner, R., Rajagopalan, S., & Ziouzenkova, O. (2013). Autocrine function of aldehyde dehydrogenase 1 as a determinant of diet- and sex-specific differences in visceral adiposity. Diabetes, 62, 124–136.CrossRefPubMedGoogle Scholar
  204. Yatsunenko, T., Rey, F. E., Manary, M. J., Trehan, I., Dominguez-Bello, M. G., Contreras, M., Magris, M., Hidalgo, G., Baldassano, R. N., Anokhin, A. P., Heath, A. C., Warner, B., Reeder, J., Kuczynski, J., Caporaso, J. G., Lozupone, C. A., Lauber, C., Clemente, J. C., Knights, D., Knight, R., & Gordon, J. I. (2012). Human gut microbiome viewed across age and geography. Nature, 486, 222–227.PubMedPubMedCentralGoogle Scholar
  205. Yurkovetskiy, L., Burrows, M., Khan, A. A., Graham, L., Volchkov, P., Becker, L., Antonopoulos, D., Umesaki, Y., & Chervonsky, A. V. (2013). Gender bias in autoimmunity is influenced by microbiota. Immunity, 39, 400–412.CrossRefPubMedGoogle Scholar
  206. Zhang, M. A., Rego, D., Moshkova, M., Kebir, H., Chruscinski, A., Nguyen, H., Akkermann, R., Stanczyk, F. Z., Prat, A., Steinman, L., & Dunn, S. E. (2012). Peroxisome proliferator-activated receptor (PPAR)alpha and -gamma regulate IFNgamma and IL-17A production by human T cells in a sex-specific way. Proceedings of the National Academy of Sciences of the United States of America, 109, 9505–9510.CrossRefPubMedPubMedCentralGoogle Scholar
  207. Zimmet, P. Z., Magliano, D. J., Herman, W. H., & Shaw, J. E. (2014). Diabetes: A 21st century challenge. The Lancet Diabetes and Endocrinology, 2, 56–64.CrossRefPubMedGoogle Scholar
  208. Zunino, S. J., Storms, D. H., & Stephensen, C. B. (2007). Diets rich in polyphenols and vitamin A inhibit the development of type I autoimmune diabetes in nonobese diabetic mice. The Journal of Nutrition, 137, 1216–1221.CrossRefPubMedGoogle Scholar

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© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of ImmunologyUniversity of TorontoTorontoCanada
  2. 2.Program in Genetics and Genome Biology, Hospital for Sick ChildrenTorontoCanada
  3. 3.Department of Immunology, and Department of Medical BiophysicsUniversity of TorontoTorontoCanada

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