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Colonic Bacteroides are positively associated with trabecular bone structure and programmed by maternal vitamin D in male but not female offspring in an obesogenic environment

Abstract

Background/Objectives:

The gut microbiota is determined early in life, possibly including pregnancy. Pioneering data suggest vitamin D, a nutrient important for bone health, affects this microbiota. We found that high maternal vitamin D lowered circulating lipopolysaccharide (LPS), improved intestinal barrier and bone health in male but not female offspring in an obesogenic environment. This study determined if high maternal dietary vitamin D programs Bacteroides and Prevotella and whether this associates with bone mineral content, density and structure of male and female adult offspring fed an obesogenic diet.

Methods:

C57BL/6J females received an AIN93G diet with high or low vitamin D from before mating until weaning. Post-weaning, male and female offspring remained on their respective vitamin D level or were switched and fed a high fat and sucrose diet until killing (age 7 months). Bacteroides and Prevotella were quantified in dams’ feces and offspring colonic contents. LPS concentrations, bone mineral density and content, strength and structure data were integrated from our previous studies in the same mice. Spearman correlations were completed between Bacteroides and LPS, and bone outcomes.

Results:

There was a maternal vitamin D effect on colonic Bacteroides but not Prevotella (dam diet: <0.001 and 0.735) in adult male offspring, independent of dams fecal Bacteroides before birth (P=0.998). In males, but not females, Bacteroides correlated with LPS (r=−0.488, P=0.018), trabecular femur peak load (r=0.362, P=0.033), vertebral trabecular separation (r=−0.605, P=0.006), trabecular number (r=0.614, P=0.005) and bone volume fraction (r=0.549, P=0.015).

Conclusions:

Dietary vitamin D programs Bacteroides in male adult offspring only, which correlated negatively with systemic inflammation and positively with bone strength and structure. This may have implications on maternal diet and nutritional guidelines targeting sexes in a different manner.

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References

  1. Obesity and overweight: Fact Sheet. World Health Organization. [Available from: Available online http://www.who.int/mediacentre/factsheets/fs311/en/.

  2. Guo SS, Wu W, Chumlea WC, Roche AF . Predicting overweight and obesity in adulthood from body mass index values in childhood and adolescence. Am J Clin Nutr 2002; 76: 653–658.

    Article  CAS  Google Scholar 

  3. Schellong K, Schulz S, Harder T, Plagemann A . Birth weight and long-term overweight risk: systematic review and a meta-analysis including 643,902 persons from 66 studies and 26 countries globally. PLoS ONE 2012; 7: e47776.

    Article  CAS  Google Scholar 

  4. Compston JE, Watts NB, Chapurlat R, Cooper C, Boonen S, Greenspan S et al. Obesity is not protective against fracture in postmenopausal women: GLOW. Am J Med 2011; 124: 1043–1050.

    Article  Google Scholar 

  5. Pirro M, Fabbriciani G, Leli C, Callarelli L, Manfredelli MR, Fioroni C et al. High weight or body mass index increase the risk of vertebral fractures in postmenopausal osteoporotic women. J Bone Miner Metab 2010; 28: 88–93.

    Article  Google Scholar 

  6. Nielson CM, Marshall LM, Adams AL, LeBlanc ES, Cawthon PM, Ensrud K et al. BMI and fracture risk in older men: the osteoporotic fractures in men study (MrOS). J Bone Miner Res 2011; 26: 496–502.

    Article  Google Scholar 

  7. Nielson CM, Srikanth P, Orwoll ES . Obesity and fracture in men and women: an epidemiologic perspective. J Bone Miner Res 2012; 27: 1–10.

    Article  Google Scholar 

  8. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007; 56: 1761–1772.

    Article  CAS  Google Scholar 

  9. Smith BJ, Lerner MR, Bu SY, Lucas EA, Hanas JS, Lightfoot SA et al. Systemic bone loss and induction of coronary vessel disease in a rat model of chronic inflammation. Bone 2006; 38: 378–386.

    Article  CAS  Google Scholar 

  10. Villa CR, Ward WE, Comelli EM . Gut microbiota-bone axis. Crit Rev Food Sci Nutr 2017; 57: 1664–1672.

    Article  Google Scholar 

  11. Villa CR, Chen J, Wen B, Sacco SM, Taibi A, Ward WE et al. Maternal vitamin D beneficially programs metabolic, gut and bone health of mouse male offspring in an obesogenic environment. Int J Obes (Lond) 2016; 40: 1875–1883.

    Article  CAS  Google Scholar 

  12. Villa CR, Chen J, Wen B, Sacco SM, Taibi A, Ward WE et al. Maternal dietary vitamin D does not program systemic inflammation and bone health in adult female mice fed an obesogenic diet. Nutrients 2016; 8: 11.

    Article  Google Scholar 

  13. Hart PH, Lucas RM, Walsh JP, Zosky GR, Whitehouse AJ, Zhu K et al. Vitamin D in fetal development: findings from a birth cohort study. Pediatrics 2015; 135: e167–e173.

    Article  Google Scholar 

  14. Zhu K, Whitehouse AJ, Hart PH, Kusel M, Mountain J, Lye S et al. Maternal vitamin D status during pregnancy and bone mass in offspring at 20 years of age: a prospective cohort study. J Bone Miner Res 2014; 29: 1088–1095.

    Article  CAS  Google Scholar 

  15. Javaid MK, Crozier SR, Harvey NC, Gale CR, Dennison EM, Boucher BJ et al. Maternal vitamin D status during pregnancy and childhood bone mass at age 9 years: a longitudinal study. Lancet 2006; 367: 36–43.

    Article  CAS  Google Scholar 

  16. Koren O, Goodrich JK, Cullender TC, Spor A, Laitinen K, Backhed HK et al. Host remodeling of the gut microbiome and metabolic changes during pregnancy. Cell 2012; 150: 470–480.

    Article  CAS  Google Scholar 

  17. Chu DM, Antony KM, Ma J, Prince AL, Showalter L, Moller M et al. The early infant gut microbiome varies in association with a maternal high-fat diet. Genome Med 2016; 8: 77.

    Article  Google Scholar 

  18. Luoto R, Kalliomaki M, Laitinen K, Delzenne NM, Cani PD, Salminen S et al. Initial dietary and microbiological environments deviate in normal-weight compared to overweight children at 10 years of age. J Pediatr Gastroenterol Nutr 2011; 52: 90–95.

    Article  Google Scholar 

  19. Kalliomaki M, Collado MC, Salminen S, Isolauri E . Early differences in fecal microbiota composition in children may predict overweight. Am J Clin Nutr 2008; 87: 534–538.

    Article  CAS  Google Scholar 

  20. Nutrition UNESCO. Double burden of malnutrition - a common agenda. 33rd. Annual Session of the Standing Committee on Nutrition. United Nations: Geneva, Switzerland, 2006.

  21. Lucas A . Long-term programming effects of early nutrition — implications for the preterm infant. J Perinatol 2005; 25 (Suppl 2): S2–S6.

    Article  Google Scholar 

  22. Cortese R, Lu L, Yu Y, Ruden D, Claud EC . Epigenome-microbiome crosstalk: a potential new paradigm influencing neonatal susceptibility to disease. Epigenetics 2016; 11: 205–215.

    Article  Google Scholar 

  23. Lagishetty V, Misharin AV, Liu NQ, Lisse TS, Chun RF, Ouyang Y et al. Vitamin D deficiency in mice impairs colonic antibacterial activity and predisposes to colitis. Endocrinology 2010; 151: 2423–2432.

    Article  CAS  Google Scholar 

  24. Ooi JH, Li Y, Rogers CJ, Cantorna MT . Vitamin D regulates the gut microbiome and protects mice from dextran sodium sulfate-induced colitis. J Nutr 2013; 143: 1679–1686.

    Article  CAS  Google Scholar 

  25. Assa A, Vong L, Pinnell LJ, Avitzur N, Johnson-Henry KC, Sherman PM . Vitamin D deficiency promotes epithelial barrier dysfunction and intestinal inflammation. J Infect Dis 2014; 210: 1296–1305.

    Article  CAS  Google Scholar 

  26. Chen J, Waddell A, Lin YD, Cantorna MT . Dysbiosis caused by vitamin D receptor deficiency confers colonization resistance to Citrobacter rodentium through modulation of innate lymphoid cells. Mucosal Immunol 2014; 8: 618–626.

    Article  Google Scholar 

  27. Jin D, Wu S, Zhang YG, Lu R, Xia Y, Dong H et al. Lack of vitamin D receptor causes dysbiosis and changes the functions of the murine intestinal microbiome. Clin Ther 2015; 37: 996–1009 e7.

    Article  CAS  Google Scholar 

  28. Jahani R, Fielding KA, Chen J, Villa CR, Castelli LM, Ward WE et al. Low vitamin D status throughout life results in an inflammatory prone status but does not alter bone mineral or strength in healthy 3-month-old CD-1 male mice. Mol Nutr Food Res 2014; 58: 1491–1501.

    Article  CAS  Google Scholar 

  29. Wang J, Wang Y, Gao W, Wang B, Zhao H, Zeng Y et al. Diversity analysis of gut microbiota in osteoporosis and osteopenia patients. PeerJ 2017; 5: e3450.

    Article  Google Scholar 

  30. Wu GD, Chen J, Hoffmann C, Bittinger K, Chen YY, Keilbaugh SA et al. Linking long-term dietary patterns with gut microbial enterotypes. Science 2011; 334: 105–108.

    Article  CAS  Google Scholar 

  31. Roager HM, Licht TR, Poulsen SK, Larsen TM, Bahl MI . Microbial enterotypes, inferred by the prevotella-to-bacteroides ratio, remained stable during a 6-month randomized controlled diet intervention with the new nordic diet. Appl Environ Microbiol 2014; 80: 1142–1149.

    Article  Google Scholar 

  32. Hjorth MF, Roager HM, Larsen TM, Poulsen SK, Licht TR, Bahl MI et al. Pre-treatment microbial Prevotella-to-Bacteroides ratio, determines body fat loss success during a 6-month randomized controlled diet intervention. Int J Obes (Lond) 2017.

  33. De Filippo C, Cavalieri D, Di Paola M, Ramazzotti M, Poullet JB, Massart S et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci USA 2010; 107: 14691–14696.

    Article  Google Scholar 

  34. De Filippis F, Pellegrini N, Laghi L, Gobbetti M, Ercolini D . Unusual sub-genus associations of faecal Prevotella and Bacteroides with specific dietary patterns. Microbiome 2016; 4: 57.

    Article  Google Scholar 

  35. Gorvitovskaia A, Holmes SP, Huse SM . Interpreting Prevotella and Bacteroides as biomarkers of diet and lifestyle. Microbiome 2016; 4: 15.

    Article  Google Scholar 

  36. Weaver CM . Diet, gut microbiome, and bone health. Curr Osteoporos Rep 2015; 13: 125–130.

    Article  Google Scholar 

  37. Scholz-Ahrens KE, Adolph B, Rochat F, Barclay DV, de Vrese M, Açil Y et al. Effects of probiotics, prebiotics, and synbiotics on mineral metabolism in ovariectomized rats — impact of bacterial mass, intestinal absorptive area and reduction of bone turn-over. NFS J 2016; 3: 41–50.

    Article  Google Scholar 

  38. Lukens JR, Gurung P, Vogel P, Johnson GR, Carter RA, McGoldrick DJ et al. Dietary modulation of the microbiome affects autoinflammatory disease. Nature 2014; 516: 246–249.

    Article  CAS  Google Scholar 

  39. Glenn AJ, Fielding KA, Chen J, Comelli EM, Ward WE . Long-term vitamin D3 supplementation does not prevent colonic inflammation or modulate bone health in IL-10 knockout mice at young adulthood. Nutrients 2014; 6: 3847–3862.

    Article  Google Scholar 

  40. Boos A, Riner K, Hassig M, Liesegang A . Immunohistochemical demonstration of vitamin D receptor distribution in goat intestines. Cells Tissues Organs 2007; 186: 121–128.

    Article  CAS  Google Scholar 

  41. Thompson LU, Chen JM, Li T, Strasser-Weippl K, Goss PE . Dietary flaxseed alters tumor biological markers in postmenopausal breast cancer. Clin Cancer Res 2005; 11: 3828–3835.

    Article  CAS  Google Scholar 

  42. Singh N, Arioli S, Wang A, Villa CR, Jahani R, Song YS et al. Impact of Bifidobacterium bifidum MIMBb75 on mouse intestinal microorganisms. FEMS Microbiol Ecol 2013; 85: 369–375.

    Article  CAS  Google Scholar 

  43. Furet JP, Firmesse O, Gourmelon M, Bridonneau C, Tap J, Mondot S et al. Comparative assessment of human and farm animal faecal microbiota using real-time quantitative PCR. FEMS Microbiol Ecol 2009; 68: 351–362.

    Article  CAS  Google Scholar 

  44. Martin FE, Nadkarni MA, Jacques NA, Hunter N . Quantitative microbiological study of human carious dentine by culture and real-time PCR: association of anaerobes with histopathological changes in chronic pulpitis. J Clin Microbiol 2002; 40: 1698–1704.

    Article  CAS  Google Scholar 

  45. Belenchia AM, Jones KL, Will M, Beversdorf DQ, Vieira-Potter V, Rosenfeld CS et al. Maternal vitamin D deficiency during pregnancy affects expression of adipogenic-regulating genes peroxisome proliferator-activated receptor gamma (PPARgamma) and vitamin D receptor (VDR) in lean male mice offspring. Eur J Nutr 2016. PMID: 28004271..

  46. Maia-Ceciliano TC, Barreto-Vianna AR, Barbosa-da-Silva S, Aguila MB, Faria TS, Mandarim-de-Lacerda CA . Maternal vitamin D-restricted diet has consequences in the formation of pancreatic islet/insulin-signaling in the adult offspring of mice. Endocrine 2016; 54: 60–69.

    Article  CAS  Google Scholar 

  47. Blighe K, Chawes BL, Kelly RS, Mirzakhani H, McGeachie M, Litonjua AA et al. Vitamin D prenatal programming of childhood metabolomics profiles at age 3 y. Am J Clin Nutr 2017; 106: 1092–1099.

    Article  CAS  Google Scholar 

  48. Mandal S, Godfrey KM, McDonald D, Treuren WV, Bjornholt JV, Midtvedt T et al. Fat and vitamin intakes during pregnancy have stronger relations with a pro-inflammatory maternal microbiota than does carbohydrate intake. Microbiome 2016; 4: 55.

    Article  Google Scholar 

  49. Schaible TD, Harris RA, Dowd SE, Smith CW, Kellermayer R . Maternal methyl-donor supplementation induces prolonged murine offspring colitis susceptibility in association with mucosal epigenetic and microbiomic changes. Hum Mol Genet 2011; 20: 1687–1696.

    Article  CAS  Google Scholar 

  50. Xue J, Schoenrock SA, Valdar W, Tarantino LM, Ideraabdullah FY . Maternal vitamin D depletion alters DNA methylation at imprinted loci in multiple generations. Clin Epigenet 2016; 8: 107.

    Article  Google Scholar 

  51. Yousefi P, Huen K, Dave V, Barcellos L, Eskenazi B, Holland N . Sex differences in DNA methylation assessed by 450K BeadChip in newborns. BMC Genomics 2015; 16: 911.

    Article  Google Scholar 

  52. Tapp HS, Commane DM, Bradburn DM, Arasaradnam R, Mathers JC, Johnson IT et al. Nutritional factors and gender influence age-related DNA methylation in the human rectal mucosa. Aging Cell 2013; 12: 148–155.

    Article  CAS  Google Scholar 

  53. Kellermayer R, Balasa A, Zhang W, Lee S, Mirza S, Chakravarty A et al. Epigenetic maturation in colonic mucosa continues beyond infancy in mice. Hum Mol Genet 2010; 19: 2168–2176.

    Article  CAS  Google Scholar 

  54. Ciubotaru I, Green SJ, Kukreja S, Barengolts E . Significant differences in fecal microbiota are associated with various stages of glucose tolerance in African American male veterans. Transl Res 2015; 166: 401–411.

    Article  CAS  Google Scholar 

  55. Luthold RV, Fernandes GR, Franco-de-Moraes AC, Folchetti LG, Ferreira SR . Gut microbiota interactions with the immunomodulatory role of vitamin D in normal individuals. Metabolism 2017; 69: 76–86.

    Article  CAS  Google Scholar 

  56. Schwartz B, Smirnoff P, Shany S, Liel Y . Estrogen controls expression and bioresponse of 1,25-dihydroxyvitamin D receptors in the rat colon. Mol Cell Biochem 2000; 203: 87–93.

    Article  CAS  Google Scholar 

  57. Hildebrandt MA, Hoffmann C, Sherrill-Mix SA, Keilbaugh SA, Hamady M, Chen YY et al. High-fat diet determines the composition of the murine gut microbiome independently of obesity. Gastroenterology 2009; 137: 1716–24 e1-2.

    Article  CAS  Google Scholar 

  58. Whisner CM, Martin BR, Nakatsu CH, McCabe GP, McCabe LD, Peacock M et al. Soluble maize fibre affects short-term calcium absorption in adolescent boys and girls: a randomised controlled trial using dual stable isotopic tracers. Br J Nutr 2014; 112: 446–456.

    Article  CAS  Google Scholar 

  59. Fischbach MA, Sonnenburg JL . Eating for two: how metabolism establishes interspecies interactions in the gut. Cell Host Microbe 2011; 10: 336–347.

    Article  CAS  Google Scholar 

  60. Gernand AD, Schulze KJ, Stewart CP, West KP Jr., Christian P . Micronutrient deficiencies in pregnancy worldwide: health effects and prevention. Nat Rev Endocrinol 2016; 12: 274–289.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Shivani Kasee for technical help. This project was funded by a matching grant from the Centrum Foundation of Pfizer Consumer Healthcare Research Innovation Fund and the Department of Nutritional Sciences at the University of Toronto to EMC and WEW and from a Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery grant to EMC (grant # RGPIN 356124-2013). The μCT system was purchased with funding from the Canada Foundation for Innovation to WEW (grant #222084). CRV was partially funded by the Banting and Best Diabetes Centre–Novo Nordisk Studentship and –Tamarack Graduate Award in Diabetes Research and by an Ontario Graduate Scholarship. WEW holds a Canada Research Chair in Bone and Muscle Development at Brock University. EMC holds the Lawson Family Chair in Microbiome Nutrition Research at the University of Toronto.

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Correspondence to E M Comelli.

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Villa, C., Taibi, A., Chen, J. et al. Colonic Bacteroides are positively associated with trabecular bone structure and programmed by maternal vitamin D in male but not female offspring in an obesogenic environment. Int J Obes 42, 696–703 (2018). https://doi.org/10.1038/ijo.2017.294

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