Association between Polycystic Ovary Syndrome and Gut Microbiota
Yanjie Guo, Yane Qi, Xuefei Yang, Lihui Zhao, Shu Wen, Yinhui Liu, Li Tang, Yanjie Guo, Yane Qi, Xuefei Yang, Lihui Zhao, Shu Wen, Yinhui Liu, Li Tang
Abstract
Polycystic ovary syndrome (PCOS) is the most frequent endocrinopathy in women of reproductive age. It is difficult to treat PCOS because of its complex etiology and pathogenesis. Here, we characterized the roles of gut microbiota on the pathogenesis and treatments in letrozole (a nonsteroidal aromatase inhibitor) induced PCOS rat model. Changes in estrous cycles, hormonal levels, ovarian morphology and gut microbiota by PCR-DGGE and real-time PCR were determined. The results showed that PCOS rats displayed abnormal estrous cycles with increasing androgen biosynthesis and exhibited multiple large cysts with diminished granulosa layers in ovarian tissues. Meanwhile, the composition of gut microbiota in letrozole-treated rats was different from that in the controls. Lactobacillus, Ruminococcus and Clostridium were lower while Prevotella was higher in PCOS rats when compared with control rats. After treating PCOS rats with Lactobacillus and fecal microbiota transplantation (FMT) from healthy rats, it was found that the estrous cycles were improved in all 8 rats in FMT group, and in 6 of the 8 rats in Lactobacillus transplantation group with decreasing androgen biosynthesis. Their ovarian morphologies normalized. The composition of gut microbiota restored in both FMT and Lactobacillus treated groups with increasing of Lactobacillus and Clostridium, and decreasing of Prevotella. These results indicated that dysbiosis of gut microbiota was associated with the pathogenesis of PCOS. Microbiota interventions through FMT and Lactobacillus transplantation were beneficial for the treatments of PCOS rats.
Conflict of interest statement
Competing Interests: The authors have declared that no competing interests exist.
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References
- Norman RJ, Dewailly D, Legro RS, Hickey TE. Polycystic ovary syndrome. Lancet. 2007;370(9588):685–97. 10.1016/S0140-6736(07)61345-2 .
- Homburg R. Polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol. 2008;22(2):261–74. 10.1016/j.bpobgyn.2007.07.009 .
- Dokras A. Cardiovascular disease risk in women with PCOS. Steroids. 2013;78(8):773–6. 10.1016/j.steroids.2013.04.009 .
- Hsu MI. Changes in the PCOS phenotype with age. Steroids. 2013;78(8):761–6. 10.1016/j.steroids.2013.04.005 .
- Lim SS, Norman RJ, Davies MJ, Moran LJ. The effect of obesity on polycystic ovary syndrome: a systematic review and meta-analysis. Obes Rev. 2013;14(2):95–109. 10.1111/j.1467-789X.2012.01053.x .
- Balen A. The pathophysiology of polycystic ovary syndrome: trying to understand PCOS and its endocrinology. Best Pract Res Clin Obstet Gynaecol. 2004;18(5):685–706. 10.1016/j.bpobgyn.2004.05.004 .
- Ehrmann DA. Polycystic ovary syndrome. N Engl J Med. 2005;352(12):1223–36. 10.1056/NEJMra041536 .
- Goodarzi MO, Dumesic DA, Chazenbalk G, Azziz R. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol. 2011;7(4):219–31. 10.1038/nrendo.2010.217 .
- Franks S, Gharani N, Waterworth D, Batty S, White D, Williamson R, et al. The genetic basis of polycystic ovary syndrome. Hum Reprod. 1997;12(12):2641–8. .
- Fox R, Ryan A. Polycystic ovary syndrome: not ovarian, not simple, unkind. Hum Fertil (Camb). 2002;5(1 Suppl):S28–32. .
- Haag LM, Fischer A, Otto B, Plickert R, Kühl AA, Göbel UB, et al. Intestinal microbiota shifts towards elevated commensal Escherichia coli loads abrogate colonization resistance against Campylobacter jejuni in mice. PLOS One. 2012;7(5):e35988 10.1371/journal.pone.0035988
- McNeil NI. The contribution of the large intestine to energy supplies in man. Am J Clin Nutr. 1984;39(2):338–42. .
- Maloy KJ, Powrie F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature. 2011;474(7351):298–306. 10.1038/nature10208 .
- Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 472(7341):57–63. Epub 2011/04/09. doi: nature09922 [pii] 10.1038/nature09922
- Markle JG, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM, Rolle-Kampczyk U, et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science. 339(6123):1084–8. Epub 2013/01/19. doi: science.1233521 [pii] 10.1126/science.1233521 .
- Moran CP, Shanahan F. Gut microbiota and obesity: role in aetiology and potential therapeutic target. Best Pract Res Clin Gastroenterol. 28(4):585–97. Epub 2014/09/10. doi: S1521-6918(14)00083-3 [pii] 10.1016/j.bpg.2014.07.005 .
- Flak MB, Neves JF, Blumberg RS. Immunology. Welcome to the microgenderome. Science. 2013;339(6123):1044–5. 10.1126/science.1236226
- Markle JG, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM, Rolle-Kampczyk U, et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science. 2013;339(6123):1084–8. 10.1126/science.1233521 .
- Tremellen K, Pearce K. Dysbiosis of Gut Microbiota (DOGMA)—a novel theory for the development of Polycystic Ovarian Syndrome. Med Hypotheses. 2012;79(1):104–12. 10.1016/j.mehy.2012.04.016 .
- Yang S, Li W, Challis JR, Reid G, Kim SO, Bocking AD. Probiotic Lactobacillus rhamnosus GR-1 supernatant prevents lipopolysaccharide-induced preterm birth and reduces inflammation in pregnant CD-1 mice. Am J Obstet Gynecol. 211(1):44 e1–e12. Epub 2014/02/04. doi: S0002-9378(14)00058-1 [pii] 10.1016/j.ajog.2014.01.029 .
- Andreasen AS, Larsen N, Pedersen-Skovsgaard T, Berg RM, Moller K, Svendsen KD, et al. Effects of Lactobacillus acidophilus NCFM on insulin sensitivity and the systemic inflammatory response in human subjects. Br J Nutr. 104(12):1831–8. Epub 2010/09/08. doi: S0007114510002874 [pii] 10.1017/S0007114510002874 .
- Johnson-Henry KC, Donato KA, Shen-Tu G, Gordanpour M, Sherman PM. Lactobacillus rhamnosus strain GG prevents enterohemorrhagic Escherichia coli O157:H7-induced changes in epithelial barrier function. Infect Immun. 2008;76(4):1340–8. Epub 2008/01/30. doi: IAI.00778-07 [pii] 10.1128/IAI.00778-07
- Parassol N, Freitas M, Thoreux K, Dalmasso G, Bourdet-Sicard R, Rampal P. Lactobacillus casei DN-114 001 inhibits the increase in paracellular permeability of enteropathogenic Escherichia coli-infected T84 cells. Res Microbiol. 2005;156(2):256–62. Epub 2005/03/08. doi: S0923-2508(04)00263-3 [pii] 10.1016/j.resmic.2004.09.013 .
- Vrieze A, Van Nood E, Holleman F, Salojarvi J, Kootte RS, Bartelsman JF, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 143(4):913–6 e7. Epub 2012/06/26. doi: S0016-5085(12)00892-X [pii] 10.1053/j.gastro.2012.06.031 .
- Li M, Liang P, Li Z, Wang Y, Zhang G, Gao H, et al. Fecal microbiota transplantation and bacterial consortium transplantation have comparable effects on the re-establishment of mucosal barrier function in mice with intestinal dysbiosis. Front Microbiol. 6:692 Epub 2015/07/29. 10.3389/fmicb.2015.00692
- Kafali H, Iriadam M, Ozardali I, Demir N. Letrozole-induced polycystic ovaries in the rat: a new model for cystic ovarian disease. Arch Med Res. 2004;35(2):103–8. 10.1016/j.arcmed.2003.10.005 .
- Joossens M, Huys G, Cnockaert M, De Preter V, Verbeke K, Rutgeerts P, et al. Dysbiosis of the faecal microbiota in patients with Crohn's disease and their unaffected relatives. Gut. 2011;60(5):631–7. 10.1136/gut.2010.223263 .
- Clarke G, Grenham S, Scully P, Fitzgerald P, Moloney RD, Shanahan F, et al. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry. 2013;18(6):666–73. 10.1038/mp.2012.77 .
- Lebbe M, Woodruff TK. Involvement of androgens in ovarian health and disease. Mol Hum Reprod. 2013;19(12):828–37. 10.1093/molehr/gat065
- Corbin CJ, Trant JM, Walters KW, Conley AJ. Changes in testosterone metabolism associated with the evolution of placental and gonadal isozymes of porcine aromatase cytochrome P450. Endocrinology. 1999;140(11):5202–10. 10.1210/endo.140.11.7140 .
- Chen J, Shen S, Tan Y, Xia D, Xia Y, Cao Y, et al. The correlation of aromatase activity and obesity in women with or without polycystic ovary syndrome. J Ovarian Res. 2015;8(1):11 10.1186/s13048-015-0139-1
- Diamanti-Kandarakis E. Polycystic ovarian syndrome: pathophysiology, molecular aspects and clinical implications. Expert Rev Mol Med. 2008;10:e3 10.1017/S1462399408000598 .
- Sun J, Jin C, Wu H, Zhao J, Cui Y, Liu H, et al. Effects of electro-acupuncture on ovarian P450arom, P450c17α and mRNA expression induced by letrozole in PCOS rats. PLOS One. 2013;8(11):e79382 10.1371/journal.pone.0079382
- Küpeli Akkol E, İlhan M, Ayşe Demirel M, Keleş H, Tümen I, Süntar İ. Thuja occidentalis L. and its active compound, α-thujone: Promising effects in the treatment of polycystic ovary syndrome without inducing osteoporosis. J Ethnopharmacol. 2015. 10.1016/j.jep.2015.03.029 .
- Brook I. Microbiology and antimicrobial management of sinusitis. J Laryngol Otol. 2005;119(4):251–8. 10.1258/0022215054020304 .
- Oakley BB, Fiedler TL, Marrazzo JM, Fredricks DN. Diversity of human vaginal bacterial communities and associations with clinically defined bacterial vaginosis. Appl Environ Microbiol. 2008;74(15):4898–909. 10.1128/AEM.02884-07
- Zambon JJ, Reynolds HS, Slots J. Black-pigmented Bacteroides spp. in the human oral cavity. Infect Immun. 1981;32(1):198–203.
- Umeda M, Chen C, Bakker I, Contreras A, Morrison JL, Slots J. Risk indicators for harboring periodontal pathogens. J Periodontol. 1998;69(10):1111–8. 10.1902/jop.1998.69.10.1111 .
- Akcalı A, Bostanci N, Özçaka Ö, Öztürk-Ceyhan B, Gümüş P, Buduneli N, et al. Association between polycystic ovary syndrome, oral microbiota and systemic antibody responses. PLOS One. 2014;9(9):e108074 10.1371/journal.pone.0108074
- Kumar PS. Sex and the subgingival microbiome: do female sex steroids affect periodontal bacteria? Periodontol 2000. 2013;61(1):103–24. 10.1111/j.1600-0757.2011.00398.x .
- Soory M, Ahmad S. 5 alpha reductase activity in human gingiva and gingival fibroblasts in response to bacterial culture supernatants, using [14C]4-androstenedione as substrate. Arch Oral Biol. 1997;42(4):255–62. .
- Soory M. Bacterial steroidogenesis by periodontal pathogens and the effect of bacterial enzymes on steroid conversions by human gingival fibroblasts in culture. J Periodontal Res. 1995;30(2):124–31. .
- McFarland LV. Beneficial microbes: health or hazard? Eur J Gastroenterol Hepatol. 2000;12(10):1069–71. .
- Fuhrman BJ, Feigelson HS, Flores R, Gail MH, Xu X, Ravel J, et al. Associations of the fecal microbiome with urinary estrogens and estrogen metabolites in postmenopausal women. J Clin Endocrinol Metab. 99(12):4632–40. Epub 2014/09/12. 10.1210/jc.2014-2222
- Nilsson ME, Vandenput L, Tivesten A, Norlen AK, Lagerquist MK, Windahl SH, et al. Measurement of a Comprehensive Sex Steroid Profile in Rodent Serum by High-Sensitive Gas Chromatography-Tandem Mass Spectrometry. Endocrinology. 156(7):2492–502. Epub 2015/04/10. 10.1210/en.2014-1890 .
- Hulston CJ, Churnside AA, Venables MC. Probiotic supplementation prevents high-fat, overfeeding-induced insulin resistance in human subjects. Br J Nutr. 2015;113(4):596–602. 10.1017/S0007114514004097
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