AIMS: Ovarian hormone deficiency is one of the main risk factors for osteoporosis and bone fractures in women, and these risks can be mitigated by menopausal hormone therapy. Recent evidence suggests that gut microbiota may link changes in estrogen levels and bone metabolism. This study was conducted to investigate the potential relationship between hormonal and bone changes induced by oophorectomy and subsequent hormonal therapy and shifts in gut microbiota composition. METHODS: We collected 159 stool and blood samples in several intervals from 58 women, who underwent bilateral oophorectomy. Changes in fecal microbiota were assessed in paired samples collected from each woman before and after oophorectomy or the start of hormone therapy. Bacterial composition was determined by sequencing the 16S rRNA gene on Illumina MiSeq. Blood levels of estradiol, FSH, biomarkers of bone metabolism, and indices of low-grade inflammation were measured using laboratory analytical systems and commercial ELISA. Areal bone mineral density (BMD) of the lumbar spine, proximal femur, and femur neck was measured using dual-energy X-ray absorptiometry. RESULTS: We found no significant changes in gut microbiota composition 6 months after oophorectomy, despite major changes in hormone levels, BMD, and bone metabolism. A small decrease in bacterial diversity was apparent 18 months after surgery in taxonomy-aware metrics. Hormonal therapy after oophorectomy prevented bone loss but only marginally affected gut microbiota. There were no significant differences in β-diversity related to hormonal status, although several microbes (e.g., Lactococcus lactis) followed estrogen levels. Body mass index (BMI) was the most significantly associated with microbiota variance. Microbiota was not a suitable predictive factor for the state of bone metabolism. CONCLUSIONS: We conclude that neither the loss of estrogens due to oophorectomy nor their gain due to subsequent hormonal therapy is associated with a specific gut microbiota signature. Sources of variability in microbiota composition are more related to interindividual differences than hormonal status.

Department of Obstetrics and Gynecology Charles University Prague 1st Faculty of Medicine Prague Czechia

Department of Rheumatology 1st Faculty of Medicine Charles University Prague Prague Czechia

General University Hospital Prague Prague Czechia

Institute of Rheumatology Prague Czechia

Laboratory of Cellular and Molecular Immunology Institute of Microbiology Czech Academy of Sciences Prague Czechia

Laboratory of Fungal Genetics and Metabolism Institute of Microbiology Czech Academy of Sciences Prague Czechia

Zobrazit více v PubMed

Compston JE, McClung MR, Leslie WD. Osteoporosis. Lancet (2019) 393(10169):364–76. doi: 10.1016/S0140-6736(18)32112-3 PubMed DOI

Lorentzon M, Johansson H, Harvey NC, Liu E, Vandenput L, Crandall CJ, et al. . Menopausal hormone therapy reduces the risk of fracture regardless of falls risk or baseline FRAX probability-results from the women's health initiative hormone therapy trials. Osteoporos Int (2022) 33(11):2297–305. doi: 10.1007/s00198-022-06483-y PubMed DOI PMC

Khosla S, Shane E. A crisis in the treatment of osteoporosis. J Bone Miner Res (2016) 31(8):1485–7. doi: 10.1002/jbmr.2888 PubMed DOI

Khosla S, Oursler MJ, Monroe DG. Estrogen and the skeleton. Trends Endocrinol Metab (2012) 23(11):576–81. doi: 10.1016/j.tem.2012.03.008 PubMed DOI PMC

Manolagas SC, O'Brien CA, Almeida M. The role of estrogen and androgen receptors in bone health and disease. Nat Rev Endocrinol (2013) 9:699–712. doi: 10.1038/nrendo.2013.179 PubMed DOI PMC

Wei Y, Fu J, Wu W, Ma P, Ren L, Wu J. Estrogen prevents cellular senescence and bone loss through Usp10-dependent p53 degradation in osteocytes and osteoblasts: The role of estrogen in bone cell senescence. Cell Tissue Res (2021) 386(2):297–308. doi: 10.1007/s00441-021-03496-7 PubMed DOI

Khastgir G, Studd J, Holland N, Alaghband-Zadeh J, Fox S, Chow J. Anabolic effect of estrogen replacement on bone in postmenopausal women with osteoporosis: histomorphometric evidence in a longitudinal study. J Clin Endocrinol Metab (2001) 86(1):289–95. doi: 10.1210/jcem.86.1.7161 PubMed DOI

Doolittle ML, Saul D, Kaur J, Rowsey JL, Eckhardt B, Vos S, et al. . Skeletal effects of inducible ERα deletion in osteocytes in adult mice. J Bone Miner Res (2022) 37(9):1750–60. doi: 10.1002/jbmr.4644 PubMed DOI PMC

Srivastava S, Toraldo G, Weitzmann MN, Cenci S, Ross FP, Pacifici R. Estrogen decreases osteoclast formation by down-regulating receptor activator of NF-kappa b ligand (RANKL)-induced JNK activation. J Biol Chem (2001) 276(12):8836–40. doi: 10.1074/jbc.M010764200 PubMed DOI

Pacifici R. Role of T cells in ovariectomy induced bone loss–revisited. J Bone Miner Res (2012) 27(2):231–9. doi: 10.1002/jbmr.1500 PubMed DOI

Kim HJ, Yoon HJ, Lee DK, Jin X, Che X, Choi JY. The estrogen-related receptor gamma modulator, GSK5182, inhibits osteoclast differentiation and accelerates osteoclast apoptosis. BMB Rep (2021) 54(5):266–71. doi: 10.5483/BMBRep.2021.54.5.243 PubMed DOI PMC

Zhang W, Gao R, Rong X, Zhu S, Cui Y, Liu H, et al. . Immunoporosis: Role of immune system in the pathophysiology of different types of osteoporosis. Front Endocrinol (Lausanne) (2022) 13:965258. doi: 10.3389/fendo.2022.965258 PubMed DOI PMC

Lean JM, Davies JT, Fuller K, Jagger CJ, Kirstein B, Partington GA, et al. . A crucial role for thiol antioxidants in estrogen-deficiency bone loss. J Clin Invest (2003) 112(6):915–23. doi: 10.1172/JCI18859 PubMed DOI PMC

Eriksen EF, Langdahl B, Vesterby A, Rungby J, Kassem M. Hormone replacement therapy prevents osteoclastic hyperactivity: A histomorphometric study in early postmenopausal women. J Bone Miner Res (1999) 14(7):1217–21. doi: 10.1359/jbmr.1999.14.7.1217 PubMed DOI

Bhattacharyya S, Siegel ER, Achenbach SJ, Khosla S, Suva LJ. Serum biomarker profile associated with high bone turnover and BMD in postmenopausal women. J Bone Miner Res (2008) 23(7):1106–17. doi: 10.1359/jbmr.080235 PubMed DOI PMC

Cenci S, Toraldo G, Weitzmann MN, Roggia C, Gao Y, Qian WP, et al. . Estrogen deficiency induces bone loss by increasing T cell proliferation and lifespan through IFN-gamma-induced class II transactivator. Proc Natl Acad Sci U.S.A. (2003) 100(18):10405–10. doi: 10.1073/pnas.1533207100 PubMed DOI PMC

Tyagi AM, Darby TM, Hsu E, Yu M, Pal S, Dar H, et al. . The gut microbiota is a transmissible determinant of skeletal maturation. Elife (2021) 10:e64237. doi: 10.7554/eLife.64237 PubMed DOI PMC

Tyagi AM, Yu M, Darby TM, Vaccaro C, Li JY, Owens JA, et al. . The microbial metabolite butyrate stimulates bone formation via T regulatory cell-mediated regulation of WNT10B expression. Immunity (2018) 49(6):1116–1131.e1117. doi: 10.1016/j.immuni.2018.10.013 PubMed DOI PMC

Li JY, Yu M, Pal S, Tyagi AM, Dar H, Adams J, et al. . Parathyroid hormone-dependent bone formation requires butyrate production by intestinal microbiota. J Clin Invest (2020) 130(4):1767–81. doi: 10.1172/JCI133473 PubMed DOI PMC

Li JY, Chassaing B, Tyagi AM, Vaccaro C, Luo T, Adams J, et al. . Sex steroid deficiency-associated bone loss is microbiota dependent and prevented by probiotics. J Clin Invest (2016) 126(6):2049–63. doi: 10.1172/JCI86062 PubMed DOI PMC

Yu M, Pal S, Paterson CW, Li JY, Tyagi AM, Adams J, et al. . Ovariectomy induces bone loss via microbial-dependent trafficking of intestinal TNF+ T cells and Th17 cells. J Clin Invest (2021) 131(4):e143137. doi: 10.1172/JCI143137 PubMed DOI PMC

Menon R, Watson SE, Thomas LN, Allred CD, Dabney A, Azcarate-Peril MA, et al. . Diet complexity and estrogen receptor beta status affect the composition of the murine intestinal microbiota. Appl Environ Microbiol (2013) 79(18):5763–73. doi: 10.1128/AEM.01182-13 PubMed DOI PMC

Atkins GJ, Welldon KJ, Wijenayaka AR, Bonewald LF, Findlay DM. Vitamin K promotes mineralization, osteoblast-to-osteocyte transition, and an anticatabolic phenotype by {gamma}-carboxylation-dependent and -independent mechanisms. Am J Physiol Cell Physiol (2009) 297(6):C1358–1367. doi: 10.1152/ajpcell.00216.2009 PubMed DOI

Van de Wiele T, Vanhaecke L, Boeckaert C, Peru K, Headley J, Verstraete W, et al. . Human colon microbiota transform polycyclic aromatic hydrocarbons to estrogenic metabolites. Environ Health Perspect (2005) 113(1):6–10. doi: 10.1289/ehp.7259 PubMed DOI PMC

Yano JM, Yu K, Donaldson GP, Shastri GG, Ann P, Ma L, et al. . Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell (2015) 161(2):264–76. doi: 10.1016/j.cell.2015.02.047 PubMed DOI PMC

Yan J, Charles JF. Gut microbiota and IGF-1. Calcif Tissue Int (2018) 102(4):406–14. doi: 10.1007/s00223-018-0395-3 PubMed DOI PMC

Wang N, Ma S, Fu L. Gut microbiota dysbiosis as one cause of osteoporosis by impairing intestinal barrier function. Calcif Tissue Int (2022) 110(2):225–35. doi: 10.1007/s00223-021-00911-7 PubMed DOI

Santos-Marcos JA, Rangel-Zuniga OA, Jimenez-Lucena R, Quintana-Navarro GM, Garcia-Carpintero S, Malagon MM, et al. . Influence of gender and menopausal status on gut microbiota. Maturitas (2018) 116:43–53. doi: 10.1016/j.maturitas.2018.07.008 PubMed DOI

Shin JH, Park YH, Sim M, Kim SA, Joung H, Shin DM. Serum level of sex steroid hormone is associated with diversity and profiles of human gut microbiome. Res Microbiol (2019) 170(4-5):192–201. doi: 10.1016/j.resmic.2019.03.003 PubMed DOI

Zhao H, Chen J, Li X, Sun Q, Qin P, Wang Q. Compositional and functional features of the female premenopausal and postmenopausal gut microbiota. FEBS Lett (2019) 593(18):2655–64. doi: 10.1002/1873-3468.13527 PubMed DOI

Hass MA, Nichol P, Lee L, Levin RM. Estrogen modulates permeability and prostaglandin levels in the rabbit urinary bladder. Prostaglandins Leukot Essent Fatty Acids (2009) 80(2-3):125–9. doi: 10.1016/j.plefa.2008.11.010 PubMed DOI

Patrick DM, Leone AK, Shellenberger JJ, Dudowicz KA, King JM. Proinflammatory cytokines tumor necrosis factor-alpha and interferon-gamma modulate epithelial barrier function in madin-Darby canine kidney cells through mitogen activated protein kinase signaling. BMC Physiol (2006) 6:2. doi: 10.1186/1472-6793-6-2 PubMed DOI PMC

Hernandez CJ, Guss JD, Luna M, Goldring SR. Links between the microbiome and bone. J Bone Miner Res (2016) 31(9):1638–46. doi: 10.1002/jbmr.2887 PubMed DOI PMC

Gomez A, Luckey D, Taneja V. The gut microbiome in autoimmunity: Sex matters. Clin Immunol (2015) 159(2):154–62. doi: 10.1016/j.clim.2015.04.016 PubMed DOI PMC

Yu M, Malik Tyagi A, Li JY, Adams J, Denning TL, Weitzmann MN, et al. . PTH induces bone loss via microbial-dependent expansion of intestinal TNF(+) T cells and Th17 cells. Nat Commun (2020) 11(1):468. doi: 10.1038/s41467-019-14148-4 PubMed DOI PMC

Schierova D, Roubalova R, Kolar M, Stehlikova Z, Rob F, Jackova Z, et al. . Fecal microbiome changes and specific anti-bacterial response in patients with IBD during anti-TNF therapy. Cells (2021) 10(11):3188. doi: 10.3390/cells10113188 PubMed DOI PMC

Bolyen E, Rideout JR, Dillon MR, Bokulich NA, Abnet CC, Al-Ghalith GA, et al. . Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2. Nat Biotechnol (2019) 37(8):852–7. doi: 10.1038/s41587-019-0209-9 PubMed DOI PMC

Callahan BJ, McMurdie PJ, Rosen MJ, Han AW, Johnson AJ, Holmes SP. DADA2: High-resolution sample inference from illumina amplicon data. Nat Methods (2016) 13(7):581–3. doi: 10.1038/nmeth.3869 PubMed DOI PMC

Bokulich NA, Dillon MR, Bolyen E, Kaehler BD, Huttley GA, Caporaso JG. q2-sample-classifier: Machine-learning tools for microbiome classification and regression. J Open Res Softw (2018) 3(30):934. doi: 10.21105/joss.00934 PubMed DOI PMC

Anderson MJ. A new method for non-parametric multivariate analysis of variance. Austral Ecol (2001) 26(1):32–46. doi: 10.1111/j.1442-9993.2001.01070.pp.x DOI

Zapala MA, Schork NJ. Multivariate regression analysis of distance matrices for testing associations between gene expression patterns and related variables. Proc Natl Acad Sci U.S.A. (2006) 103(51):19430–5. doi: 10.1073/pnas.0609333103 PubMed DOI PMC

Morton JT, Marotz C, Washburne A, Silverman J, Zaramela LS, Edlund A, et al. . Establishing microbial composition measurement standards with reference frames. Nat Commun (2019) 10(1):2719. doi: 10.1038/s41467-019-10656-5 PubMed DOI PMC

Kaul A, Mandal S, Davidov O, Peddada SD. Analysis of microbiome data in the presence of excess zeros. Front Microbiol (2017) 8:2114. doi: 10.3389/fmicb.2017.02114 PubMed DOI PMC

Mendes E, Acetturi BG, Thomas AM, Martins FDS, Crisma AR, Murata G, et al. . Prophylactic supplementation of bifidobacterium longum 5(1A) protects mice from ovariectomy-induced exacerbated allergic airway inflammation and airway hyperresponsiveness. Front Microbiol (2017) 8:1732. doi: 10.3389/fmicb.2017.01732 PubMed DOI PMC

Zeibich L, Koebele SV, Bernaud VE, Ilhan ZE, Dirks B, Northup-Smith SN, et al. . Surgical menopause and estrogen therapy modulate the gut microbiota, obesity markers, and spatial memory in rats. Front Cell Infect Microbiol (2021) 11:702628. doi: 10.3389/fcimb.2021.702628 PubMed DOI PMC

Keshavarz Azizi Raftar S, Hoseini Tavassol Z, Amiri M, Ejtahed HS, Zangeneh M, Sadeghi S, et al. . Assessment of fecal akkermansia muciniphila in patients with osteoporosis and osteopenia: a pilot study. J Diabetes Metab Disord (2021) 20(1):279–84. doi: 10.1007/s40200-021-00742-1 PubMed DOI PMC

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. doi: 10.7717/peerj.3450 PubMed DOI PMC

Rettedal EA, Ilesanmi-Oyelere BL, Roy NC, Coad J, Kruger MC. The gut microbiome is altered in postmenopausal women with osteoporosis and osteopenia. JBMR Plus (2021) 5(3):e10452. doi: 10.1002/jbm4.10452 PubMed DOI PMC

Das M, Cronin O, Keohane DM, Cormac EM, Nugent H, Nugent M, et al. . Gut microbiota alterations associated with reduced bone mineral density in older adults. Rheumatol (Oxford) (2019) 58(12):2295–304. doi: 10.1093/rheumatology/kez302 PubMed DOI PMC

Wei M, Li C, Dai Y, Zhou H, Cui Y, Zeng Y, et al. . High-throughput absolute quantification sequencing revealed osteoporosis-related gut microbiota alterations in han Chinese elderly. Front Cell Infect Microbiol (2021) 11:630372. doi: 10.3389/fcimb.2021.630372 PubMed DOI PMC

Wang Q, Sun Q, Li X, Wang Z, Zheng H, Ju Y, et al. . Linking gut microbiome to bone mineral density: A shotgun metagenomic dataset from 361 elderly women. Gigabyte (2021) 1–13. doi: 10.46471/gigabyte.12 PubMed DOI PMC

Li C, Huang Q, Yang R, Dai Y, Zeng Y, Tao L, et al. . Gut microbiota composition and bone mineral loss-epidemiologic evidence from individuals in wuhan, China. Osteoporos Int (2019) 30(5):1003–13. doi: 10.1007/s00198-019-04855-5 PubMed DOI

Wang Y, Gao X, Lv J, Zeng Y, Li Q, Wang L, et al. . Gut microbiome signature are correlated with bone mineral density alterations in the Chinese elders. Front Cell Infect Microbiol (2022) 12:827575. doi: 10.3389/fcimb.2022.827575 PubMed DOI PMC

Orwoll ES, Parimi N, Wiedrick J, Lapidus J, Napoli N, Wilkinson JE, et al. . Analysis of the associations between the human fecal microbiome and bone density, structure, and strength: The osteoporotic fractures in men (MrOS) cohort. J Bone Miner Res (2022) 37(4):597–607. doi: 10.1002/jbmr.4518 PubMed DOI PMC

Xu X, Jia X, Mo L, Liu C, Zheng L, Yuan Q, et al. . Intestinal microbiota: a potential target for the treatment of postmenopausal osteoporosis. Bone Res (2017) 5:17046. doi: 10.1038/boneres.2017.46 PubMed DOI PMC

Ohlsson C, Engdahl C, Fak F, Andersson A, Windahl SH, Farman HH, et al. . Probiotics protect mice from ovariectomy-induced cortical bone loss. PloS One (2014) 9(3):e92368. doi: 10.1371/journal.pone.0092368 PubMed DOI PMC

Montazeri-Najafabady N, Ghasemi Y, Dabbaghmanesh MH, Talezadeh P, Koohpeyma F, Gholami A. Supportive role of probiotic strains in protecting rats from ovariectomy-induced cortical bone loss. Probiotics Antimicrob Proteins (2019) 11(4):1145–54. doi: 10.1007/s12602-018-9443-6 PubMed DOI

Gholami A, Dabbaghmanesh MH, Ghasemi Y, Koohpeyma F, Talezadeh P, Montazeri-Najafabady N. The ameliorative role of specific probiotic combinations on bone loss in the ovariectomized rat model. BMC Complement Med Ther (2022) 22(1):241. doi: 10.1186/s12906-022-03713-y PubMed DOI PMC

Lawenius L, Scheffler JM, Gustafsson KL, Henning P, Nilsson KH, Collden H, et al. . Pasteurized akkermansia muciniphila protects from fat mass gain but not from bone loss. Am J Physiol Endocrinol Metab (2020) 318(4):E480–91. doi: 10.1152/ajpendo.00425.2019 PubMed DOI PMC

Kimoto-Nira H, Mizumachi K, Okamoto T, Sasaki K, Kurisaki J. Influence of long-term consumption of a lactococcus lactis strain on the intestinal immunity and intestinal flora of the senescence-accelerated mouse. Br J Nutr (2009) 102(2):181–5. doi: 10.1017/S0007114508143574 PubMed DOI

Lambert MNT, Thybo CB, Lykkeboe S, Rasmussen LM, Frette X, Christensen LP, et al. . Combined bioavailable isoflavones and probiotics improve bone status and estrogen metabolism in postmenopausal osteopenic women: A randomized controlled trial. Am J Clin Nutr (2017) 106(3):909–20. doi: 10.3945/ajcn.117.153353 PubMed DOI

Nilsson AG, Sundh D, Backhed F, Lorentzon M. Lactobacillus reuteri reduces bone loss in older women with low bone mineral density: A randomized, placebo-controlled, double-blind, clinical trial. J Intern Med (2018) 284(3):307–17. doi: 10.1111/joim.12805 PubMed DOI

Takimoto T, Hatanaka M, Hoshino T, Takara T, Tanaka K, Shimizu A, et al. . Effect of bacillus subtilis c-3102 on bone mineral density in healthy postmenopausal Japanese women: A randomized, placebo-controlled, double-blind clinical trial. Biosci Microbiota Food Health (2018) 37(4):87–96. doi: 10.12938/bmfh.18-006 PubMed DOI PMC

Jansson P-A, Curiac D, Lazou Ahrén I, Hansson F, Martinsson Niskanen T, Sjögren K, et al. . Probiotic treatment using a mix of three lactobacillus strains for lumbar spine bone loss in postmenopausal women: A randomised, double-blind, placebo-controlled, multicentre trial. Lancet Rheumatol (2019) 1(3):e154–62. doi: 10.1016/S2665-9913(19)30068-2 PubMed DOI

Palleja A, Mikkelsen KH, Forslund SK, Kashani A, Allin KH, Nielsen T, et al. . Recovery of gut microbiota of healthy adults following antibiotic exposure. Nat Microbiol (2018) 3(11):1255–65. doi: 10.1038/s41564-018-0257-9 PubMed DOI

Anthony WE, Wang B, Sukhum KV, D'Souza AW, Hink T, Cass C, et al. . Acute and persistent effects of commonly used antibiotics on the gut microbiome and resistome in healthy adults. Cell Rep (2022) 39(2):110649. doi: 10.1016/j.celrep.2022.110649 PubMed DOI PMC

Elvers KT, Wilson VJ, Hammond A, Duncan L, Huntley AL, Hay AD, et al. . Antibiotic-induced changes in the human gut microbiota for the most commonly prescribed antibiotics in primary care in the UK: A systematic review. BMJ Open (2020) 10(9):e035677. doi: 10.1136/bmjopen-2019-035677 PubMed DOI PMC

Straub RH. The complex role of estrogens in inflammation. Endocr Rev (2007) 28(5):521–74. doi: 10.1210/er.2007-0001 PubMed DOI

Faubion L, White TA, Peterson BJ, Geske JR, LeBrasseur NK, Schafer MJ, et al. . Effect of menopausal hormone therapy on proteins associated with senescence and inflammation. Physiol Rep (2020) 8(16):e14535. doi: 10.14814/phy2.14535 PubMed DOI PMC

Sze MA, Schloss PD. Looking for a signal in the noise: Revisiting obesity and the microbiome. mBio (2016) 7(4):e01018–16. doi: 10.1128/mBio.01018-16 PubMed DOI PMC

Sheng S, Yan S, Chen J, Zhang Y, Wang Y, Qin Q, et al. . Gut microbiome is associated with metabolic syndrome accompanied by elevated gamma-glutamyl transpeptidase in men. Front Cell Infect Microbiol (2022) 12:946757. doi: 10.3389/fcimb.2022.946757 PubMed DOI PMC

Singh P, Rawat A, Alwakeel M, Sharif E, Al Khodor S. The potential role of vitamin d supplementation as a gut microbiota modifier in healthy individuals. Sci Rep (2020) 10(1):21641. doi: 10.1038/s41598-020-77806-4 PubMed DOI PMC

Thomas RL, Jiang L, Adams JS, Xu ZZ, Shen J, Janssen S, et al. . Vitamin d metabolites and the gut microbiome in older men. Nat Commun (2020) 11(1):5997. doi: 10.1038/s41467-020-19793-8 PubMed DOI PMC

Lin X, Xiao H-M, Liu H-M, Lv W-Q, Greenbaum J, Yuan S-J, et al. . Gut microbiota impacts bone via b.vulgatus-valeric acid-related pathways. medRxiv (2020). doi: 10.1101/2020.03.16.20037077 PubMed DOI PMC

Shindo K, Fukushima K. Deconjugation of bile acids by human intestinal bacteria. Gastroenterol Jpn (1976) 11(3):167–74. doi: 10.1007/BF02777700 PubMed DOI

Qi X, Yun C, Sun L, Xia J, Wu Q, Wang Y, et al. . Gut microbiota-bile acid-interleukin-22 axis orchestrates polycystic ovary syndrome. Nat Med (2019) 25(8):1225–33. doi: 10.1038/s41591-019-0509-0 PubMed DOI PMC

Gao L, Kuraji R, Zhang MJ, Martinez A, Radaic A, Kamarajan P, et al. . Nisin probiotic prevents inflammatory bone loss while promoting reparative proliferation and a healthy microbiome. NPJ Biofilms Microbiomes (2022) 8(1):45. doi: 10.1038/s41522-022-00307-x PubMed DOI PMC

Sojan JM, Raman R, Muller M, Carnevali O, Renn J. Probiotics enhance bone growth and rescue BMP inhibition: New transgenic zebrafish lines to study bone health. Int J Mol Sci (2022) 23(9):4748. doi: 10.3390/ijms23094748 PubMed DOI PMC

Liu R, Hong J, Xu X, Feng Q, Zhang D, Gu Y, et al. . Gut microbiome and serum metabolome alterations in obesity and after weight-loss intervention. Nat Med (2017) 23(7):859–68. doi: 10.1038/nm.4358 PubMed DOI

Choi S, Hwang YJ, Shin MJ, Yi H. Difference in the gut microbiome between ovariectomy-induced obesity and diet-induced obesity. J Microbiol Biotechnol (2017) 27(12):2228–36. doi: 10.4014/jmb.1710.10001 PubMed DOI

Vasikaran S, Eastell R, Bruyere O, Foldes AJ, Garnero P, Griesmacher A, et al. . Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: A need for international reference standards. Osteoporos Int (2011) 22(2):391–420. doi: 10.1007/s00198-010-1501-1 PubMed DOI

Hashimoto K, Nozaki M, Inoue Y, Sano M, Nakano H. The chronological change of vertebral bone loss following oophorectomy using dual energy X-ray absorptiometry: The correlation with specific markers of bone metabolism. Maturitas (1995) 22(3):185–91. doi: 10.1016/0378-5122(95)00940-m PubMed DOI

Challberg J, Ashcroft L, Lalloo F, Eckersley B, Clayton R, Hopwood P, et al. . Menopausal symptoms and bone health in women undertaking risk reducing bilateral salpingo-oophorectomy: Significant bone health issues in those not taking HRT. Br J Cancer (2011) 105(1):22–7. doi: 10.1038/bjc.2011.202 PubMed DOI PMC

Fakkert IE, Abma EM, Westrik IG, Lefrandt JD, Wolffenbuttel BH, Oosterwijk JC, et al. . Bone mineral density and fractures after risk-reducing salpingo-oophorectomy in women at increased risk for breast and ovarian cancer. Eur J Cancer (2015) 51(3):400–8. doi: 10.1016/j.ejca.2014.11.022 PubMed DOI

Farlay D, Bala Y, Rizzo S, Bare S, Lappe JM, Recker R, et al. . Bone remodeling and bone matrix quality before and after menopause in healthy women. Bone (2019) 128:115030. doi: 10.1016/j.bone.2019.08.003 PubMed DOI

Jiang H, Robinson DL, Lee PVS, Krejany EO, Yates CJ, Hickey M, et al. . Loss of bone density and bone strength following premenopausal risk-reducing bilateral salpingo-oophorectomy: A prospective controlled study (WHAM study). Osteoporos Int (2021) 32(1):101–12. doi: 10.1007/s00198-020-05608-5 PubMed DOI

Peris P, Alvarez L, Monegal A, Guanabens N, Duran M, Pons F, et al. . Biochemical markers of bone turnover after surgical menopause and hormone replacement therapy. Bone (1999) 25(3):349–53. doi: 10.1016/s8756-3282(99)00175-1 PubMed DOI

Yasumizu T, Fukada Y, Hoshi K. Changes in serum levels of type I collagen-related proteins after surgically induced menopause and correlations with bone loss in the lumbar spine. Endocr J (1999) 46(2):337–43. doi: 10.1507/endocrj.46.337 PubMed DOI

Ohta H, Makita K, Komukai S, Nozawa S. Bone resorption versus estrogen loss following oophorectomy and menopause. Maturitas (2002) 43(1):27–33. doi: 10.1016/s0378-5122(02)00180-9 PubMed DOI

Garcia-Perez MA, Moreno-Mercer J, Tarin JJ, Cano A. Bone turnover markers and PTH levels in surgical versus natural menopause. Calcif Tissue Int (2004) 74(2):143–9. doi: 10.1007/s00223-003-0054-0 PubMed DOI

Bahar S, Abali R, Guzel S, Bozkurt S, Guzel EC, Aral H, et al. . Comparison of the acute alterations in serum bone turnover markers and bone mineral density among women with surgical menopause. Eur J Obstet Gynecol Reprod Biol (2011) 159(1):194–7. doi: 10.1016/j.ejogrb.2011.06.033 PubMed DOI

Fakkert IE, van der Veer E, Abma EM, Lefrandt JD, Wolffenbuttel BH, Oosterwijk JC, et al. . Elevated bone turnover markers after risk-reducing salpingo-oophorectomy in women at increased risk for breast and ovarian cancer. PloS One (2017) 12(1):e0169673. doi: 10.1371/journal.pone.0169673 PubMed DOI PMC

Ardawi MS, Al-Kadi HA, Rouzi AA, Qari MH. Determinants of serum sclerostin in healthy pre- and postmenopausal women. J Bone Miner Res (2011) 26(12):2812–22. doi: 10.1002/jbmr.479 PubMed DOI

Tamura T, Udagawa N, Takahashi N, Miyaura C, Tanaka S, Yamada Y, et al. . Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6. Proc Natl Acad Sci U.S.A. (1993) 90(24):11924–8. doi: 10.1073/pnas.90.24.11924 PubMed DOI PMC

Girasole G, Giuliani N, Modena AB, Passeri G, Pedrazzoni M. Oestrogens prevent the increase of human serum soluble interleukin-6 receptor induced by ovariectomy in vivo and decrease its release in human osteoblastic cells in vitro . Clin Endocrinol (Oxf) (1999) 51(6):801–7. doi: 10.1046/j.1365-2265.1999.00896.x PubMed DOI

Abrahamsen B, Bonnevie-Nielsen V, Ebbesen EN, Gram J, Beck-Nielsen H. Cytokines and bone loss in a 5-year longitudinal study–hormone replacement therapy suppresses serum soluble interleukin-6 receptor and increases interleukin-1-receptor antagonist: the Danish osteoporosis prevention study. J Bone Miner Res (2000) 15(8):1545–54. doi: 10.1359/jbmr.2000.15.8.1545 PubMed DOI

David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, et al. . Diet rapidly and reproducibly alters the human gut microbiome. Nature (2014) 505(7484):559–63. doi: 10.1038/nature12820 PubMed DOI PMC

Fragiadakis GK, Wastyk HC, Robinson JL, Sonnenburg ED, Sonnenburg JL, Gardner CD. Long-term dietary intervention reveals resilience of the gut microbiota despite changes in diet and weight. Am J Clin Nutr (2020) 111(6):1127–36. doi: 10.1093/ajcn/nqaa046 PubMed DOI PMC

Associations Among Estrogens, the Gut Microbiome and Osteoporosis