PURPOSE OF THE REVIEW: The purpose of this Review was to summarize the evidence on the associations among estrogen status, cellular senescence, the gut microbiome and osteoporosis. RECENT FINDINGS: Indicate that osteoporosis is a global public health problem that impacts individuals and society. In postmenopausal women, a decrease in estrogen levels is associated with a decrease in gut microbial diversity and richness, as well as increased permeability of the gut barrier, which allows for low-grade inflammation. The direct effects of estrogen status on the association between bone and the gut microbiome were observed in untreated and treated ovariectomized women. In addition to the direct effects of estrogens on bone remodeling, estrogen therapy could reduce the risk of postmenopausal osteoporosis by preventing increased gut epithelial permeability, bacterial translocation and inflammaging. However, in studies comparing the gut microbiota of older women, there were no changes at the phylum level, suggesting that age-related comorbidities may have a greater impact on changes in the gut microbiota than menopausal status does. Estrogens modify bone health not only by directly influencing bone remodeling, but also indirectly by influencing the gut microbiota, gut barrier function and the resulting changes in immune system reactivity.

Department of Rheumatology 1st Faculty of Medicine Charles University Kateřinská 32 Praha 2 121 08 Czech Republic

Institute of Rheumatology Prague Czechia

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

Zobrazit více v PubMed

Kanis JA, Burlet N, Cooper C, Delmas PD, Reginster JY, Borgstrom F, et al. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int. 2008;19(4):399–428. 10.1007/s00198-008-0560-z. PubMed PMC

Willers C, Norton N, Harvey NC, Jacobson T, Johansson H, Lorentzon M, et al. Osteoporosis in Europe: a compendium of country-specific reports. Arch Osteoporos. 2022;17(1):23. 10.1007/s11657-021-00969-8. PubMed PMC

Trajanoska K, Schoufour JD, de Jonge EAL, Kieboom BCT, Mulder M, Stricker BH, et al. Fracture incidence and secular trends between 1989 and 2013 in a population based cohort: The Rotterdam Study. Bone. 2018;114:116–24. 10.1016/j.bone.2018.06.004. PubMed

da Silva PFL, Ogrodnik M, Kucheryavenko O, Glibert J, Miwa S, Cameron K, et al. The bystander effect contributes to the accumulation of senescent cells in vivo. Aging Cell. 2019;18(1):e12848. 10.1111/acel.12848. PubMed PMC

Steinmann GG, Klaus B, Muller-Hermelink HK. The involution of the ageing human thymic epithelium is independent of puberty. A morphometric study Scand J Immunol. 1985;22(5):563–75. 10.1111/j.1365-3083.1985.tb01916.x. PubMed

Adeel S, Singh K, Vydareny KH, Kumari M, Shah E, Weitzmann MN, et al. Bone loss in surgically ovariectomized premenopausal women is associated with T lymphocyte activation and thymic hypertrophy. J Investig Med. 2013;61(8):1178–83. 10.2310/JIM.0000000000000016. PubMed PMC

Thomas R, Wang W, Su DM. Contributions of Age-Related Thymic Involution to Immunosenescence and Inflammaging. Immun Ageing. 2020;17:2. 10.1186/s12979-020-0173-8. PubMed PMC

Pangrazzi L, Weinberger B. T cells, aging and senescence. Exp Gerontol. 2020;134:110887. 10.1016/j.exger.2020.110887. PubMed

Farr JN, Fraser DG, Wang H, Jaehn K, Ogrodnik MB, Weivoda MM, et al. Identification of Senescent Cells in the Bone Microenvironment. J Bone Miner Res. 2016;31(11):1920–9. 10.1002/jbmr.2892. PubMed PMC

Li CJ, Xiao Y, Sun YC, He WZ, Liu L, Huang M, et al. Senescent immune cells release grancalcin to promote skeletal aging. Cell Metab. 2021;33(10):1957-73 e6. 10.1016/j.cmet.2021.08.009. PubMed

Bano G, Trevisan C, Carraro S, Solmi M, Luchini C, Stubbs B, et al. Inflammation and sarcopenia: A systematic review and meta-analysis. Maturitas. 2017;96:10–5. 10.1016/j.maturitas.2016.11.006. PubMed

Liu ZJ, Zhuge Y, Velazquez OC. Trafficking and differentiation of mesenchymal stem cells. J Cell Biochem. 2009;106(6):984–91. 10.1002/jcb.22091. PubMed

Mi B, Xiong Y, Knoedler S, Alfertshofer M, Panayi AC, Wang H, et al. Ageing-related bone and immunity changes: insights into the complex interplay between the skeleton and the immune system. Bone Research. 2024;12(1):42. 10.1038/s41413-024-00346-4. PubMed PMC

Ru JY, Wang YF. Osteocyte apoptosis: the roles and key molecular mechanisms in resorption-related bone diseases. Cell Death Dis. 2020;11(10):846. 10.1038/s41419-020-03059-8. PubMed PMC

Josephson AM, Bradaschia-Correa V, Lee S, Leclerc K, Patel KS, Muinos Lopez E, et al. Age-related inflammation triggers skeletal stem/progenitor cell dysfunction. Proc Natl Acad Sci U S A. 2019;116(14):6995–7004. 10.1073/pnas.1810692116. PubMed 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. 10.1007/s00441-021-03496-7. PubMed

Farr JN, Xu M, Weivoda MM, Monroe DG, Fraser DG, Onken JL, et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat Med. 2017;23(9):1072–9. 10.1038/nm.4385. PubMed PMC

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. 10.14814/phy2.14535. PubMed PMC

Tlaskalova-Hogenova H, Stepankova R, Kozakova H, Hudcovic T, Vannucci L, Tuckova L, et al. The role of gut microbiota (commensal bacteria) and the mucosal barrier in the pathogenesis of inflammatory and autoimmune diseases and cancer: contribution of germ-free and gnotobiotic animal models of human diseases. Cell Mol Immunol. 2011;8(2):110–20. 10.1038/cmi.2010.67. PubMed PMC

Levy M, Kolodziejczyk AA, Thaiss CA, Elinav E. Dysbiosis and the immune system. Nat Rev Immunol. 2017;17(4):219–32. 10.1038/nri.2017.7. PubMed

Baechle JJ, Chen N, Makhijani P, Winer S, Furman D, Winer DA. Chronic inflammation and the hallmarks of aging. Mol Metab. 2023;74:101755. 10.1016/j.molmet.2023.101755. PubMed PMC

Kverka M, Tlaskalova-Hogenova H. Intestinal Microbiota: Facts and Fiction. Dig Dis. 2017;35(1–2):139–47. 10.1159/000449095. PubMed

Bajer L, Kverka M, Kostovcik M, Macinga P, Dvorak J, Stehlikova Z, et al. Distinct gut microbiota profiles in patients with primary sclerosing cholangitis and ulcerative colitis. World J Gastroenterol. 2017;23(25):4548–58. 10.3748/wjg.v23.i25.4548. PubMed PMC

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. 10.1038/nature12820. PubMed PMC

Thaiss CA, Zeevi D, Levy M, Zilberman-Schapira G, Suez J, Tengeler AC, et al. Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis. Cell. 2014;159(3):514–29. 10.1016/j.cell.2014.09.048. PubMed

Byberg L, Bellavia A, Larsson SC, Orsini N, Wolk A, Michaelsson K. Mediterranean Diet and Hip Fracture in Swedish Men and Women. J Bone Miner Res. 2016;31(12):2098–105. 10.1002/jbmr.2896. PubMed

Kimble R, Gouinguenet P, Ashor A, Stewart C, Deighton K, Matu J, et al. Effects of a mediterranean diet on the gut microbiota and microbial metabolites: A systematic review of randomized controlled trials and observational studies. Crit Rev Food Sci Nutr. 2023;63(27):8698–719. 10.1080/10408398.2022.2057416. PubMed

O’Toole PW, Jeffery IB. Gut microbiota and aging. Science. 2015;350(6265):1214–5. 10.1126/science.aac8469. PubMed

Gupta VK, Paul S, Dutta C. Geography, Ethnicity or Subsistence-Specific Variations in Human Microbiome Composition and Diversity. Front Microbiol. 2017;8:1162. 10.3389/fmicb.2017.01162. PubMed PMC

Xu Y, Liu X, Liu X, Chen D, Wang M, Jiang X, et al. The Roles of the Gut Microbiota and Chronic Low-Grade Inflammation in Older Adults With Frailty. Front Cell Infect Microbiol. 2021;11:675414. 10.3389/fcimb.2021.675414. PubMed PMC

Claesson MJ, Cusack S, O’Sullivan O, Greene-Diniz R, de Weerd H, Flannery E, et al. Composition, variability, and temporal stability of the intestinal microbiota of the elderly. Proc Natl Acad Sci U S A. 2011;108(Suppl 1):4586–91. 10.1073/pnas.1000097107. PubMed PMC

Biagi E, Nylund L, Candela M, Ostan R, Bucci L, Pini E, et al. Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians. PLoS ONE. 2010;5(5):e10667. 10.1371/journal.pone.0010667. PubMed PMC

Ren J, Li H, Zeng G, Pang B, Wang Q, Wei J. Gut microbiome-mediated mechanisms in aging-related diseases: are probiotics ready for prime time? Frontiers in Pharmacology. 2023;14:1178596. 10.3389/fphar.2023.1178596. PubMed PMC

Odamaki T, Kato K, Sugahara H, Hashikura N, Takahashi S, Xiao JZ, et al. Age-related changes in gut microbiota composition from newborn to centenarian: a cross-sectional study. BMC Microbiol. 2016;16:90. 10.1186/s12866-016-0708-5. PubMed PMC

Xu C, Zhu H, Qiu P. Aging progression of human gut microbiota. BMC Microbiol. 2019;19(1):236. 10.1186/s12866-019-1616-2. PubMed PMC

Badal VD, Vaccariello ED, Murray ER, Yu KE, Knight R, Jeste DV, et al. The Gut Microbiome, Aging, and Longevity: A Systematic Review. Nutrients. 2020;12(12):3759. 10.3390/nu12123759. PubMed PMC

Bosco N, Noti M. The aging gut microbiome and its impact on host immunity. Genes Immun. 2021;22(5):289–303. 10.1038/s41435-021-00126-8. PubMed PMC

Warman DJ, Jia H, Kato H. The Potential Roles of Probiotics, Resistant Starch, and Resistant Proteins in Ameliorating Inflammation during Aging (Inflammaging). Nutrients. 2022;14(4):747. PubMed PMC

Andersen SL, Sebastiani P, Dworkis DA, Feldman L, Perls TT. Health span approximates life span among many supercentenarians: compression of morbidity at the approximate limit of life span. J Gerontol A Biol Sci Med Sci. 2012;67(4):395–405. 10.1093/gerona/glr223. PubMed PMC

Liu X, Zou L, Nie C, Qin Y, Tong X, Wang J, et al. Mendelian randomization analyses reveal causal relationships between the human microbiome and longevity. Sci Rep. 2023;13(1):5127. 10.1038/s41598-023-31115-8. PubMed PMC

Biagi E, Franceschi C, Rampelli S, Severgnini M, Ostan R, Turroni S, et al. Gut Microbiota and Extreme Longevity. Current biology : CB. 2016;26(11):1480–5. 10.1016/j.cub.2016.04.016. PubMed

Omar JM, Chan Y-M, Jones ML, Prakash S, Jones PJH. Lactobacillus fermentum and Lactobacillus amylovorus as probiotics alter body adiposity and gut microflora in healthy persons. J Funct Foods. 2013;5(1):116–23. 10.1016/j.jff.2012.09.001.

Kostic AD, Chun E, Robertson L, Glickman JN, Gallini CA, Michaud M, et al. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe. 2013;14(2):207–15. 10.1016/j.chom.2013.07.007. PubMed PMC

He Y, Mujagond P, Tang W, Wu W, Zheng H, Chen X, et al. Non-nucleatum Fusobacterium species are dominant in the Southern Chinese population with distinctive correlations to host diseases compared with F. nucleatum. Gut. 2021;70(4):810–2. 10.1136/gutjnl-2020-322090. PubMed

Zepeda-Rivera M, Minot SS, Bouzek H, Wu H, Blanco-Míguez A, Manghi P, et al. A distinct Fusobacterium nucleatum clade dominates the colorectal cancer niche. Nature. 2024;628(8007):424–32. 10.1038/s41586-024-07182-w. PubMed PMC

Baker JM, Al-Nakkash L, Herbst-Kralovetz MM. Estrogen-gut microbiome axis: Physiological and clinical implications. Maturitas. 2017;103:45–53. 10.1016/j.maturitas.2017.06.025. PubMed

Chen KL, Madak-Erdogan Z. Estrogen and Microbiota Crosstalk: Should We Pay Attention? Trends Endocrinol Metab. 2016;27(11):752–5. 10.1016/j.tem.2016.08.001. PubMed

Kwa M, Plottel CS, Blaser MJ, Adams S. The Intestinal Microbiome and Estrogen Receptor-Positive Female Breast Cancer. J Natl Cancer Inst. 2016;108(8):djw029. 10.1093/jnci/djw029. PubMed PMC

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. 10.1289/ehp.7259. PubMed PMC

Hogan AM, Collins D, Baird AW, Winter DC. Estrogen and its role in gastrointestinal health and disease. Int J Colorectal Dis. 2009;24(12):1367–75. 10.1007/s00384-009-0785-0. PubMed

Waclawiková B, Codutti A, Alim K, El Aidy S. Gut microbiota-motility interregulation: insights from in vivo, ex vivo and in silico studies. Gut Microbes. 2022;14(1):1997296. 10.1080/19490976.2021.1997296. PubMed PMC

So SY, Savidge TC. Sex-Bias in Irritable Bowel Syndrome: Linking Steroids to the Gut-Brain Axis. Front Endocrinol. 2021;12:684096. 10.3389/fendo.2021.684096. PubMed PMC

So SY, Savidge TC. Gut feelings: the microbiota-gut-brain axis on steroids. Am J Physiol Gastrointest Liver Physiol. 2022;322(1):G1–20. 10.1152/ajpgi.00294.2021. PubMed 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. 10.1172/JCI86062. PubMed PMC

Shieh A, Epeldegui M, Karlamangla AS, Greendale GA. Gut permeability, inflammation, and bone density across the menopause transition. JCI Insight. 2020;5(2). 10.1172/jci.insight.134092. PubMed PMC

Salazar AM, Aparicio R, Clark RI, Rera M, Walker DW. Intestinal barrier dysfunction: an evolutionarily conserved hallmark of aging. Dis Model Mech. 2023;16(4):dmm049969. 10.1242/dmm.049969. PubMed PMC

Benedek G, Zhang J, Nguyen H, Kent G, Seifert HA, Davin S, et al. Estrogen protection against EAE modulates the microbiota and mucosal-associated regulatory cells. J Neuroimmunol. 2017;310:51–9. 10.1016/j.jneuroim.2017.06.007. PubMed PMC

Chen KLA, Zhao YC, Hieronymi K, Smith BP, Madak-Erdogan Z. Bazedoxifene and conjugated estrogen combination maintains metabolic homeostasis and benefits liver health. PLoS ONE. 2017;12(12):e0189911. 10.1371/journal.pone.0189911. PubMed PMC

Kaliannan K, Robertson RC, Murphy K, Stanton C, Kang C, Wang B, et al. Estrogen-mediated gut microbiome alterations influence sexual dimorphism in metabolic syndrome in mice. Microbiome. 2018;6(1):205. 10.1186/s40168-018-0587-0. PubMed PMC

Acharya KD, Gao X, Bless EP, Chen J, Tetel MJ. Estradiol and high fat diet associate with changes in gut microbiota in female ob/ob mice. Sci Rep. 2019;9(1):20192. 10.1038/s41598-019-56723-1. PubMed PMC

Wang N, Meng F, Ma S, Fu L. Species-level gut microbiota analysis in ovariectomized osteoporotic rats by Shallow shotgun sequencing. Gene. 2022;817:146205. 10.1016/j.gene.2022.146205. PubMed

Meng Q, Ma M, Zhang W, Bi Y, Cheng P, Yu X, et al. The gut microbiota during the progression of atherosclerosis in the perimenopausal period shows specific compositional changes and significant correlations with circulating lipid metabolites. Gut Microbes. 2021;13(1):1–27. 10.1080/19490976.2021.1880220. PubMed PMC

d’Afflitto M, Upadhyaya A, Green A, Peiris M. Association Between Sex Hormone Levels and Gut Microbiota Composition and Diversity-A Systematic Review. J Clin Gastroenterol. 2022;56(5):384–92. 10.1097/MCG.0000000000001676. PubMed PMC

Yang M, Wen S, Zhang J, Peng J, Shen X, Xu L. Systematic Review and Meta-analysis: Changes of Gut Microbiota before and after Menopause. Dis Markers. 2022;2022:3767373. 10.1155/2022/3767373. PubMed PMC

Huang R, Liu P, Bai Y, Huang J, Pan R, Li H, et al. Changes in the gut microbiota of osteoporosis patients based on 16S rRNA gene sequencing: a systematic review and meta-analysis. J Zhejiang Univ Sci B. 2022;23(12):1002–13. 10.1631/jzus.B2200344. PubMed PMC

Xue Y, Wang X, Liu H, Kang J, Liang X, Yao A, et al. Assessment of the relationship between gut microbiota and bone mineral density: a two-sample Mendelian randomization study. Front Microbiol. 2024;15:1298838. 10.3389/fmicb.2024.1298838. PubMed PMC

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. 10.1016/j.maturitas.2018.07.008. PubMed

Zhu J, Liao M, Yao Z, Liang W, Li Q, Liu J, et al. Breast cancer in postmenopausal women is associated with an altered gut metagenome. Microbiome. 2018;6(1):136. 10.1186/s40168-018-0515-3. PubMed PMC

Jackova Z, Stepan JJ, Coufal S, Kostovcik M, Galanova N, Reiss Z, et al. Interindividual differences contribute to variation in microbiota composition more than hormonal status: A prospective study. Front Endocrinol. 2023;14:1139056. 10.3389/fendo.2023.1139056. PubMed PMC

Mayneris-Perxachs J, Arnoriaga-Rodriguez M, Luque-Cordoba D, Priego-Capote F, Perez-Brocal V, Moya A, et al. Gut microbiota steroid sexual dimorphism and its impact on gonadal steroids: influences of obesity and menopausal status. Microbiome. 2020;8(1):136. 10.1186/s40168-020-00913-x. PubMed PMC

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. 10.1002/1873-3468.13527. PubMed

He J, Xu S, Zhang B, Xiao C, Chen Z, Si F, et al. Gut microbiota and metabolite alterations associated with reduced bone mineral density or bone metabolic indexes in postmenopausal osteoporosis. Aging (Albany NY). 2020;12(9):8583–604. 10.18632/aging.103168. PubMed PMC

Ozaki D, Kubota R, Maeno T, Abdelhakim M, Hitosugi N. Association between gut microbiota, bone metabolism, and fracture risk in postmenopausal Japanese women. Osteoporos Int. 2021;32(1):145–56. 10.1007/s00198-020-05728-y. PubMed PMC

Wu J, Zhuo Y, Liu Y, Chen Y, Ning Y, Yao J. Association between premature ovarian insufficiency and gut microbiota. BMC Pregnancy Childbirth. 2021;21(1):418. 10.1186/s12884-021-03855-w. PubMed 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. 10.3389/fcimb.2021.630372. PubMed 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. 10.1002/jbm4.10452. PubMed PMC

Peters BA, Xue X, Sheira LA, Qi Q, Sharma A, Santoro N, et al. Menopause Is Associated With Immune Activation in Women With HIV. J Infect Dis. 2022;225(2):295–305. 10.1093/infdis/jiab341. PubMed PMC

Wu Z, Pfeiffer RM, Byrd DA, Wan Y, Ansong D, Clegg-Lamptey JN, et al. Associations of Circulating Estrogens and Estrogen Metabolites with Fecal and Oral Microbiome in Postmenopausal Women in the Ghana Breast Health Study. Microbiol Spectr. 2023;11(4):e0157223. 10.1128/spectrum.01572-23. PubMed PMC

Huang D, Wang J, Zeng Y, Li Q, Wang Y. Identifying microbial signatures for patients with postmenopausal osteoporosis using gut microbiota analyses and feature selection approaches. Front Microbiol. 2023;14:1113174. 10.3389/fmicb.2023.1113174. PubMed PMC

Peters B, Hanna D, Wang Y, Weber K, Topper E, Appleton A, et al. Sex Hormones, the Stool Microbiome, and Subclinical Atherosclerosis in Women With and Without HIV. J Clin Endocrinol Metab. 2024;109(2):483–97. 10.1210/clinem/dgad510. PubMed 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. 10.7717/peerj.3450. PubMed PMC

Ling CW, Miao Z, Xiao ML, Zhou H, Jiang Z, Fu Y, et al. The Association of Gut Microbiota With Osteoporosis Is Mediated by Amino Acid Metabolism: Multiomics in a Large Cohort. J Clin Endocrinol Metab. 2021;106(10):e3852–64. 10.1210/clinem/dgab492. PubMed

Wang Z, Chen K, Wu C, Chen J, Pan H, Liu Y, et al. An emerging role of Prevotella histicola on estrogen deficiency-induced bone loss through the gut microbiota-bone axis in postmenopausal women and in ovariectomized mice. Am J Clin Nutr. 2021;114(4):1304–13. 10.1093/ajcn/nqab194. PubMed

Custodero C, Mankowski RT, Lee SA, Chen Z, Wu S, Manini TM, et al. Evidence-based nutritional and pharmacological interventions targeting chronic low-grade inflammation in middle-age and older adults: A systematic review and meta-analysis. Ageing Res Rev. 2018;46:42–59. 10.1016/j.arr.2018.05.004. PubMed PMC

Inan MS, Rasoulpour RJ, Yin L, Hubbard AK, Rosenberg DW, Giardina C. The luminal short-chain fatty acid butyrate modulates NF-kappaB activity in a human colonic epithelial cell line. Gastroenterology. 2000;118(4):724–34. 10.1016/s0016-5085(00)70142-9. PubMed

Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 2013;504(7480):446–50. 10.1038/nature12721. PubMed

Huang S, Chen J, Cui Z, Ma K, Wu D, Luo J, et al. Lachnospiraceae-derived butyrate mediates protection of high fermentable fiber against placental inflammation in gestational diabetes mellitus. Sci Adv. 2023;9(44):eadi7337. 10.1126/sciadv.adi7337. PubMed PMC

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

Schwarzer M, Gautam UK, Makki K, Lambert A, Brabec T, Joly A, et al. Microbe-mediated intestinal NOD2 stimulation improves linear growth of undernourished infant mice. Science. 2023;379(6634):826–33. 10.1126/science.ade9767. PubMed

Zeng Y, Wu Y, Zhang Q, Xiao X. Crosstalk between glucagon-like peptide 1 and gut microbiota in metabolic diseases. mBio. 2024;15(1):e0203223. 10.1128/mbio.02032-23. PubMed PMC

Liu H, Xiao H, Lin S, Zhou H, Cheng Y, Xie B, et al. Effect of gut hormones on bone metabolism and their possible mechanisms in the treatment of osteoporosis. Front Pharmacol. 2024;15:1372399. 10.3389/fphar.2024.1372399. PubMed PMC

Covasa M, Stephens RW, Toderean R, Cobuz C. Intestinal Sensing by Gut Microbiota: Targeting Gut Peptides. Front Endocrinol. 2019;10:82. 10.3389/fendo.2019.00082. PubMed PMC

Bikle DD. Vitamin D and bone. Curr Osteoporos Rep. 2012;10:151–9. 10.1007/s11914-012-0098-z. PubMed 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. 10.1128/AEM.01182-13. PubMed PMC

Yamamoto EA, Jorgensen TN. Relationships Between Vitamin D, Gut Microbiome, and Systemic Autoimmunity. Front Immunol. 2019;10:3141. 10.3389/fimmu.2019.03141. PubMed PMC

Colin EM, Van Den Bemd GJ, Van Aken M, Christakos S, De Jonge HR, Deluca HF, et al. Evidence for involvement of 17beta-estradiol in intestinal calcium absorption independent of 1,25-dihydroxyvitamin D3 level in the Rat. J Bone Miner Res. 1999;14(1):57–64. 10.1359/jbmr.1999.14.1.57. PubMed

Ten Bolscher M, Netelenbos JC, Barto R, Van Buuren LM, Vandervijgh WJ. Estrogen regulation of intestinal calcium absorption in the intact and ovariectomized adult rat. J Bone Miner Res. 1999;14(7):1197–202. 10.1359/jbmr.1999.14.7.1197. PubMed

Liel Y, Shany S, Smirnoff P, Schwartz B. Estrogen increases 1,25-dihydroxyvitamin D receptors expression and bioresponse in the rat duodenal mucosa. Endocrinology. 1999;140(1):280–5. 10.1210/endo.140.1.6408. PubMed

Fakhoury HMA, Kvietys PR, AlKattan W, Anouti FA, Elahi MA, Karras SN, et al. Vitamin D and intestinal homeostasis: Barrier, microbiota, and immune modulation. J Steroid Biochem Mol Biol. 2020;200:105663. 10.1016/j.jsbmb.2020.105663. PubMed

Fawaz L, Mrad MF, Kazan JM, Sayegh S, Akika R, Khoury SJ. Comparative effect of 25(OH)D3 and 1,25(OH)2D3 on Th17 cell differentiation. Clin Immunol. 2016;166–167:59–71. 10.1016/j.clim.2016.02.011. PubMed

Schieren A, Koch S, Pecht T, Simon MC. Impact of Physiological Fluctuations of Sex Hormones During the Menstrual Cycle on Glucose Metabolism and the Gut Microbiota. Exp Clin Endocrinol Diabetes. 2024;132(5):267–78. 10.1055/a-2273-5602. PubMed PMC

Mihajlovic J, Leutner M, Hausmann B, Kohl G, Schwarz J, Röver H, et al. Combined hormonal contraceptives are associated with minor changes in composition and diversity in gut microbiota of healthy women. Environ Microbiol. 2021;23(6):3037–47. 10.1111/1462-2920.15517. PubMed

Vighi G, Marcucci F, Sensi L, Di Cara G, Frati F. Allergy and the gastrointestinal system. Clin Exp Immunol. 2008;153(Suppl 1):3–6. 10.1111/j.1365-2249.2008.03713.x. PubMed PMC

Mörbe UM, Jørgensen PB, Fenton TM, von Burg N, Riis LB, Spencer J, et al. Human gut-associated lymphoid tissues (GALT); diversity, structure, and function. Mucosal Immunol. 2021;14(4):793–802. 10.1038/s41385-021-00389-4. PubMed

Ryan MR, Shepherd R, Leavey JK, Gao Y, Grassi F, Schnell FJ, et al. An IL-7-dependent rebound in thymic T cell output contributes to the bone loss induced by estrogen deficiency. Proc Natl Acad Sci U S A. 2005;102(46):16735–40. 10.1073/pnas.0505168102. PubMed PMC

Weitzmann MN, Pacifici R. Estrogen deficiency and bone loss: an inflammatory tale. J Clin Invest. 2006;116(5):1186–94. 10.1172/JCI28550. PubMed PMC

Eghbali-Fatourechi G, Khosla S, Sanyal A, Boyle WJ, Lacey DL, Riggs BL. Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J Clin Invest. 2003;111(8):1221–30. 10.1172/JCI17215. PubMed PMC

Charatcharoenwitthaya N, Khosla S, Atkinson EJ, McCready LK, Riggs BL. Effect of blockade of TNF-alpha and interleukin-1 action on bone resorption in early postmenopausal women. J Bone Miner Res. 2007;22(5):724–9. 10.1359/jbmr.070207. PubMed

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

Ono T, Hayashi M, Sasaki F, Nakashima T. RANKL biology: bone metabolism, the immune system, and beyond. Inflamm Regen. 2020;40:2. 10.1186/s41232-019-0111-3. PubMed PMC

Marahleh A, Kitaura H, Ohori F, Noguchi T, Mizoguchi I. The osteocyte and its osteoclastogenic potential. Front Endocrinol. 2023;14:1121727. 10.3389/fendo.2023.1121727. PubMed PMC

Bengtsson AK, Ryan EJ. Immune function of the decoy receptor osteoprotegerin. Crit Rev Immunol. 2002;22(3):201–15. PubMed

Knoop KA, Kumar N, Butler BR, Sakthivel SK, Taylor RT, Nochi T, et al. RANKL is necessary and sufficient to initiate development of antigen-sampling M cells in the intestinal epithelium. J Immunol. 2009;183(9):5738–47. 10.4049/jimmunol.0901563. PubMed PMC

Mabbott NA, Donaldson DS, Ohno H, Williams IR, Mahajan A. Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium. Mucosal Immunol. 2013;6(4):666–77. 10.1038/mi.2013.30. PubMed PMC

Nakamura Y, Kimura S, Hase K. M cell-dependent antigen uptake on follicle-associated epithelium for mucosal immune surveillance. Inflamm Regen. 2018;38(1):15. 10.1186/s41232-018-0072-y. PubMed PMC

Kimura S, Nakamura Y, Kobayashi N, Shiroguchi K, Kawakami E, Mutoh M, et al. Osteoprotegerin-dependent M cell self-regulation balances gut infection and immunity. Nat Commun. 2020;11(1):234. 10.1038/s41467-019-13883-y. PubMed 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. 10.1007/s00223-021-00911-7. PubMed

Naydenov NG, Baranwal S, Khan S, Feygin A, Gupta P, Ivanov AI. Novel mechanism of cytokine-induced disruption of epithelial barriers: Janus kinase and protein kinase D-dependent downregulation of junction protein expression. Tissue Barriers. 2013;1(4):e25231. 10.4161/tisb.25231. PubMed PMC

Ozaki H, Ishii K, Horiuchi H, Arai H, Kawamoto T, Okawa K, et al. Cutting edge: combined treatment of TNF-alpha and IFN-gamma causes redistribution of junctional adhesion molecule in human endothelial cells. J Immunol. 1999;163(2):553–7. PubMed

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). 10.1172/JCI143137. PubMed PMC

Cline-Smith A, Axelbaum A, Shashkova E, Chakraborty M, Sanford J, Panesar P, et al. Ovariectomy Activates Chronic Low-Grade Inflammation Mediated by Memory T Cells, Which Promotes Osteoporosis in Mice. J Bone Miner Res. 2020;35(6):1174–87. 10.1002/jbmr.3966. PubMed PMC

Li JY, D’Amelio P, Robinson J, Walker LD, Vaccaro C, Luo T, et al. IL-17A Is Increased in Humans with Primary Hyperparathyroidism and Mediates PTH-Induced Bone Loss in Mice. Cell Metab. 2015;22(5):799–810. 10.1016/j.cmet.2015.09.012. PubMed PMC

Tyagi AM, Mansoori MN, Srivastava K, Khan MP, Kureel J, Dixit M, et al. Enhanced immunoprotective effects by anti-IL-17 antibody translates to improved skeletal parameters under estrogen deficiency compared with anti-RANKL and anti-TNF-alpha antibodies. J Bone Miner Res. 2014;29(9):1981–92. 10.1002/jbmr.2228. PubMed

Dart DA, Waxman J, Aboagye EO, Bevan CL. Visualising androgen receptor activity in male and female mice. PLoS ONE. 2013;8(8):e71694. 10.1371/journal.pone.0071694. PubMed PMC

Wada-Hiraike O, Imamov O, Hiraike H, Hultenby K, Schwend T, Omoto Y, et al. Role of estrogen receptor beta in colonic epithelium. Proc Natl Acad Sci U S A. 2006;103(8):2959–64. 10.1073/pnas.0511271103. PubMed PMC

Peters BA, Santoro N, Kaplan RC, Qi Q. Spotlight on the Gut Microbiome in Menopause: Current Insights. Int J Women’s Health. 2022;14:1059–72. 10.2147/IJWH.S340491. PubMed PMC

Leite G, Barlow G, Parodi G, Pimentel M, Chang C, Hosseini A, et al. Duodenal microbiome changes in postmenopausal women: effects of hormone therapy and implications for cardiovascular risk. Menopause. 2022;29(3):264–75. 10.1097/GME.0000000000001917. PubMed PMC

Kawano N, Koji T, Hishikawa Y, Murase K, Murata I, Kohno S. Identification and localization of estrogen receptor alpha- and beta-positive cells in adult male and female mouse intestine at various estrogen levels. Histochem Cell Biol. 2004;121(5):399–405. 10.1007/s00418-004-0644-6. PubMed

Moorefield EC, Andres SF, Blue RE, Van Landeghem L, Mah AT, Santoro MA, et al. Aging effects on intestinal homeostasis associated with expansion and dysfunction of intestinal epithelial stem cells. Aging (Albany NY). 2017;9(8):1898–915. 10.18632/aging.101279. PubMed PMC

Sehl ME, Ganz PA. Potential Mechanisms of Age Acceleration Caused by Estrogen Deprivation: Do Endocrine Therapies Carry the Same Risks? JNCI Cancer Spectrum. 2018;2(3):pky035. 10.1093/jncics/pky035. PubMed PMC

Hohman LS, Osborne LC. A gut-centric view of aging: Do intestinal epithelial cells contribute to age-associated microbiota changes, inflammaging, and immunosenescence? Aging Cell. 2022;21(9):e13700. 10.1111/acel.13700. PubMed PMC

Tan TG, Sefik E, Geva-Zatorsky N, Kua L, Naskar D, Teng F, et al. Identifying species of symbiont bacteria from the human gut that, alone, can induce intestinal Th17 cells in mice. Proc Natl Acad Sci U S A. 2016;113(50):E8141–50. 10.1073/pnas.1617460113. PubMed 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. 10.1038/s41467-019-14148-4. PubMed PMC

Chetty A, Blekhman R. Multi-omic approaches for host-microbiome data integration. Gut Microbes. 2024;16(1):2297860. 10.1080/19490976.2023.2297860. PubMed PMC

Gomez A, Petrzelkova KJ, Burns MB, Yeoman CJ, Amato KR, Vlckova K, et al. Gut Microbiome of Coexisting BaAka Pygmies and Bantu Reflects Gradients of Traditional Subsistence Patterns. Cell Rep. 2016;14(9):2142–53. 10.1016/j.celrep.2016.02.013. PubMed

Human Microbiome Project C. Structure function and diversity of the healthy human microbiome. Nature. 2012;486(7402):207–14. 10.1038/nature11234. PubMed PMC

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(3):470–80. 10.1016/j.cell.2012.07.008. PubMed PMC

Pena JA, Li SY, Wilson PH, Thibodeau SA, Szary AJ, Versalovic J. Genotypic and phenotypic studies of murine intestinal lactobacilli: species differences in mice with and without colitis. Appl Environ Microbiol. 2004;70(1):558–68. 10.1128/AEM.70.1.558-568.2004. PubMed PMC

Ottman N, Smidt H, de Vos WM, Belzer C. The function of our microbiota: who is out there and what do they do? Front Cell Infect Microbiol. 2012;2:104. 10.3389/fcimb.2012.00104. PubMed PMC

Adlercreutz H, Pulkkinen MO, Hamalainen EK, Korpela JT. Studies on the role of intestinal bacteria in metabolism of synthetic and natural steroid hormones. J Steroid Biochem. 1984;20(1):217–29. 10.1016/0022-4731(84)90208-5. PubMed

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. 2014;99(12):4632–40. 10.1210/jc.2014-2222. PubMed PMC

Chen TY, Huang WY, Liu KH, Kor CT, Chao YC, Wu HM. The relationship between hot flashes and fatty acid binding protein 2 in postmenopausal women. PLoS ONE. 2022;17(10):e0276391. 10.1371/journal.pone.0276391. PubMed PMC

LeBoff MS, Greenspan SL, Insogna KL, Lewiecki EM, Saag KG, Singer AJ, et al. The clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int. 2022;33(10):2049–102. 10.1007/s00198-021-05900-y. PubMed PMC

Stepan JJ, Hruskova H, Kverka M. Update on Menopausal Hormone Therapy for Fracture Prevention. Curr Osteoporos Rep. 2019;17(6):465–73. 10.1007/s11914-019-00549-3. PubMed PMC