Contributions of the intestinal microbiota to bone

Conteúdo do artigo principal

Rafael Pacheco da Costa
Carlos Rocha Oliveira
Adriana Gibotti


Introduction: Overall bone metabolism is highly regulated by the intestine, mainly mediated by parathyroid hormone (PTH) and vitamin D. However, emerging pieces of evidence have shown this regulation is also strongly associated with intestinal microbiota by releasing metabolites, which affects directly or indirectly the bone. Objective: To review the contributions of the intestinal microbiota to bone. Methods: Thus, a narrative review from articles on contributions of intestinal microbiota to bone was conducted using database PubMed covering a period from 1997 until July 2023. Articles published in the form of original articles, systematic review or meta-analysis using the descriptors: bone and microbiota, bone and bacteria, gut microbiota and bone and probiotics were read and summarized throughout text. Results: Initially, we searched for understanding, which bacteria are resident or transitory and which are the factors released that either indirectly or directly act on bone, thus modifying its quantity or quality. Therein, we briefly explored how intestine, and bone are interconnected and finally about how the type of intestinal microbiota is associated with bone metabolism, quality and quantity. In particular, we reported some main studies on probiotics and bone health. Conclusion: This review brought together information from the literature on the role of intestinal bacteria in bone, revealing possibilities for directing the microbiota to maintain or gain bone in quantity and quality and thus prevent bone fractures in a close future, especially for osteoporotic individuals.

Detalhes do artigo

Como Citar
Pacheco da Costa R, Rocha Oliveira C, Gibotti A. Contributions of the intestinal microbiota to bone. Braz. J. Nat. Sci [Internet]. 23º de janeiro de 2024 [citado 23º de julho de 2024];5(1):E195202 -, 1. Disponível em:
Artigo em fluxo contínuo
Biografia do Autor

Rafael Pacheco da Costa, Western São Paulo University School of Medicine at Guarujá - UNOESTE

Western São Paulo University School of Medicine at Guarujá - UNOESTE

Carlos Rocha Oliveira, Anhembi Morumbi University School of Medicine São José dos Campos

Anhembi Morumbi University School of Medicine São José dos Campos

Adriana Gibotti, Western São Paulo University School of Medicine at Guarujá - UNOESTE

Western São Paulo University School of Medicine at Guarujá - UNOESTE


Consortium HMP. Structure, function and diversity of the healthy human microbiome. Nature. 2012;486(7402):207-14.

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.

Biver E, Berenbaum F, Valdes AM, Araujo de Carvalho I, Bindels LB, Brandi ML, et al. Gut microbiota and osteoarthritis management: An expert consensus of the European society for clinical and economic aspects of osteoporosis, osteoarthritis and musculoskeletal diseases (ESCEO). Ageing Res Rev. 2019;55:100946.

Kanis JA. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: synopsis of a WHO report. WHO Study Group. Osteoporos Int. 1994;4(6):368-81.

Fasano A. Leaky gut and autoimmune diseases. Clin Rev Allergy Immunol. 2012;42(1):71-8.

Castaneda M, Smith KM, Nixon JC, Hernandez CJ, Rowan S. Alterations to the gut microbiome impair bone tissue strength in aged mice. Bone Rep. 2021;14:101065.

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.

Tu Y, Yang R, Xu X, Zhou X. The microbiota-gut-bone axis and bone health. J Leukoc Biol. 2021;110(3):525-37.

Lin H, Liu T, Li X, Gao X, Wu T, Li P. The role of gut microbiota metabolite trimethylamine N-oxide in functional impairment of bone marrow mesenchymal stem cells in osteoporosis disease. Ann Transl Med. 2020;8(16):1009.

Anaya JM, Bollag WB, Hamrick MW, Isales CM. The Role of Tryptophan Metabolites in Musculoskeletal Stem Cell Aging. Int J Mol Sci. 2020;21(18).

Chevalier C, Kieser S, Çolakoğlu M, Hadadi N, Brun J, Rigo D, et al. Warmth Prevents Bone Loss Through the Gut Microbiota. Cell Metab. 2020;32(4):575-90.e7.

D'Amelio P, Sassi F. Gut Microbiota, Immune System, and Bone. Calcif Tissue Int. 2018;102(4):415-25.

Malmir H, Ejtahed HS, Soroush AR, Mortazavian AM, Fahimfar N, Ostovar A, et al. Probiotics as a New Regulator for Bone Health: A Systematic Review and Meta-Analysis. Evid Based Complement Alternat Med. 2021;2021:3582989.

Rodríguez JM, Murphy K, Stanton C, Ross RP, Kober OI, Juge N, et al. The composition of the gut microbiota throughout life, with an emphasis on early life. Microb Ecol Health Dis. 2015;26:26050.

Biagi E, Franceschi C, Rampelli S, Severgnini M, Ostan R, Turroni S, et al. Gut Microbiota and Extreme Longevity. Curr Biol. 2016;26(11):1480-5.

Rampelli S, Soverini M, D'Amico F, Barone M, Tavella T, Monti D, et al. Shotgun Metagenomics of Gut Microbiota in Humans with up to Extreme Longevity and the Increasing Role of Xenobiotic Degradation. mSystems. 2020;5(2).

Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464(7285):59-65.

Checa-Ros A, Jeréz-Calero A, Molina-Carballo A, Campoy C, Muñoz-Hoyos A. Current Evidence on the Role of the Gut Microbiome in ADHD Pathophysiology and Therapeutic Implications. Nutrients. 2021;13(1).

Cummings JH, Macfarlane GT. Role of intestinal bacteria in nutrient metabolism. JPEN J Parenter Enteral Nutr. 1997;21(6):357-65.

Emmons AL, Mundorff AZ, Keenan SW, Davoren J, Andronowski J, Carter DO, et al. Characterizing the postmortem human bone microbiome from surface-decomposed remains. PLoS One. 2020;15(7):e0218636.

Macfarlane GT, Macfarlane S. Human colonic microbiota: ecology, physiology and metabolic potential of intestinal bacteria. Scand J Gastroenterol Suppl. 1997;222:3-9.

Delgado-Calle J, Tu X, Pacheco-Costa R, McAndrews K, Edwards R, Pellegrini GG, et al. Control of Bone Anabolism in Response to Mechanical Loading and PTH by Distinct Mechanisms Downstream of the PTH Receptor. J Bone Miner Res. 2017;32(3):522-35.

Christakos S, Li S, De La Cruz J, Shroyer NF, Criss ZK, Verzi MP, et al. Vitamin D and the intestine: Review and update. J Steroid Biochem Mol Biol. 2020;196:105501.

Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, et al. Endotext. 2000.

Rios-Arce ND, Schepper JD, Dagenais A, Schaefer L, Daly-Seiler CS, Gardinier JD, et al. Post-antibiotic gut dysbiosis-induced trabecular bone loss is dependent on lymphocytes. Bone. 2020;134:115269.

Sjögren K, Engdahl C, Henning P, Lerner UH, Tremaroli V, Lagerquist MK, et al. The gut microbiota regulates bone mass in mice. J Bone Miner Res. 2012;27(6):1357-67.

Jones D, Glimcher LH, Aliprantis AO. Osteoimmunology at the nexus of arthritis, osteoporosis, cancer, and infection. J Clin Invest. 2011;121(7):2534-42.

Koh A, De Vadder F, Kovatcheva-Datchary P, Bäckhed F. From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites. Cell. 2016;165(6):1332-45.

Lucas S, Omata Y, Hofmann J, Böttcher M, Iljazovic A, Sarter K, et al. Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss. Nat Commun. 2018;9(1):55.

Yan J, Takakura A, Zandi-Nejad K, Charles JF. Mechanisms of gut microbiota-mediated bone remodeling. Gut Microbes. 2018;9(1):84-92.

Kalyanaraman H, Schall N, Pilz RB. Nitric oxide and cyclic GMP functions in bone. Nitric Oxide. 2018;76:62-70.

Li X, Shang Q, Gao Z, Hao F, Guo H, Guo C. Fecal microbiota transplantation (FMT) could reverse the severity of experimental necrotizing enterocolitis (NEC) via oxidative stress modulation. Free Radic Biol Med. 2017;108:32-43.

Alcaino C, Knutson KR, Treichel AJ, Yildiz G, Strege PR, Linden DR, et al. A population of gut epithelial enterochromaffin cells is mechanosensitive and requires Piezo2 to convert force into serotonin release. Proc Natl Acad Sci U S A. 2018;115(32):E7632-E41.

Sugisawa E, Takayama Y, Takemura N, Kondo T, Hatakeyama S, Kumagai Y, et al. RNA Sensing by Gut Piezo1 Is Essential for Systemic Serotonin Synthesis. Cell. 2020;182(3):609-24.e21.

Terauchi M, Li JY, Bedi B, Baek KH, Tawfeek H, Galley S, et al. T lymphocytes amplify the anabolic activity of parathyroid hormone through Wnt10b signaling. Cell Metab. 2009;10(3):229-40.

Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med. 2013;19(2):179-92.

Schepper JD, Collins F, Rios-Arce ND, Kang HJ, Schaefer L, Gardinier JD, et al. Involvement of the Gut Microbiota and Barrier Function in Glucocorticoid-Induced Osteoporosis. J Bone Miner Res. 2020;35(4):801-20.

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.

Pacifici R. Bone Remodeling and the Microbiome. Cold Spring Harb Perspect Med. 2018;8(4).

de Sire A, de Sire R, Curci C, Castiglione F, Wahli W. Role of Dietary Supplements and Probiotics in Modulating Microbiota and Bone Health: The Gut-Bone Axis. Cells. 2022;11(4).

Roberts JL, Liu G, Darby TM, Fernandes LM, Diaz-Hernandez ME, Jones RM, et al. Bifidobacterium adolescentis supplementation attenuates fracture-induced systemic sequelae. Biomed Pharmacother. 2020;132:110831.

Luo Y, Chen GL, Hannemann N, Ipseiz N, Krönke G, Bäuerle T, et al. Microbiota from Obese Mice Regulate Hematopoietic Stem Cell Differentiation by Altering the Bone Niche. Cell Metab. 2015;22(5):886-94.

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.

Yan J, Charles JF. Gut Microbiota and IGF-1. Calcif Tissue Int. 2018;102(4):406-14.

Yan J, Herzog JW, Tsang K, Brennan CA, Bower MA, Garrett WS, et al. Gut microbiota induce IGF-1 and promote bone formation and growth. Proc Natl Acad Sci U S A. 2016;113(47):E7554-E63.

Novince CM, Whittow CR, Aartun JD, Hathaway JD, Poulides N, Chavez MB, et al. Commensal Gut Microbiota Immunomodulatory Actions in Bone Marrow and Liver have Catabolic Effects on Skeletal Homeostasis in Health. Sci Rep. 2017;7(1):5747.

Cho I, Yamanishi S, Cox L, Methé BA, Zavadil J, Li K, et al. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature. 2012;488(7413):621-6.

Nobel YR, Cox LM, Kirigin FF, Bokulich NA, Yamanishi S, Teitler I, et al. Metabolic and metagenomic outcomes from early-life pulsed antibiotic treatment. Nat Commun. 2015;6:7486.

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.

Guss JD, Horsfield MW, Fontenele FF, Sandoval TN, Luna M, Apoorva F, et al. Alterations to the Gut Microbiome Impair Bone Strength and Tissue Material Properties. J Bone Miner Res. 2017;32(6):1343-53.

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.

Vahidi G, Moody M, Welhaven HD, Davidson L, Rezaee T, Behzad R, et al. Germ-free C57BL/6 mice have increased bone mass and altered matrix properties but not decreased bone fracture resistance. J Bone Miner Res. 2023.

Luna M, Guss JD, Vasquez-Bolanos LS, Castaneda M, Rojas MV, Strong JM, et al. Components of the Gut Microbiome That Influence Bone Tissue-Level Strength. J Bone Miner Res. 2021;36(9):1823-34.

Hathaway-Schrader JD, Poulides NA, Carson MD, Kirkpatrick JE, Warner AJ, Swanson BA, et al. Specific Commensal Bacterium Critically Regulates Gut Microbiota Osteoimmunomodulatory Actions During Normal Postpubertal Skeletal Growth and Maturation. JBMR Plus. 2020;4(3):e10338.

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.

McCabe LR, Irwin R, Tekalur A, Evans C, Schepper JD, Parameswaran N, et al. Exercise prevents high fat diet-induced bone loss, marrow adiposity and dysbiosis in male mice. Bone. 2019;118:20-31.

Josefsdottir KS, Baldridge MT, Kadmon CS, King KY. Antibiotics impair murine hematopoiesis by depleting the intestinal microbiota. Blood. 2017;129(6):729-39.

Zeng X, Li X, Wei C, Shi C, Hu K, Kong D, et al. Fecal microbiota transplantation from young mice rejuvenates aged hematopoietic stem cells by suppressing inflammation. Blood. 2023;141(14):1691-707.

Liu JH, Chen CY, Liu ZZ, Luo ZW, Rao SS, Jin L, et al. Extracellular Vesicles from Child Gut Microbiota Enter into Bone to Preserve Bone Mass and Strength. Adv Sci (Weinh). 2021;8(9):2004831.

Fittipaldi S, Visconti VV, Tarantino U, Novelli G, Botta A. Genetic variability in noncoding RNAs: involvement of miRNAs and long noncoding RNAs in osteoporosis pathogenesis. Epigenomics. 2020;12(22):2035-49.

Hensley AP, McAlinden A. The role of microRNAs in bone development. Bone. 2021;143:115760.

Suez J, Zmora N, Segal E, Elinav E. The pros, cons, and many unknowns of probiotics. Nat Med. 2019;25(5):716-29.

Lu L, Chen X, Liu Y, Yu X. Gut microbiota and bone metabolism. FASEB J. 2021;35(7):e21740.

Dar HY, Shukla P, Mishra PK, Anupam R, Mondal RK, Tomar GB, et al. Lactobacillus acidophilus inhibits bone loss and increases bone heterogeneity in osteoporotic mice via modulating Treg-Th17 cell balance. Bone Rep. 2018;8:46-56.

Sapra L, Dar HY, Bhardwaj A, Pandey A, Kumari S, Azam Z, et al. Lactobacillus rhamnosus attenuates bone loss and maintains bone health by skewing Treg-Th17 cell balance in Ovx mice. Sci Rep. 2021;11(1):1807.

Parvaneh M, Karimi G, Jamaluddin R, Ng MH, Zuriati I, Muhammad SI. Lactobacillus helveticus (ATCC 27558) upregulates Runx2 and Bmp2 and modulates bone mineral density in ovariectomy-induced bone loss rats. Clin Interv Aging. 2018;13:1555-64.

Lee CC, Liao YC, Lee MC, Lin KJ, Hsu HY, Chiou SY, et al. TWK10 Attenuates Aging-Associated Muscle Weakness, Bone Loss, and Cognitive Impairment by Modulating the Gut Microbiome in Mice. Front Nutr. 2021;8:708096.

Myeong J-Y, Jung H-Y, Chae H-S, Cho HH, Kim D-K, Jang Y-J, et al. Protective Effects of the Postbiotic Lactobacillus plantarum MD35 on Bone Loss in an Ovariectomized Mice Model. Probiotics and Antimicrobial Proteins. 2023.

Lee CS, Kim SH. Anti-inflammatory and Anti-osteoporotic Potential of Lactobacillus plantarum A41 and L. fermentum SRK414 as Probiotics. Probiotics Antimicrob Proteins. 2020;12(2):623-34.

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. The Lancet Rheumatology. 2019;1(3):e154-e62.

Li P, Ji B, Luo H, Sundh D, Lorentzon M, Nielsen J. One-year supplementation with Lactobacillus reuteri ATCC PTA 6475 counteracts a degradation of gut microbiota in older women with low bone mineral density. NPJ Biofilms Microbiomes. 2022;8(1):84.

Zhao F, Guo Z, Kwok LY, Zhao Z, Wang K, Li Y, et al. Bifidobacterium lactis Probio-M8 improves bone metabolism in patients with postmenopausal osteoporosis, possibly by modulating the gut microbiota. Eur J Nutr. 2023;62(2):965-76.

Schepper JD, Collins FL, Rios-Arce ND, Raehtz S, Schaefer L, Gardinier JD, et al. Probiotic Lactobacillus reuteri Prevents Postantibiotic Bone Loss by Reducing Intestinal Dysbiosis and Preventing Barrier Disruption. J Bone Miner Res. 2019;34(4):681-98.

Artigos mais lidos pelo mesmo(s) autor(es)