The Gut-bone Axis: How Bacterial Metabolites Bridge the Distance

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2019 Jul 16

PMID 31305265

Citations 154

Authors

Mario M Zaiss

Rheinallt M Jones

Georg Schett

Roberto Pacifici

Affiliations

Soon will be listed here.

Abstract

The gut microbiome is a key regulator of bone health that affects postnatal skeletal development and skeletal involution. Alterations in microbiota composition and host responses to the microbiota contribute to pathological bone loss, while changes in microbiota composition that prevent, or reverse, bone loss may be achieved by nutritional supplements with prebiotics and probiotics. One mechanism whereby microbes influence organs of the body is through the production of metabolites that diffuse from the gut into the systemic circulation. Recently, short-chain fatty acids (SCFAs), which are generated by fermentation of complex carbohydrates, have emerged as key regulatory metabolites produced by the gut microbiota. This Review will focus on the effects of SCFAs on the musculoskeletal system and discuss the mechanisms whereby SCFAs regulate bone cells.

Citing Articles

Gut microbiota and osteonecrosis: A Mendelian randomization study.

Cai Y, Zhou C, Guan J, Dai B, Zhang X, Jiang J Medicine (Baltimore). 2025; 104(10):e41703.

PMID: 40068074 PMC: 11902940. DOI: 10.1097/MD.0000000000041703.

Gut-X axis.

Lin X, Yu Z, Liu Y, Li C, Hu H, Hu J Imeta. 2025; 4(1):e270.

PMID: 40027477 PMC: 11865426. DOI: 10.1002/imt2.270.

A review of mathematical modeling of bone remodeling from a systems biology perspective.

Cook C, Lighty A, Smith B, Ford Versypt A Front Syst Biol. 2025; 4.

PMID: 40012834 PMC: 11864782. DOI: 10.3389/fsysb.2024.1368555.

Study on the mechanism of Shuanghe decoction against steroid-induced osteonecrosis of the femoral head: insights from network pharmacology, metabolomics, and gut microbiota.

Zhu K, Liu W, Peng Y, Wang X, Wang Z, Zheng J J Orthop Surg Res. 2025; 20(1):202.

PMID: 40001178 PMC: 11863617. DOI: 10.1186/s13018-025-05619-0.

Gut-disc axis: A Mendelian randomization study on the relationship between gut microbiota and cervical spondylosis.

Zhang J, Wang B, Du P, Song H, Yang L, Zhou Y Medicine (Baltimore). 2025; 104(7):e41536.

PMID: 39960933 PMC: 11835084. DOI: 10.1097/MD.0000000000041536.

References

Tahara Y, Yamazaki M, Sukigara H, Motohashi H, Sasaki H, Miyakawa H . Gut Microbiota-Derived Short Chain Fatty Acids Induce Circadian Clock Entrainment in Mouse Peripheral Tissue. Sci Rep. 2018; 8(1):1395. PMC: 5780501. DOI: 10.1038/s41598-018-19836-7. View

Gurav A, Sivaprakasam S, Bhutia Y, Boettger T, Singh N, Ganapathy V . Slc5a8, a Na+-coupled high-affinity transporter for short-chain fatty acids, is a conditional tumour suppressor in colon that protects against colitis and colon cancer under low-fibre dietary conditions. Biochem J. 2015; 469(2):267-78. PMC: 4943859. DOI: 10.1042/BJ20150242. View

Jones R, Desai C, Darby T, Luo L, Wolfarth A, Scharer C . Lactobacilli Modulate Epithelial Cytoprotection through the Nrf2 Pathway. Cell Rep. 2015; 12(8):1217-25. PMC: 4640184. DOI: 10.1016/j.celrep.2015.07.042. View

Pintado J, Guyot J, Ampe F . Multiple competitive PCR-DGGE as a tool for quantifying and profiling defined mixed cultures of lactic acid bacteria during production of probiotics from complex polysaccharides. J Appl Microbiol. 2003; 95(5):921-33. DOI: 10.1046/j.1365-2672.2003.02058.x. View

Marsh A, Sanchez T, Midkelsen O, Keiser J, Mayor G . Cortical bone density of adult lacto-ovo-vegetarian and omnivorous women. J Am Diet Assoc. 1980; 76(2):148-51. View

Lucas S, Omata Y, Hofmann J, Bottcher M, Iljazovic A, Sarter K . Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss. Nat Commun. 2018; 9(1):55. PMC: 5754356. DOI: 10.1038/s41467-017-02490-4. View

Saemann M, Parolini O, Bohmig G, Kelemen P, Krieger P, Neumuller J . Bacterial metabolite interference with maturation of human monocyte-derived dendritic cells. J Leukoc Biol. 2002; 71(2):238-46. View

Shen X, Carlstrom M, Borniquel S, Jadert C, Kevil C, Lundberg J . Microbial regulation of host hydrogen sulfide bioavailability and metabolism. Free Radic Biol Med. 2013; 60:195-200. PMC: 4077044. DOI: 10.1016/j.freeradbiomed.2013.02.024. View

Nastasi C, Candela M, Bonefeld C, Geisler C, Hansen M, Krejsgaard T . The effect of short-chain fatty acids on human monocyte-derived dendritic cells. Sci Rep. 2015; 5:16148. PMC: 4635422. DOI: 10.1038/srep16148. View

10.

Scholz-Ahrens K, Delling G, Stampa B, Helfenstein A, Hahne H, Acil Y . Glucocorticosteroid-induced osteoporosis in adult primiparous Göttingen miniature pigs: effects on bone mineral and mineral metabolism. Am J Physiol Endocrinol Metab. 2007; 293(1):E385-95. DOI: 10.1152/ajpendo.00627.2006. View

11.

Kelly C, Zheng L, Campbell E, Saeedi B, Scholz C, Bayless A . Crosstalk between Microbiota-Derived Short-Chain Fatty Acids and Intestinal Epithelial HIF Augments Tissue Barrier Function. Cell Host Microbe. 2015; 17(5):662-71. PMC: 4433427. DOI: 10.1016/j.chom.2015.03.005. View

12.

Kim S, Kim D, Mogun H, Eddings W, Polinski J, Franklin J . Impact of the U.S. Food and Drug Administration's Safety-Related Announcements on the Use of Bisphosphonates After Hip Fracture. J Bone Miner Res. 2016; 31(8):1536-40. PMC: 5040596. DOI: 10.1002/jbmr.2832. View

13.

Chang P, Hao L, Offermanns S, Medzhitov R . The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci U S A. 2014; 111(6):2247-52. PMC: 3926023. DOI: 10.1073/pnas.1322269111. View

14.

Narva M, Collin M, Lamberg-Allardt C, Karkkainen M, Poussa T, Vapaatalo H . Effects of long-term intervention with Lactobacillus helveticus-fermented milk on bone mineral density and bone mineral content in growing rats. Ann Nutr Metab. 2004; 48(4):228-34. DOI: 10.1159/000080455. View

15.

Wang J, Wang Y, Gao W, Wang B, Zhao H, Zeng Y . Diversity analysis of gut microbiota in osteoporosis and osteopenia patients. PeerJ. 2017; 5:e3450. PMC: 5474093. DOI: 10.7717/peerj.3450. View

16.

Wikoff W, Anfora A, Liu J, Schultz P, Lesley S, Peters E . Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci U S A. 2009; 106(10):3698-703. PMC: 2656143. DOI: 10.1073/pnas.0812874106. View

17.

Guo J, Liu M, Yang D, Bouxsein M, Saito H, Galvin R . Suppression of Wnt signaling by Dkk1 attenuates PTH-mediated stromal cell response and new bone formation. Cell Metab. 2010; 11(2):161-71. PMC: 2819982. DOI: 10.1016/j.cmet.2009.12.007. View

18.

Pluznick J . A novel SCFA receptor, the microbiota, and blood pressure regulation. Gut Microbes. 2014; 5(2):202-7. PMC: 4063845. DOI: 10.4161/gmic.27492. View

19.

Derrien M, Vaughan E, Plugge C, de Vos W . Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. Int J Syst Evol Microbiol. 2004; 54(Pt 5):1469-1476. DOI: 10.1099/ijs.0.02873-0. View

20.

Yan F, Polk D . Probiotics and immune health. Curr Opin Gastroenterol. 2011; 27(6):496-501. PMC: 4006993. DOI: 10.1097/MOG.0b013e32834baa4d. View