Progress of research on the gut microbiome and its metabolite short-chain fatty acids in postmenopausal osteoporosis: a literature review

Abstract

Postmenopausal osteoporosis (PMOP) is a systemic metabolic bone disease caused by the decrease in estrogen levels after menopause. It leads to bone loss, microstructural damage, and an increased risk of fractures. Studies have found that the gut microbiota and its metabolites can regulate bone metabolism through the gut–bone axis and the gut–brain axis. As research progresses, PMOP has been found to be associated with gut microbiota dysbiosis and Th17/Treg imbalance. The gut microbiota is closely related to the development and differentiation of Treg and Th17 cells. Among them, the metabolites of the gut microbiota such as short-chain fatty acids (SCFAs) can regulate the differentiation of effector T cells by acting on molecular receptors on immune cells, thereby regulating the bone immune process. The multifaceted relationship among the gut microbiota, SCFAs, Th17/Treg cell-mediated bone immunity, and bone metabolism is eliciting attention from researchers. Through a review of existing literature, we have comprehensively summarized the effects of the gut microbiota and SCFAs on PMOP, especially from the perspective of Th17/Treg balance. Regulating this balance may provide new opportunities for PMOP treatment.

Keywords

postmenopausal osteoporosis / gut microbiota / short-chain fatty acids / Th17 cells / Treg cells

References

[1] NIH consensus development panel on osteoporosis prevention. Osteoporosis prevention, diagnosis, and therapy. JAMA 2001; 285(6): 785–795

[2] Ensrud KE, Crandall CJ. Osteoporosis. Ann Intern Med 2017; 167(3): ITC17–ITC32

[3] Foger-Samwald U, Dovjak P, Azizi-Semrad U, Kerschan-Schindl K, Pietschmann P. Osteoporosis: pathophysiology and therapeutic options. EXCLI J 2020; 19: 1017–1037

[4] Clarke BL. Economic costs of severe osteoporotic fractures continue to increase at expense of refracture. J Bone Miner Res 2022; 37(10): 1809–1810

[5] Johnell O, Kanis J. Epidemiology of osteoporotic fractures. Osteoporos Int 2005; 16(Suppl 2): S3–S7

[6] Black DM, Rosen CJ. Postmenopausal osteoporosis. N Engl J Med 2016; 374(3): 254–262

[7] Watts NB, Bilezikian JP, Camacho PM, Greenspan SL, Harris ST, Hodgson SF, Kleerekoper M, Luckey MM, McClung MR, Pollack RP, Petak SM; AACE Osteoporosis Task Force. American association of clinical endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocr Pract 2010; 16(Suppl 3): 1–37

[8] Gedmintas L, Solomon DH, Kim SC. Bisphosphonates and risk of subtrochanteric, femoral shaft, and atypical femur fracture: a systematic review and meta-analysis. J Bone Miner Res 2013; 28(8): 1729–1737

[9] Cai J, Sun L, Gonzalez FJ. Gut microbiota-derived bile acids in intestinal immunity, inflammation, and tumorigenesis. Cell Host Microbe 2022; 30(3): 289–300

[10] Gregson CL, Armstrong DJ, Bowden J, Cooper C, Edwards J, Gittoes NJL, Harvey N, Kanis J, Leyland S, Low R, McCloskey E, Moss K, Parker J, Paskins Z, Poole K, Reid DM, Stone M, Thomson J, Vine N, Compston J. UK clinical guideline for the prevention and treatment of osteoporosis. Arch Osteoporos 2022; 17(1): 58

[11] van der Burgh AC, de Keyser CE, Zillikens MC, Stricker BH. The effects of osteoporotic and non-osteoporotic medications on fracture risk and bone mineral density. Drugs 2021; 81(16): 1831–1858

[12] Seely KD, Kotelko CA, Douglas H, Bealer B, Brooks AE. The human gut microbiota: a key mediator of osteoporosis and osteogenesis. Int J Mol Sci 2021; 22(17): 9452

[13] Xu Q, Li D, Chen J, Yang J, Yan J, Xia Y, Zhang F, Wang X, Cao H. Crosstalk between the gut microbiota and postmenopausal osteoporosis: mechanisms and applications. Int Immunopharmacol 2022; 110: 108998

[14] Li L, Rao S, Cheng Y, Zhuo X, Deng C, Xu N, Zhang H, Yang L. Microbial osteoporosis: the interplay between the gut microbiota and bones via host metabolism and immunity. MicrobiologyOpen 2019; 8(8): e00810

[15] Wen K, Tao L, Tao Z, Meng Y, Zhou S, Chen J, Yang K, Da W, Zhu Y. Fecal and serum metabolomic signatures and microbial community profiling of postmenopausal osteoporosis mice model. Front Cell Infect Microbiol 2020; 10: 535310

[16] He J, Xu S, Zhang B, Xiao C, Chen Z, Si F, Fu J, Lin X, Zheng G, Yu G, Chen J. Gut microbiota and metabolite alterations associated with reduced bone mineral density or bone metabolic indexes in postmenopausal osteoporosis. Aging (Albany NY) 2020; 12(9): 8583–8604

[17] Rizzoli R. Nutritional influence on bone: role of gut microbiota. Aging Clin Exp Res 2019; 31(6): 743–751

[18] Zhang YW, Li YJ, Lu PP, Dai GC, Chen XX, Rui YF. The modulatory effect and implication of gut microbiota on osteoporosis: from the perspective of “brain-gut-bone” axis. Food Funct 2021; 12(13): 5703–5718

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

[20] Lyu Z, Hu Y, Guo Y, Liu D. Modulation of bone remodeling by the gut microbiota: a new therapy for osteoporosis. Bone Res 2023; 11(1): 31

[21] Novince CM, Whittow CR, Aartun JD, Hathaway JD, Poulides N, Chavez MB, Steinkamp HM, Kirkwood KA, Huang E, Westwater C, Kirkwood KL. Commensal gut microbiota immunomodulatory actions in bone marrow and liver have catabolic effects on skeletal homeostasis in health. Sci Rep 2017; 7(1): 5747

[22] Uchida Y, Irie K, Fukuhara D, Kataoka K, Hattori T, Ono M, Ekuni D, Kubota S, Morita M. Commensal microbiota enhance both osteoclast and osteoblast activities. Molecules 2018; 23(7): 1517

[23] Zhang YW, Cao MM, Li YJ, Zhang RL, Wu MT, Yu Q, Rui YF. Fecal microbiota transplantation as a promising treatment option for osteoporosis. J Bone Miner Metab 2022; 40(6): 874–889

[24] Wang J, Wang Y, Gao W, Wang B, Zhao H, Zeng Y, Ji Y, Hao D. Diversity analysis of gut microbiota in osteoporosis and osteopenia patients. PeerJ 2017; 5: e3450

[25] Ma Z, Liu Y, Shen W, Yang J, Wang T, Li Y, Ma J, Zhang X, Wang H. Osteoporosis in postmenopausal women is associated with disturbances in gut microbiota and migration of peripheral immune cells. BMC Musculoskelet Disord 2024; 25(1): 791

[26] Yan L, Wang X, Yu T, Qi Z, Li H, Nan H, Wang K, Luo D, Hua F, Wang W. Characteristics of the gut microbiota and serum metabolites in postmenopausal women with reduced bone mineral density. Front Cell Infect Microbiol 2024; 14: 1367325

[27] Wang Z, Chen K, Wu C, Chen J, Pan H, Liu Y, Wu P, Yuan J, Huang F, Lang J, Du J, Xu J, Jin K, Chen L. 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): 1304–1313

[28] Yang X, Chang T, Yuan Q, Wei W, Wang P, Song X, Yuan H. Changes in the composition of gut and vaginal microbiota in patients with postmenopausal osteoporosis. Front Immunol 2022; 13: 930244

[29] Chen T, Meng F, Wang N, Hao Y, Fu L. The characteristics of gut microbiota and its relation with diet in postmenopausal osteoporosis. Calcif Tissue Int 2024; 115(4): 393–404

[30] 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): 145–156

[31] Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, Liu H, Cross JR, Pfeffer K, Coffer PJ, Rudensky AY. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 2013; 504(7480): 451–455

[32] 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

[33] Yang DH, Yang MY. The role of macrophage in the pathogenesis of osteoporosis. Int J Mol Sci 2019; 20(9): 2093

[34] Gilman J, Cashman KD. The effect of probiotic bacteria on transepithelial calcium transport and calcium uptake in human intestinal-like Caco-2 cells. Curr Issues Intest Microbiol 2006; 7: 1–5

[35] Wu S, Yang W, De Luca F. Insulin-like growth factor-independent effects of growth hormone on growth plate chondrogenesis and longitudinal bone growth. Endocrinology 2015; 156(7): 2541–2551

[36] Ding K, Hua F, Ding W. Gut microbiome and osteoporosis. Aging Dis 2020; 11(2): 438–447

[37] Xu X, Jia X, Mo L, Liu C, Zheng L, Yuan Q, Zhou X. Intestinal microbiota: a potential target for the treatment of postmenopausal osteoporosis. Bone Res 2017; 5(1): 17046

[38] Sapra L, Dar HY, Bhardwaj A, Pandey A, Kumari S, Azam Z, Upmanyu V, Anwar A, Shukla P, Mishra PK, Saini C, Verma B, Srivastava RK. Lactobacillus rhamnosus attenuates bone loss and maintains bone health by skewing Treg-Th17 cell balance in Ovx mice. Sci Rep 2021; 11(1): 1807

[39] Xie H, Hua Z, Guo M, Lin S, Zhou Y, Weng Z, Wu L, Chen Z, Xu Z, Li W. Gut microbiota and metabonomics used to explore the mechanism of Qing’e Pills in alleviating osteoporosis. Pharm Biol 2022; 60(1): 785–800

[40] Terashima A, Takayanagi H. Overview of osteoimmunology. Calcif Tissue Int 2018; 102(5): 503–511

[41] Fasching P, Stradner M, Graninger W, Dejaco C, Fessler J. Therapeutic potential of targeting the Th17/Treg axis in autoimmune disorders. Molecules 2017; 22(1): 134

[42] Li JY, Chassaing B, Tyagi AM, Vaccaro C, Luo T, Adams J, Darby TM, Weitzmann MN, Mulle JG, Gewirtz AT, Jones RM, Pacifici R. Sex steroid deficiency-associated bone loss is microbiota dependent and prevented by probiotics. J Clin Invest 2016; 126(6): 2049–2063

[43] Cenci S, Weitzmann MN, Roggia C, Namba N, Novack D, Woodring J, Pacifici R. Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha. J Clin Invest 2000; 106(10): 1229–1237

[44] Li JY, Tawfeek H, Bedi B, Yang X, Adams J, Gao KY, Zayzafoon M, Weitzmann MN, Pacifici R. Ovariectomy disregulates osteoblast and osteoclast formation through the T-cell receptor CD40 ligand. Proc Natl Acad Sci USA 2011; 108(2): 768–773

[45] Uehara IA, Soldi LR, Silva MJB. Current perspectives of osteoclastogenesis through estrogen modulated immune cell cytokines. Life Sci 2020; 256: 117921

[46] Wang X, Sun B, Wang Y, Gao P, Song J, Chang W, Xiao Z, Xi Y, Li Z, An F, Yan C. Research progress of targeted therapy regulating Th17/Treg balance in bone immune diseases. Front Immunol 2024; 15: 1333993

[47] Zhu L, Hua F, Ding W, Ding K, Zhang Y, Xu C. The correlation between the Th17/Treg cell balance and bone health. Immun Ageing 2020; 17(1): 30

[48] Yu M, Malik Tyagi A, Li JY, Adams J, Denning TL, Weitzmann MN, Jones RM, Pacifici R. PTH induces bone loss via microbial-dependent expansion of intestinal TNF⁺ T cells and Th17 cells. Nat Commun 2020; 11(1): 468

[49] Yu M, Pal S, Paterson CW, Li JY, Tyagi AM, Adams J, Coopersmith CM, Weitzmann MN, Pacifici R. Ovariectomy induces bone loss via microbial-dependent trafficking of intestinal TNF⁺ T cells and Th17 cells. J Clin Invest 2021; 131(4): e143137

[50] Ibáñez L, Rouleau M, Wakkach A, Blin-Wakkach C. Gut microbiome and bone. Joint Bone Spine 2019; 86(1): 43–47

[51] Zhang YW, Cao MM, Li YJ, Lu PP, Dai GC, Zhang M, Wang H, Rui YF. Fecal microbiota transplantation ameliorates bone loss in mice with ovariectomy-induced osteoporosis via modulating gut microbiota and metabolic function. J Orthop Translat 2022; 37: 46–60

[52] Hsu E, Pacifici R. From osteoimmunology to osteomicrobiology: how the microbiota and the immune system regulate bone. Calcif Tissue Int 2018; 102(5): 512–521

[53] Zhao F, Guo Z, Kwok LY, Zhao Z, Wang K, Li Y, Sun Z, Zhao J, Zhang H. Bifidobacterium lactis Probio-M8 improves bone metabolism in patients with postmenopausal osteoporosis, possibly by modulating the gut microbiota. Eur J Nutr 2023; 62: 965–976

[54] Jafarnejad S, Djafarian K, Fazeli MR, Yekaninejad MS, Rostamian A, Keshavarz SA. Effects of a multispecies probiotic supplement on bone health in osteopenic postmenopausal women: A randomized, double-blind, controlled trial. J Am Coll Nutr 2017; 36(7): 497–506

[55] Resciniti SM, Biesiekierski JR, Ghasem-Zadeh A, Moschonis G. The effectiveness of a lactobacilli-based probiotic food supplement on bone mineral density and bone metabolism in Australian early postmenopausal women: protocol for a double-blind randomized placebo-controlled Trial. Nutrients 2024; 16(8): 1150

[56] Lambert MNT, Thybo CB, Lykkeboe S, Rasmussen LM, Frette X, Christensen LP, Jeppesen PB. 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): 909–920

[57] Gupta V, Garg R. Probiotics. Indian J Med Microbiol 2009; 27(3): 202–209

[58] Britton RA, Irwin R, Quach D, Schaefer L, Zhang J, Lee T, Parameswaran N, McCabe LR. Probiotic L. reuteri treatment prevents bone loss in a menopausal ovariectomized mouse model. J Cell Physiol 2014; 229(11): 1822–1830

[59] Chen J, Liu X, Li S, Li J, Fang G, Chen Y, Zhang X. Effects of Lactobacillus acidophilus and L. reuteri on bone mass and gut microbiota in ovariectomized mice. Cell Mol Biol 2023; 69(9): 43–51

[60] Ribeiro JL, Santos TA, Garcia MT, Carvalho B, Esteves J, Moraes RM, Anbinder AL. Heat-killed Limosilactobacillus reuteri ATCC PTA 6475 prevents bone loss in ovariectomized mice: A preliminary study. PLoS One 2024; 19(5): e0304358

[61] Ohlsson C, Engdahl C, Fak F, Andersson A, Windahl SH, Farman HH, Moverare-Skrtic S, Islander U, Sjogren K. Probiotics protect mice from ovariectomy-induced cortical bone loss. PLoS One 2014; 9(3): e92368

[62] Rahmani D, Faal B, Zali H, Tackallou SH, Niknam Z. The beneficial effects of simultaneous supplementation of Lactobacillus reuteri and calcium fluoride nanoparticles on ovariectomy-induced osteoporosis. BMC Complement Med Ther 2023; 23(1): 340

[63] 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): 1145–1154

[64] Tsai WH, Lin WC, Chou CH, Yang LC. The probiotic Lactiplantibacillus plantarum attenuates ovariectomy-induced osteoporosis through osteoimmunological signaling. Food Funct 2023; 14(15): 6929–6940

[65] Lee S, Jung DH, Park M, Yeon SW, Jung SH, Yun SI, Park HO, Yoo W. The effect of Lactobacillus gasseri BNR17 on postmenopausal symptoms in ovariectomized rats. J Microbiol Biotechnol 2021; 31(9): 1281–1287

[66] Guo M, Liu H, Yu Y, Zhu X, Xie H, Wei C, Mei C, Shi Y, Zhou N, Qin K, Li W. Lactobacillus rhamnosus GG ameliorates osteoporosis in ovariectomized rats by regulating the Th17/Treg balance and gut microbiota structure. Gut Microbes 2023; 15(1): 2190304

[67] Nancib A, Nancib N, Meziane-Cherif D, Boubendir A, Fick M, Boudrant J. Joint effect of nitrogen sources and B vitamin supplementation of date juice on lactic acid production by Lactobacillus casei subsp. rhamnosus. Bioresour Technol 2005; 96(1): 63–67

[68] Wu J, Hu M, Jiang H, Ma J, Xie C, Zhang Z, Zhou X, Zhao J, Tao Z, Meng Y, Cai Z, Song T, Zhang C, Gao R, Cai C, Song H, Gao Y, Lin T, Wang C, Zhou X. Endothelial cell-derived lactate triggers bone mesenchymal stem cell histone lactylation to attenuate osteoporosis. Adv Sci (Weinh) 2023; 10(31): 2301300

[69] Angelin A, Gil-de-Gomez L, Dahiya S, Jiao J, Guo L, Levine MH, Wang Z, Quinn WJ 3rd, Kopinski PK, Wang L, Akimova T, Liu Y, Bhatti TR, Han R, Laskin BL, Baur JA, Blair IA, Wallace DC, Hancock WW, Beier UH. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab 2017; 25(6): 1282–1293.e7

[70] Gu J, Zhou J, Chen Q, Xu X, Gao J, Li X, Shao Q, Zhou B, Zhou H, Wei S, Wang Q, Liang Y, Lu L. Tumor metabolite lactate promotes tumorigenesis by modulating MOESIN lactylation and enhancing TGF-beta signaling in regulatory T cells. Cell Rep 2022; 40(3): 111122

[71] Rao D, Stunnenberg JA, Lacroix R, Dimitriadis P, Kaplon J, Verburg F, van van Royen PT, Hoefsmit EP, Renner K, Blank CU, Peeper DS. Acidity-mediated induction of FoxP3⁺ regulatory T cells. Eur J Immunol 2023; 53(6): 2250258

[72] Tuomela K, Levings MK. Acidity promotes the differentiation of immunosuppressive regulatory T cells. Eur J Immunol 2023; 53(6): e2350511

[73] Zhou J, Gu J, Qian Q, Zhang Y, Huang T, Li X, Liu Z, Shao Q, Liang Y, Qiao L, Xu X, Chen Q, Xu Z, Li Y, Gao J, Pan Y, Wang Y, O’Connor R, Hippen KL, Lu L, Blazar BR. Lactate supports Treg function and immune balance via MGAT1 effects on N-glycosylation in the mitochondria. J Clin Invest 2024; 134(20): e175897

[74] Zhang YT, Xing ML, Fang HH, Li WD, Wu L, Chen ZP. Effects of lactate on metabolism and differentiation of CD4⁺ T cells. Mol Immunol 2023; 154: 96–107

[75] Tyagi AM, Yu M, Darby TM, Vaccaro C, Li JY, Owens JA, Hsu E, Adams J, Weitzmann MN, Jones RM, Pacifici R. The microbial metabolite butyrate stimulates bone formation via T regulatory cell-mediated regulation of WNT10B expression. Immunity 2018; 49(6): 1116–1131.e7

[76] Grüner N, Ortlepp AL, Mattner J. Pivotal role of intestinal microbiota and intraluminal metabolites for the maintenance of gut-bone physiology. Int J Mol Sci 2023; 24(6): 5161

[77] Sapra L, Shokeen N, Porwal K, Saini C, Bhardwaj A, Mathew M, Mishra PK, Chattopadhyay N, Dar HY, Verma B, Srivastava RK. Bifidobacterium longum ameliorates ovariectomy-induced bone loss via enhancing anti-osteoclastogenic and immunomodulatory potential of regulatory B cells (Bregs). Front Immunol 2022; 13: 875788

[78] Parvaneh M, Jamaluddin R, Ebrahimi M, Karimi G, Sabran MR. Assessing the effects of probiotic supplementation, single strain versus mixed strains, on femoral mineral density and osteoblastic gene mRNA expression in rats. J Bone Miner Metab 2024; 42(3): 290–301

[79] Zhang J, Liang X, Tian X, Zhao M, Mu Y, Yi H, Zhang Z, Zhang L. Bifidobacterium improves oestrogen-deficiency-induced osteoporosis in mice by modulating intestinal immunity. Food Funct 2024; 15(4): 1840–1851

[80] Ohlsson C, Lawenius L, Andersson A, Gustafsson K, Wu J, Lagerquist M, Moverare-Skrtic S, Islander U, Sjogren K. Mild stimulatory effect of a probiotic mix on bone mass when treatment is initiated 1.5 weeks after ovariectomy in mice. Am J Physiol Endocrinol Metab 2021; 320(3): E591–E597

[81] 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

[82] Chen YC, Greenbaum J, Shen H, Deng HW. Association between gut microbiota and bone health: potential mechanisms and prospective. J Clin Endocrinol Metab 2017; 102(10): 3635–3646

[83] Wang J, Wu S, Zhang Y, Yang J, Hu Z. Gut microbiota and calcium balance. Front Microbiol 2022; 13: 1033933

[84] Tu Y, Yang R, Xu X, Zhou X. The microbiota-gut-bone axis and bone health. J Leukoc Biol 2021; 110(3): 525–537

[85] D’Amelio P, Sassi F. Gut microbiota, immune system, and bone. Calcif Tissue Int 2018; 102(4): 415–425

[86] Peng M, Biswas D. Short chain and polyunsaturated fatty acids in host gut health and foodborne bacterial pathogen inhibition. Crit Rev Food Sci Nutr 2017; 57(18): 3987–4002

[87] Gao Y, Davis B, Zhu W, Zheng N, Meng D, Walker WA. Short-chain fatty acid butyrate, a breast milk metabolite, enhances immature intestinal barrier function genes in response to inflammation in vitro and in vivo. Am J Physiol Gastrointest Liver Physiol 2021; 320(4): G521–G530

[88] Kim CH. Complex regulatory effects of gut microbial short-chain fatty acids on immune tolerance and autoimmunity. Cell Mol Immunol 2023; 20(4): 341–350

[89] Bai Y, Li Y, Marion T, Tong Y, Zaiss MM, Tang Z, Zhang Q, Liu Y, Luo Y. Resistant starch intake alleviates collagen-induced arthritis in mice by modulating gut microbiota and promoting concomitant propionate production. J Autoimmun 2021; 116: 102564

[90] Cho KM, Kim YS, Lee M, Lee HY, Bae YS. Isovaleric acid ameliorates ovariectomy-induced osteoporosis by inhibiting osteoclast differentiation. J Cell Mol Med 2021; 25(9): 4287–4297

[91] Abrams SA, Griffin IJ, Hawthorne KM, Liang L, Gunn SK, Darlington G, Ellis KJ. A combination of prebiotic short- and long-chain inulin-type fructans enhances calcium absorption and bone mineralization in young adolescents. Am J Clin Nutr 2005; 82(2): 471–476

[92] Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, Nakanishi Y, Uetake C, Kato K, Kato T, Takahashi M, Fukuda NN, Murakami S, Miyauchi E, Hino S, Atarashi K, Onawa S, Fujimura Y, Lockett T, Clarke JM, Topping DL, Tomita M, Hori S, Ohara O, Morita T, Koseki H, Kikuchi J, Honda K, Hase K, Ohno H. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 2013; 504(7480): 446–450

[93] Morrison DJ, Preston T. Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut Microbes 2016; 7(3): 189–200

[94] Lu X, Xue Z, Qian Y, Wei S, Qiao Y, Zhang W, Lu H. Changes in intestinal microflora and its metabolites underlie the cognitive impairment in preterm rats. Front Cell Infect Microbiol 2022; 12: 945851

[95] Zheng Y, Wu Y, Tao L, Chen X, Jones TJ, Wang K, Hu F. Chinese propolis prevents obesity and metabolism syndromes induced by a high fat diet and accompanied by an altered gut microbiota structure in mice. Nutrients 2020; 12(4): 959

[96] Ziętek M, Celewicz Z, Szczuko M. Short-chain fatty acids, maternal microbiota and metabolism in pregnancy. Nutrients 2021; 13(4): 1244

[97] Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, Levenez F, Yamada T, Mende DR, Li J, Xu J, Li S, Li D, Cao J, Wang B, Liang H, Zheng H, Xie Y, Tap J, Lepage P, Bertalan M, Batto JM, Hansen T, Le Paslier D, Linneberg A, Nielsen HB, Pelletier E, Renault P, Sicheritz-Ponten T, Turner K, Zhu H, Yu C, Li S, Jian M, Zhou Y, Li Y, Zhang X, Li S, Qin N, Yang H, Wang J, Brunak S, Dore J, Guarner F, Kristiansen K, Pedersen O, Parkhill J, Weissenbach J, Meta HITC, Bork P, Ehrlich SD, Wang J. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010; 464(7285): 59–65

[98] Zhernakova A, Kurilshikov A, Bonder MJ, Tigchelaar EF, Schirmer M, Vatanen T, Mujagic Z, Vila AV, Falony G, Vieira-Silva S, Wang J, Imhann F, Brandsma E, Jankipersadsing SA, Joossens M, Cenit MC, Deelen P, Swertz MA; LifeLines cohort study; Weersma RK, Feskens EJ, Netea MG, Gevers D, Jonkers D, Franke L, Aulchenko YS, Huttenhower C, Raes J, Hofker MH, Xavier RJ, Wijmenga C, Fu J. LifeLines cohort s, Weersma RK, Feskens EJ, Netea MG, Gevers D, Jonkers D, Franke L, Aulchenko YS, Huttenhower C, Raes J, Hofker MH, Xavier RJ, Wijmenga C and Fu J. Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science 2016; 352(6285): 565–569

[99] Louis P, Flint HJ. Formation of propionate and butyrate by the human colonic microbiota. Environ Microbiol 2017; 19(1): 29–41

[100] Neis EP, Dejong CH, Rensen SS. The role of microbial amino acid metabolism in host metabolism. Nutrients 2015; 7(4): 2930–2946

[101] Rios-Covian D, Gonzalez S, Nogacka AM, Arboleya S, Salazar N, Gueimonde M, de Los Reyes-Gavilan CG. An overview on fecal branched short-chain fatty acids along human life and as related with body mass index: associated dietary and anthropometric factors. Front Microbiol 2020; 11: 973

[102] Lynch CJ, Adams SH. Branched-chain amino acids in metabolic signalling and insulin resistance. Nat Rev Endocrinol 2014; 10(12): 723–736

[103] Macfarlane GT, Macfarlane S. Bacteria, colonic fermentation, and gastrointestinal health. J AOAC Int 2012; 95(1): 50–60

[104] Ramos Meyers G, Samouda H, Bohn T. Short chain fatty acid metabolism in relation to gut microbiota and genetic variability. Nutrients 2022; 14(24): 5361

[105] Scholz-Ahrens KE, Ade P, Marten B, Weber P, Timm W, Asil Y, Gluer CC, Schrezenmeir J. Prebiotics, probiotics, and synbiotics affect mineral absorption, bone mineral content, and bone structure. J Nutr 2007; 137(3): 838S–846S

[106] Onyszkiewicz M, Jaworska K, Ufnal M. Short chain fatty acids and methylamines produced by gut microbiota as mediators and markers in the circulatory system. Exp Biol Med (Maywood) 2020; 245(2): 166–175

[107] Lucas S, Omata Y, Hofmann J, Bottcher M, Iljazovic A, Sarter K, Albrecht O, Schulz O, Krishnacoumar B, Kronke G, Herrmann M, Mougiakakos D, Strowig T, Schett G, Zaiss MM. Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss. Nat Commun 2018; 9(1): 55

[108] Chakraborti CK. New-found link between microbiota and obesity. World J Gastrointest Pathophysiol 2015; 6(4): 110–119

[109] Alexander C, Swanson KS, Fahey GC Jr, Garleb KA. Perspective: physiologic importance of short-chain fatty acids from nondigestible carbohydrate fermentation. Adv Nutr 2019; 10(4): 576–589

[110] He J, Zhang P, Shen L, Niu L, Tan Y, Chen L, Zhao Y, Bai L, Hao X, Li X, Zhang S, Zhu L. Short-chain fatty acids and their association with signalling pathways in inflammation, glucose and lipid metabolism. Int J Mol Sci 2020; 21(17): 6356

[111] Bergman EN. Energy contributions of volatile fatty acids from the gastrointestinal tract in various species. Physiol Rev 1990; 70(2): 567–590

[112] Zaiss MM, Jones RM, Schett G, Pacifici R. The gut-bone axis: how bacterial metabolites bridge the distance. J Clin Invest 2019; 129(8): 3018–3028

[113] Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, Schilter HC, Rolph MS, Mackay F, Artis D, Xavier RJ, Teixeira MM, Mackay CR. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 2009; 461(7268): 1282–1286

[114] Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L, Daniels D, Muir AI, Wigglesworth MJ, Kinghorn I, Fraser NJ, Pike NB, Strum JC, Steplewski KM, Murdock PR, Holder JC, Marshall FH, Szekeres PG, Wilson S, Ignar DM, Foord SM, Wise A, Dowell SJ. The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem 2003; 278(13): 11312–11319

[115] Thangaraju M, Cresci GA, Liu K, Ananth S, Gnanaprakasam JP, Browning DD, Mellinger JD, Smith SB, Digby GJ, Lambert NA, Prasad PD, Ganapathy V. GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. Cancer Res 2009; 69(7): 2826–2832

[116] Melhem H, Kaya B, Ayata CK, Hruz P, Niess JH. Metabolite-sensing G protein-coupled receptors connect the diet-microbiota-metabolites axis to inflammatory bowel disease. Cells 2019; 8(5): 450

[117] Fleet JC, Schoch RD. Molecular mechanisms for regulation of intestinal calcium absorption by vitamin D and other factors. Crit Rev Clin Lab Sci 2010; 47(4): 181–195

[118] Kishi M, Fukaya M, Tsukamoto Y, Nagasawa T, Takehana K, Nishizawa N. Enhancing effect of dietary vinegar on the intestinal absorption of calcium in ovariectomized rats. Biosci Biotechnol Biochem 1999; 63(5): 905–910

[119] Trinidad TP, Wolever TM, Thompson LU. Effect of acetate and propionate on calcium absorption from the rectum and distal colon of humans. Am J Clin Nutr 1996; 63(4): 574–578

[120] Zhu K, Prince RL. Calcium and bone. Clin Biochem 2012; 45(12): 936–942

[121] Whisner CM, Martin BR, Nakatsu CH, Story JA, MacDonald-Clarke CJ, McCabe LD, McCabe GP, Weaver CM. Soluble corn fiber increases calcium absorption associated with shifts in the gut microbiome: A randomized dose-response trial in free-living pubertal females. J Nutr 2016; 146(7): 1298–1306

[122] Bielik V, Kolisek M. Bioaccessibility and bioavailability of minerals in relation to a healthy gut microbiome. Int J Mol Sci 2021; 22(13): 6803

[123] Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly YM, Glickman JN, Garrett WS. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 2013; 341(6145): 569–573

[124] Komatsu N, Okamoto K, Sawa S, Nakashima T, Oh-hora M, Kodama T, Tanaka S, Bluestone JA, Takayanagi H. Pathogenic conversion of Foxp3⁺ T cells into TH17 cells in autoimmune arthritis. Nat Med 2014; 20(1): 62–68

[125] Zou F, Qiu Y, Huang Y, Zou H, Cheng X, Niu Q, Luo A, Sun J. Effects of short-chain fatty acids in inhibiting HDAC and activating p38 MAPK are critical for promoting B10 cell generation and function. Cell Death Dis 2021; 12(6): 582

[126] Min HK, Na HS, Jhun J, Lee SY, Choi SS, Park GE, Lee JS, Um IG, Lee SY, Seo H, Shin TS, Kim YK, Lee JJ, Kwok SK, Cho ML, Park SH. Identification of gut dysbiosis in axial spondyloarthritis patients and improvement of experimental ankylosing spondyloarthritis by microbiome-derived butyrate with immune-modulating function. Front Immunol 2023; 14: 1096565

[127] Yang KL, Mullins BJ, Lejeune A, Ivanova E, Shin J, Bajwa S, Possemato R, Cadwell K, Scher JU, Koralov SB. Mitigation of osteoclast-mediated arthritic bone remodeling by short chain fatty acids. Arthritis Rheumatol 2024; 76(4): 647–659

[128] Hosseinkhani F, Heinken A, Thiele I, Lindenburg PW, Harms AC, Hankemeier T. The contribution of gut bacterial metabolites in the human immune signaling pathway of non-communicable diseases. Gut Microbes 2021; 13(1): 1882927

[129] Wu YL, Zhang CH, Teng Y, Pan Y, Liu NC, Liu PX, Zhu X, Su XL, Lin J. Propionate and butyrate attenuate macrophage pyroptosis and osteoclastogenesis induced by CoCrMo alloy particles. Mil Med Res 2022; 9(1): 46

[130] Wallimann A, Magrath W, Pugliese B, Stocker N, Westermann P, Heider A, Gehweiler D, Zeiter S, Claesson MJ, Richards RG, Akdis CA, Hernandez CJ, O’Mahony L, Thompson K, Moriarty TF. Butyrate inhibits osteoclast activity in vitro and regulates systemic inflammation and bone healing in a murine osteotomy model compared to antibiotic-treated mice. Mediators Inflamm 2021; 2021: 8817421

[131] Wallimann A, Magrath W, Thompson K, Moriarty T, Richards RG, Akdis CA, O’Mahony L, Hernandez CJ. Gut microbial-derived short-chain fatty acids and bone: a potential role in fracture healing. Eur Cell Mater 2021; 41: 454–470

[132] Zhao G, Monier-Faugere MC, Langub MC, Geng Z, Nakayama T, Pike JW, Chernausek SD, Rosen CJ, Donahue LR, Malluche HH, Fagin JA, Clemens TL. Targeted overexpression of insulin-like growth factor I to osteoblasts of transgenic mice: increased trabecular bone volume without increased osteoblast proliferation. Endocrinology 2000; 141(7): 2674–2682

[133] Yan J, Herzog JW, Tsang K, Brennan CA, Bower MA, Garrett WS, Sartor BR, Aliprantis AO, Charles JF. Gut microbiota induce IGF-1 and promote bone formation and growth. Proc Natl Acad Sci USA 2016; 113(47): E7554–E7563

[134] Wang Y, Nishida S, Elalieh HZ, Long RK, Halloran BP, Bikle DD. Role of IGF-I signaling in regulating osteoclastogenesis. J Bone Miner Res 2006; 21(9): 1350–1358

[135] Zaibi MS, Stocker CJ, O’Dowd J, Davies A, Bellahcene M, Cawthorne MA, Brown AJ, Smith DM, Arch JR. Roles of GPR41 and GPR43 in leptin secretory responses of murine adipocytes to short chain fatty acids. FEBS Lett 2010; 584(11): 2381–2386

[136] Lin Z, Yu G, Xiong S, Lin Y, Li Z. Leptin and melatonin’s effects on OVX rodents’ bone metabolism. Front Endocrinol (Lausanne) 2023; 14: 1185476

[137] Mei L, Li M, Zhang T. MicroRNA miR-874–3p inhibits osteoporosis by targeting leptin (LEP). Bioengineered 2021; 12(2): 11756–11767

[138] Zheng B, Jiang J, Luo K, Liu L, Lin M, Chen Y, Yan F. Increased osteogenesis in osteoporotic bone marrow stromal cells by overexpression of leptin. Cell Tissue Res 2015; 361(3): 845–856

[139] Tu Y, Kuang X, Zhang L, Xu X. The associations of gut microbiota, endocrine system and bone metabolism. Front Microbiol 2023; 14: 1124945

[140] Pacheco-Pantoja EL, Ranganath LR, Gallagher JA, Wilson PJ, Fraser WD. Receptors and effects of gut hormones in three osteoblastic cell lines. BMC Physiol 2011; 11(1): 12

[141] Li Z, Li S, Wang N, Xue P, Li Y. Liraglutide, a glucagon-like peptide-1 receptor agonist, suppresses osteoclastogenesis through the inhibition of NF-kappaB and MAPK pathways via GLP-1R. Biomed Pharmacother 2020; 130: 110523

[142] Kim TY, Shoback DM, Black DM, Rogers SJ, Stewart L, Carter JT, Posselt AM, King NJ, Schafer AL. Increases in PYY and uncoupling of bone turnover are associated with loss of bone mass after gastric bypass surgery. Bone 2020; 131: 115115

[143] Lee NJ, Nguyen AD, Enriquez RF, Doyle KL, Sainsbury A, Baldock PA, Herzog H. Osteoblast specific Y1 receptor deletion enhances bone mass. Bone 2011; 48(3): 461–467

[144] Reigstad CS, Salmonson CE, Rainey JF 3rd, Szurszewski JH, Linden DR, Sonnenburg JL, Farrugia G, Kashyap PC. Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. FASEB J 2015; 29(4): 1395–1403

[145] Xie Y, Wang C, Zhao D, Wang C, Li C. Dietary proteins regulate serotonin biosynthesis and catabolism by specific gut microbes. J Agric Food Chem 2020; 68(21): 5880–5890

[146] Ducy P, Karsenty G. The two faces of serotonin in bone biology. J Cell Biol 2010; 191(1): 7–13

[147] Knudsen JK, Leutscher P, Sorensen S. Gut microbiota in bone health and diabetes. Curr Osteoporos Rep 2021; 19(4): 462–479

[148] Lee GR. The balance of Th17 versus Treg cells in autoimmunity. Int J Mol Sci 2018; 19(3): 730

[149] Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006; 441(7090): 235–238

[150] de Vries TJ, El Bakkali I, Kamradt T, Schett G, Jansen IDC, D’Amelio P. What are the peripheral blood determinants for increased osteoclast formation in the various inflammatory diseases associated with bone loss. Front Immunol 2019; 10: 505

[151] Luu M, Pautz S, Kohl V, Singh R, Romero R, Lucas S, Hofmann J, Raifer H, Vachharajani N, Carrascosa LC, Lamp B, Nist A, Stiewe T, Shaul Y, Adhikary T, Zaiss MM, Lauth M, Steinhoff U, Visekruna A. The short-chain fatty acid pentanoate suppresses autoimmunity by modulating the metabolic-epigenetic crosstalk in lymphocytes. Nat Commun 2019; 10(1): 760

[152] Zi C, Wang D, Gao Y, He L. The role of Th17 cells in endocrine organs: Involvement of the gut, adipose tissue, liver and bone. Front Immunol 2023; 13: 1104943

[153] Okamoto K, Takayanagi H. Regulation of bone by the adaptive immune system in arthritis. Arthritis Res Ther 2011; 13(3): 219

[154] Honma M, Ikebuchi Y, Suzuki H. RANKL as a key figure in bridging between the bone and immune system: its physiological functions and potential as a pharmacological target. Pharmacol Ther 2021; 218: 107682

[155] Lorenzo J. From the gut to bone: connecting the gut microbiota with Th17 T lymphocytes and postmenopausal osteoporosis. J Clin Invest 2021; 131(5): e146619

[156] Khosla S. The microbiome adds to the complexity of parathyroid hormone action on bone. J Clin Invest 2020; 130(4): 1615–1617

[157] Okamoto K, Nakashima T, Shinohara M, Negishi-Koga T, Komatsu N, Terashima A, Sawa S, Nitta T, Takayanagi H. Osteoimmunology: the conceptual framework unifying the immune and skeletal systems. Physiol Rev 2017; 97(4): 1295–1349

[158] Yuan FL, Li X, Lu WG, Xu RS, Zhao YQ, Li CW, Li JP, Chen FH. Regulatory T cells as a potent target for controlling bone loss. Biochem Biophys Res Commun 2010; 402(2): 173–176

[159] Bozec A, Zaiss MM. T regulatory cells in bone remodelling. Curr Osteoporos Rep 2017; 15(3): 121–125

[160] Curotto de Lafaille MA, Lafaille JJ. Natural and adaptive foxp3⁺ regulatory T cells: more of the same or a division of labor?. Immunity 2009; 30(5): 626–635

[161] Hao F, Tian M, Zhang X, Jin X, Jiang Y, Sun X, Wang Y, Peng P, Liu J, Xia C, Feng Y, Wei M. Butyrate enhances CPT1A activity to promote fatty acid oxidation and iTreg differentiation. Proc Natl Acad Sci USA 2021; 118(22): e2014681118

[162] Luo CY, Wang L, Sun C, Li DJ. Estrogen enhances the functions of CD4⁺CD25⁺Foxp3⁺ regulatory T cells that suppress osteoclast differentiation and bone resorption in vitro. Cell Mol Immunol 2011; 8(1): 50–58

[163] Wu D, Cline-Smith A, Shashkova E, Perla A, Katyal A, Aurora R. T-Cell mediated inflammation in postmenopausal osteoporosis. Front Immunol 2021; 12: 687551

[164] Xu H, Wang W, Liu X, Huang W, Zhu C, Xu Y, Yang H, Bai J, Geng D. Targeting strategies for bone diseases: signaling pathways and clinical studies. Signal Transduct Target Ther 2023; 8(1): 202

[165] Tanaka Y. Clinical immunity in bone and joints. J Bone Miner Metab 2019; 37(1): 2–8

[166] Zhao L, Jiang S, Hantash BM. Transforming growth factor beta1 induces osteogenic differentiation of murine bone marrow stromal cells. Tissue Eng Part A 2010; 16(2): 725–733

[167] Pacifici R. Role of gut microbiota in the skeletal response to PTH. J Clin Endocrinol Metab 2021; 106(3): 636–645

[168] Yu M, D’Amelio P, Tyagi AM, Vaccaro C, Li JY, Hsu E, Buondonno I, Sassi F, Adams J, Weitzmann MN, DiPaolo R, Pacifici R. Regulatory T cells are expanded by teriparatide treatment in humans and mediate intermittent PTH-induced bone anabolism in mice. EMBO Rep 2018; 19(1): 156–171

[169] Li JY, Yu M, Pal S, Tyagi AM, Dar H, Adams J, Weitzmann MN, Jones RM, Pacifici R. Parathyroid hormone-dependent bone formation requires butyrate production by intestinal microbiota. J Clin Invest 2020; 130(4): 1767–1781

[170] Yang L, Li Z, Li X, Wang Z, Wang S, Sasaki Y, Takai H, Ogata Y. Butyric acid stimulates bone sialoprotein gene transcription. J Oral Sci 2010; 52(2): 231–237

[171] Katono T, Kawato T, Tanabe N, Suzuki N, Iida T, Morozumi A, Ochiai K, Maeno M. Sodium butyrate stimulates mineralized nodule formation and osteoprotegerin expression by human osteoblasts. Arch Oral Biol 2008; 53(10): 903–909

[172] Kondo T, Chiba T, Tousen Y. Short-chain fatty acids, acetate and propionate, directly upregulate osteoblastic differentiation. Int J Food Sci Nutr 2022; 73(6): 800–808

[173] Iida T, Kawato T, Tanaka H, Tanabe N, Nakai K, Zhao N, Suzuki N, Ochiai K, Maeno M. Sodium butyrate induces the production of cyclooxygenases and prostaglandin E₂ in ROS 17/2.8 osteoblastic cells. Arch Oral Biol 2011; 56(7): 678–686

[174] Morozumi A. High concentration of sodium butyrate suppresses osteoblastic differentiation and mineralized nodule formation in ROS17/2.8 cells. J Oral Sci 2011; 53(4): 509–516

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

[176] Chang PV, Hao L, Offermanns S, Medzhitov R. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci USA 2014; 111(6): 2247–2252

[177] Kim DS, Kwon JE, Lee SH, Kim EK, Ryu JG, Jung KA, Choi JW, Park MJ, Moon YM, Park SH, Cho ML, Kwok SK. Attenuation of rheumatoid inflammation by sodium butyrate through reciprocal targeting of HDAC2 in osteoclasts and HDAC8 in T Cells. Front Immunol 2018; 9: 1525

[178] Montalvany-Antonucci CC, Duffles LF, de Arruda JAA, Zicker MC, de Oliveira S, Macari S, Garlet GP, Madeira MFM, Fukada SY, Andrade I Jr, Teixeira MM, Mackay C, Vieira AT, Vinolo MA, Silva TA. Short-chain fatty acids and FFAR2 as suppressors of bone resorption. Bone 2019; 125: 112–121

[179] Dong J, Shu G, Yang J, Wang B, Chen L, Gong Z, Zhang X. Mechanistic study on the alleviation of postmenopausal osteoporosis by Lactobacillus acidophilus through butyrate-mediated inhibition of osteoclast activity. Sci Rep 2024; 14(1): 7042

[180] Rahman MM, Kukita A, Kukita T, Shobuike T, Nakamura T, Kohashi O. Two histone deacetylase inhibitors, trichostatin A and sodium butyrate, suppress differentiation into osteoclasts but not into macrophages. Blood 2003; 101(9): 3451–3459

[181] Yang KL, Mullins BJ, Lejeune A, Ivanova E, Shin J, Bajwa S, Possemato R, Cadwell K, Scher JU, Koralov SB. Mitigation of osteoclast-mediated arthritic bone remodeling by short chain fatty acids. Arthritis Rheumatol 2024; 76(4): 647–659

[182] Wallace TC, Marzorati M, Spence L, Weaver CM, Williamson PS. New frontiers in fibers: Innovative and emerging research on the gut microbiome and bone health. J Am Coll Nutr 2017; 36(3): 218–222

[183] Kwon Y, Park C, Lee J, Park DH, Jeong S, Yun CH, Park OJ, Han SH. Regulation of bone cell differentiation and activation by microbe-associated molecular patterns. Int J Mol Sci 2021; 22(11): 5805

[184] Karakan T, Tuohy KM, Janssen-van Solingen G. Low-dose lactulose as a prebiotic for improved gut health and enhanced mineral absorption. Front Nutr 2021; 8: 672925

[185] Li Z, Liang S, Ke L, Wang M, Gao K, Li D, Xu Z, Li N, Zhang P, Cheng W. Cell life-or-death events in osteoporosis: all roads lead to mitochondrial dynamics. Pharmacol Res 2024; 208: 107383

[186] Richardson KK, Adam GO, Ling W, Warren A, Marques-Carvalho A, Thostenson JD, Krager K, Aykin-Burns N, Byrum SD, Almeida M, Kim HN. Mitochondrial protein deacetylation by SIRT3 in osteoclasts promotes bone resorption with aging in female mice. Mol Metab 2024; 88: 102012

[187] Anderson G, Maes M. Gut dysbiosis dysregulates central and systemic homeostasis via suboptimal mitochondrial function: assessment, treatment and classification Implications. Curr Top Med Chem 2020; 20(7): 524–539

[188] Jin CJ, Engstler AJ, Sellmann C, Ziegenhardt D, Landmann M, Kanuri G, Lounis H, Schroder M, Vetter W, Bergheim I. Sodium butyrate protects mice from the development of the early signs of non-alcoholic fatty liver disease: role of melatonin and lipid peroxidation. Br J Nutr 2016; 116(10): 1682–1693

[189] Chen Y, Yang C, Deng Z, Xiang T, Ni Q, Xu J, Sun D, Luo F. Gut microbially produced tryptophan metabolite melatonin ameliorates osteoporosis via modulating SCFA and TMAO metabolism. J Pineal Res 2024; 76(3): e12954

[190] Li X, Liang T, Dai B, Chang L, Zhang Y, Hu S, Guo J, Xu S, Zheng L, Yao H, Lian H, Nie Y, Li Y, He X, Yao Z, Tong W, Wang X, Chow DHK, Xu J, Qin L. Excess glucocorticoids inhibit murine bone turnover via modulating the immunometabolism of the skeletal microenvironment. J Clin Invest 2024; 134(10): e166795

[191] Anderson G. Physiological processes underpinning the ubiquitous benefits and inter actions of melatonin, butyrate and green tea in neurodegenerative conditions. Melatonin Res 2024; 7(1): 20–46

[192] Anderson G. Melatonin, BAG-1 and cortisol circadian interactions in tumor pathogenesis and patterned immune responses. Explor Target Antitumor Ther 2023; 4: 962–993

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (No. 82273294) and the 1.3.5 project for discipline of excellence, West China Hospital, Sichuan University (No. 2020HXFH008).

Compliance with ethics guidelines

Conflicts of interest Yao Chen, Ying Xie, and Xijie Yu declare that they have no conflict of interest.

This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

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