Modulation of bone remodeling by the gut microbiota: a new therapy for osteoporosis

Compston, J. E., McClung, M. R. & Leslie, W. D. Osteoporosis. Lancet 393, 364–376 (2019).

Sambrook, P. & Cooper, C. Osteoporosis. Lancet 367, 2010–2018 (2006).

Sang, C. et al. TNF-α promotes osteoclastogenesis through JNK signaling-dependent induction of Semaphorin3D expression in estrogen-deficiency induced osteoporosis. J. Cell. Physiol. 232, 3396–3408 (2017).

Tan, J. et al. Decreased osteogenesis of adult mesenchymal stem cells by reactive oxygen species under cyclic stretch: a possible mechanism of age related osteoporosis. Bone Res. 3, 15003 (2015).

Yu, M. et al. PTH induces bone loss via microbial-dependent expansion of intestinal TNF(+) T cells and Th17 cells. Nat. Commun. 11, 468 (2020).

Clayton, E. S. & Hochberg, M. C. Osteoporosis and osteoarthritis, rheumatoid arthritis and spondylarthropathies. Curr. Osteoporos. Rep. 11, 257–262 (2013).

Gulati, A. M. et al. Osteoporosis in psoriatic arthritis: a cross-sectional study of an outpatient clinic population. Rmd. Open. 4, e000631 (2018).

Chevalier, C. et al. Warmth prevents bone loss through the gut microbiota. Cell. Metab. 32, 575–90.e7 (2020).

Khosla, S. & Hofbauer, L. C. Osteoporosis treatment: recent developments and ongoing challenges. Lancet Diabetes Endocrinol. 5, 898–907 (2017).

Wei, H. et al. Identification of fibroblast activation protein as an osteogenic suppressor and anti-osteoporosis drug target. Cell. Rep. 33, 108252 (2020).

Zhang, W., Dang, K., Huai, Y. & Qian, A. Osteoimmunology: the regulatory roles of T lymphocytes in osteoporosis. Front. Endocrinol. 11, 465 (2020).

Li, C. et al. Gut microbiota composition and bone mineral loss-epidemiologic evidence from individuals in Wuhan, China. Osteoporos. Int. 30, 1003–1013 (2019).

Wang, J. et al. Diversity analysis of gut microbiota in osteoporosis and osteopenia patients. PeerJ 5, e3450 (2017).

Wen, K. et al. Fecal and serum metabolomic signatures and microbial community profiling of postmenopausal osteoporosis mice model. Front. Cell. Infect. Microbiol. 10, 535310 (2020).

Sjögren, K. et al. The gut microbiota regulates bone mass in mice. J. Bone Miner. Res. 27, 1357–1367 (2012).

Novince, C. M. et al. Commensal gut microbiota immunomodulatory actions in bone marrow and liver have catabolic effects on skeletal homeostasis in health. Sci. Rep. 7, 5747 (2017).

Uchida, Y. et al. Commensal microbiota enhance both osteoclast and osteoblast activities. Molecules. 23, 1517 (2018).

Schwarzer, M. et al. Lactobacillus plantarum strain maintains growth of infant mice during chronic undernutrition. Science 351, 854–857 (2016).

Yan, J. et al. Gut microbiota induce IGF-1 and promote bone formation and growth. Proc. Natl. Acad. Sci. USA 113, E7554–e63 (2016).

Cox, L. M. et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell 158, 705–721 (2014).

Cho, I. et al. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature 488, 621–626 (2012).

Nobel, Y. R. et al. Metabolic and metagenomic outcomes from early-life pulsed antibiotic treatment. Nat. Commun. 6, 7486 (2015).

Tyagi, A. M. et al. The gut microbiota is a transmissible determinant of skeletal maturation. Elife. 10, e64237 (2021).

Yatsunenko, T. et al. Human gut microbiome viewed across age and geography. Nature 486, 222–227 (2012).

Schepper, J. D. et al. Probiotic Lactobacillus reuteri prevents postantibiotic bone loss by reducing intestinal dysbiosis and preventing barrier disruption. J. Bone Miner. Res. 34, 681–698 (2019).

Willers, M. et al. S100A8 and S100A9 are important for postnatal development of gut microbiota and immune system in mice and infants. Gastroenterology 159, 2130–45.e5 (2020).

Nash, M. J., Frank, D. N. & Friedman, J. E. Early microbes modify immune system development and metabolic homeostasis-The “Restaurant” Hypothesis Revisited. Front. Endocrinol. 8, 349 (2017).

Martin, R. et al. Early life: gut microbiota and immune development in infancy. Benef. Microbes 1, 367–382 (2010).

Hooper, L. V., Littman, D. R. & Macpherson, A. J. Interactions between the microbiota and the immune system. Science 336, 1268–1273 (2012).

Li, J. Y. et al. Sex steroid deficiency-associated bone loss is microbiota dependent and prevented by probiotics. J. Clin. Investig. 126, 2049–2063 (2016).

Macpherson, A. J. & Harris, N. L. Interactions between commensal intestinal bacteria and the immune system. Nat. Rev. Immunol. 4, 478–485 (2004).

Haak, B. W. et al. Long-term impact of oral vancomycin, ciprofloxacin and metronidazole on the gut microbiota in healthy humans. J. Antimicrob. Chemother. 74, 782–786 (2019).

Tyagi, A. M. et al. The microbial metabolite butyrate stimulates bone formation via T regulatory cell-mediated regulation of WNT10B expression. Immunity 49, 1116–31.e7 (2018).

Zhang, J. et al. Loss of bone and Wnt10b expression in male type 1 diabetic mice is blocked by the probiotic Lactobacillus reuteri. Endocrinology 156, 3169–3182 (2015).

Ciucci, T. et al. Bone marrow Th17 TNFα cells induce osteoclast differentiation, and link bone destruction to IBD. Gut 64, 1072–1081 (2015).

Lavelle, A. & Sokol, H. Gut microbiota-derived metabolites as key actors in inflammatory bowel disease. Nat. Rev. Gastroenterol. Hepatol. 17, 223–237 (2020).

Ali, T., Lam, D., Bronze, M. S. & Humphrey, M. B. Osteoporosis in inflammatory bowel disease. Am. J. Med. 122, 599–604 (2009).

Peek, C. T. et al. Intestinal inflammation promotes MDL-1(+) osteoclast precursor expansion to trigger osteoclastogenesis and bone loss. Cell. Mol. Gastroenterol. Hepatol. 14, 731–750 (2022).

Wong, B. R. et al. TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src. Mol. Cell. 4, 1041–1049 (1999).

Wong, B. R., Josien, R. & Choi, Y. TRANCE is a TNF family member that regulates dendritic cell and osteoclast function. J. Leukoc. Biol. 65, 715–724 (1999).

Josien, R., Wong, B. R., Li, H. L., Steinman, R. M. & Choi, Y. TRANCE, a TNF family member, is differentially expressed on T cell subsets and induces cytokine production in dendritic cells. J. Immunol. 162, 2562–2568 (1999).

Wong, B. R. et al. TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells. J. Biol. Chem. 272, 25190–25194 (1997).

Wong, B. R. et al. TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor. J. Exp. Med. 186, 2075–2080 (1997).

Okamoto, K. et al. Osteoimmunology: the conceptual framework unifying the immune and skeletal systems. Physiol. Rev. 97, 1295–1349 (2017).

Takayanagi, H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat. Rev. Immunol. 7, 292–304 (2007).

Arron, J. R. & Choi, Y. Bone versus immune system. Nature 408, 535–536 (2000).

Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

Alexander, M. et al. Human gut bacterial metabolism drives Th17 activation and colitis. Cell Host Microbe 30, 17–30.e9 (2022).

Atarashi, K. et al. Th17 cell induction by adhesion of microbes to intestinal epithelial cells. Cell 163, 367–380 (2015).

Adamopoulos, I. E. et al. Interleukin-17A upregulates receptor activator of NF-kappaB on osteoclast precursors. Arthritis Res. Ther. 12, R29 (2010).

Duque, G. et al. Interferon-γ plays a role in bone formation in vivo and rescues osteoporosis in ovariectomized mice. J. Bone Miner. Res. 26, 1472–1483 (2011).

Hathaway-Schrader, J. D. et al. Specific commensal bacterium critically regulates gut microbiota osteoimmunomodulatory actions during normal postpubertal skeletal growth and maturation. JBMR Plus 4, e10338 (2020).

Li, J. Y. et al. Parathyroid hormone-dependent bone formation requires butyrate production by intestinal microbiota. J. Clin. Investig. 130, 1767–1781 (2020).

Li, J. Y. et al. Ovariectomy disregulates osteoblast and osteoclast formation through the T-cell receptor CD40 ligand. Proc. Natl. Acad. Sci. USA 108, 768–773 (2011).

Sato, K. et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J. Exp. Med. 203, 2673–2682 (2006).

Adeel, S. et al. Bone loss in surgically ovariectomized premenopausal women is associated with T lymphocyte activation and thymic hypertrophy. J. Investig. Med. 61, 1178–1183 (2013).

Goto, Y. et al. Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal Th17 cell differentiation. Immunity 40, 594–607 (2014).

Pouikli, A. et al. Chromatin remodeling due to degradation of citrate carrier impairs osteogenesis of aged mesenchymal stem cells. Nat. Aging 1, 810–825 (2021).

Naskar, D., Teng, F., Felix, K. M., Bradley, C. P. & Wu, H. J. Synthetic retinoid AM80 ameliorates lung and arthritic autoimmune responses by inhibiting T follicular helper and Th17 cell responses. J. Immunol. 198, 1855–1864 (2017).

Sheridan, C. First integrin inhibitor since Tysabri nears approval for IBD. Nat. Biotechnol. 32, 205–207 (2014).

Aden, K. et al. Metabolic functions of gut microbes associate with efficacy of tumor necrosis factor antagonists in patients with inflammatory bowel diseases. Gastroenterology 157, 1279–92.e11 (2019).

Schleier, L. et al. Non-classical monocyte homing to the gut via α4β7 integrin mediates macrophage-dependent intestinal wound healing. Gut 69, 252–263 (2020).

DeSelm, C. J. et al. IL-17 mediates estrogen-deficient osteoporosis in an Act1-dependent manner. J. Cell. Biochem. 113, 2895–2902 (2012).

Dar, H. Y. et al. Bacillus clausii inhibits bone loss by skewing Treg-Th17 cell equilibrium in postmenopausal osteoporotic mice model. Nutrition 54, 118–128 (2018).

Stefka, A. T. et al. Commensal bacteria protect against food allergen sensitization. Proc. Natl. Acad. Sci. USA 111, 13145–13150 (2014).

Atarashi, K. et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500, 232–236 (2013).

Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).

Chiba, T. & Seno, H. Indigenous clostridium species regulate systemic immune responses by induction of colonic regulatory T cells. Gastroenterology 141, 1114–1116 (2011).

Lyons, A. et al. Bacterial strain-specific induction of Foxp3+ T regulatory cells is protective in murine allergy models. Clin. Exp. Allergy 40, 811–819 (2010).

Di Giacinto, C., Marinaro, M., Sanchez, M., Strober, W. & Boirivant, M. Probiotics ameliorate recurrent Th1-mediated murine colitis by inducing IL-10 and IL-10-dependent TGF-beta-bearing regulatory cells. J. Immunol. 174, 3237–3246 (2005).

Karimi, K., Inman, M. D., Bienenstock, J. & Forsythe, P. Lactobacillus reuteri-induced regulatory T cells protect against an allergic airway response in mice. Am. J. Respir. Crit. Care Med. 179, 186–193 (2009).

Bassaganya-Riera, J., Viladomiu, M., Pedragosa, M., De Simone, C. & Hontecillas, R. Immunoregulatory mechanisms underlying prevention of colitis-associated colorectal cancer by probiotic bacteria. PLoS One 7, e34676 (2012).

Fujisaki, J. et al. In vivo imaging of Treg cells providing immune privilege to the haematopoietic stem-cell niche. Nature 474, 216–219 (2011).

Luo, C. Y., Wang, L., Sun, C. & Li, D. J. Estrogen enhances the functions of CD4(+)CD25(+)Foxp3(+) regulatory T cells that suppress osteoclast differentiation and bone resorption in vitro. Cell. Mol. Immunol. 8, 50–58 (2011).

Taylor, A., Verhagen, J., Blaser, K., Akdis, M. & Akdis, C. A. Mechanisms of immune suppression by interleukin-10 and transforming growth factor-beta: the role of T regulatory cells. Immunology 117, 433–442 (2006).

Grafe, I. et al. TGF-β family signaling in mesenchymal differentiation. Cold Spring Harb. Perspect. Biol. 10, a022202 (2018).

Chang, J. et al. Inhibition of osteoblastic bone formation by nuclear factor-kappaB. Nat. Med. 15, 682–689 (2009).

Migliaccio, A. et al. Steroid-induced androgen receptor-oestradiol receptor beta-Src complex triggers prostate cancer cell proliferation. Embo. J. 19, 5406–5417 (2000).

Kousteni, S. et al. Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell 104, 719–730 (2001).

Kousteni, S. et al. Kinase-mediated regulation of common transcription factors accounts for the bone-protective effects of sex steroids. J. Clin. Investig. 111, 1651–1664 (2003).

Robinson, L. J. et al. Estrogen inhibits RANKL-stimulated osteoclastic differentiation of human monocytes through estrogen and RANKL-regulated interaction of estrogen receptor-alpha with BCAR1 and Traf6. Exp. Cell Res. 315, 1287–1301 (2009).

Samuels, A., Perry, M. J., Goodship, A. E., Fraser, W. D. & Tobias, J. H. Is high-dose estrogen-induced osteogenesis in the mouse mediated by an estrogen receptor? Bone 27, 41–46 (2000).

McDougall, K. E. et al. Estrogen receptor-alpha dependency of estrogen’s stimulatory action on cancellous bone formation in male mice. Endocrinology 144, 1994–1999 (2003).

Lindberg, M. K. et al. Estrogen receptor specificity in the regulation of the skeleton in female mice. J. Endocrinol. 171, 229–236 (2001).

Carlsten, H. Immune responses and bone loss: the estrogen connection. Immunol. Rev. 208, 194–206 (2005).

Eghbali-Fatourechi, G. et al. Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J. Clin. Investig. 111, 1221–1230 (2003).

Hofbauer, L. C. et al. Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells. Endocrinology 140, 4367–4370 (1999).

Khosla, S., Oursler, M. J. & Monroe, D. G. Estrogen and the skeleton. Trends Endocrinol. Metab. 23, 576–581 (2012).

Charatcharoenwitthaya, N., Khosla, S., Atkinson, E. J., McCready, L. K. & Riggs, B. L. Effect of blockade of TNF-alpha and interleukin-1 action on bone resorption in early postmenopausal women. J. Bone Miner. Res. 22, 724–729 (2007).

Roggia, C. et al. Up-regulation of TNF-producing T cells in the bone marrow: a key mechanism by which estrogen deficiency induces bone loss in vivo. Proc. Natl. Acad. Sci. USA 98, 13960–13965 (2001).

Cenci, S. et al. Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha. J. Clin. Invest. 106, 1229–1237 (2000).

Lee, S. K. et al. T lymphocyte-deficient mice lose trabecular bone mass with ovariectomy. J. Bone Miner. Res. 21, 1704–1712 (2006).

Pace, F. & Watnick, P. I. The interplay of sex steroids, the immune response, and the intestinal microbiota. Trends Microbiol. 29, 849–859 (2020).

Ridlon, J. M. & Bajaj, J. S. The human gut sterolbiome: bile acid-microbiome endocrine aspects and therapeutics. Acta Pharm. Sin. B 5, 99–105 (2015).

Kwa, M., Plottel, C. S., Blaser, M. J. & Adams, S. The intestinal microbiome and estrogen receptor-positive female breast cancer. J. Natl. Cancer Inst. 108, djw029 (2016).

Parida, S. & Sharma, D. The microbiome-estrogen connection and breast cancer risk. Cells. 8, 1642 (2019).

Dabek, M., McCrae, S. I., Stevens, V. J., Duncan, S. H. & Louis, P. Distribution of beta-glucosidase and beta-glucuronidase activity and of beta-glucuronidase gene gus in human colonic bacteria. FEMS Microbiol. Ecol. 66, 487–495 (2008).

Flores, R. et al. Fecal microbial determinants of fecal and systemic estrogens and estrogen metabolites: a cross-sectional study. J. Transl. Med. 10, 253 (2012).

Wein, M. N. & Kronenberg, H. M. Regulation of bone remodeling by parathyroid hormone. Cold. Spring. Harb. Perspect. Med. 8, a031237 (2018).

Walker, M. D. & Silverberg, S. J. Primary hyperparathyroidism. Nat. Rev. Endocrinol. 14, 115–125 (2018).

Iida-Klein, A. et al. Short-term continuous infusion of human parathyroid hormone 1-34 fragment is catabolic with decreased trabecular connectivity density accompanied by hypercalcemia in C57BL/J6 mice. J. Endocrinol. 186, 549–557 (2005).

Silverberg, S. J. et al. Skeletal disease in primary hyperparathyroidism. J. Bone Miner. Res. 4, 283–291 (1989).

Lips, P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Endocr. Rev. 22, 477–501 (2001).

Li, J. Y. et al. IL-17 receptor signaling in osteoblasts/osteocytes mediates PTH-induced bone loss and enhances osteocytic RANKL production. J. Bone Miner. Res. 34, 349–360 (2019).

Silva, B. C., Costa, A. G., Cusano, N. E., Kousteni, S. & Bilezikian, J. P. Catabolic and anabolic actions of parathyroid hormone on the skeleton. J. Endocrinol. Investig. 34, 801–810 (2011).

Silva, B. C. & Bilezikian, J. P. Parathyroid hormone: anabolic and catabolic actions on the skeleton. Curr. Opin. Pharmacol. 22, 41–50 (2015).

Uzawa, T., Hori, M., Ejiri, S. & Ozawa, H. Comparison of the effects of intermittent and continuous administration of human parathyroid hormone(1-34) on rat bone. Bone 16, 477–484 (1995).

Jilka, R. L. Molecular and cellular mechanisms of the anabolic effect of intermittent PTH. Bone 40, 1434–1446 (2007).

Qin, L., Raggatt, L. J. & Partridge, N. C. Parathyroid hormone: a double-edged sword for bone metabolism. Trends Endocrinol. Metab. 15, 60–65 (2004).

Zaiss, M. M., Jones, R. M., Schett, G. & Pacifici, R. The gut-bone axis: how bacterial metabolites bridge the distance. J. Clin. Investig. 129, 3018–3028 (2019).

Kishimoto, T. et al. Peptidoglycan and lipopolysaccharide synergistically enhance bone resorption and osteoclastogenesis. J. Periodontal. Res. 47, 446–454 (2012).

Flint, H. J., Duncan, S. H., Scott, K. P. & Louis, P. Links between diet, gut microbiota composition and gut metabolism. Proc. Nutr. Soc. 74, 13–22 (2015).

Morrison, D. J. & Preston, T. Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut. microbes 7, 189–200 (2016).

Derrien, M., Vaughan, E. E., Plugge, C. M. & de Vos, W. M. Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. Int. J. Syst. Evol. Microbiol 54, 1469–1476 (2004).

Shimizu, J. et al. Propionate-producing bacteria in the intestine may associate with skewed responses of IL10-producing regulatory T cells in patients with relapsing polychondritis. PLoS One 13, e0203657 (2018).

Fu, X., Liu, Z., Zhu, C., Mou, H. & Kong, Q. Nondigestible carbohydrates, butyrate, and butyrate-producing bacteria. Crit. Rev. Food Sci. Nutr. 59, S130–s52 (2019).

Mariño, E. et al. Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes. Nat. Immunol. 18, 552–562 (2017).

Lucas, S. et al. Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss. Nat. Commun. 9, 55 (2018).

Guo, P., Zhang, K., Ma, X. & He, P. Clostridium species as probiotics: potentials and challenges. J. Anim. Sci. Biotechnol. 11, 24 (2020).

Candido, E. P., Reeves, R. & Davie, J. R. Sodium butyrate inhibits histone deacetylation in cultured cells. Cell 14, 105–113 (1978).

Riggs, M. G., Whittaker, R. G., Neumann, J. R. & Ingram, V. M. n-Butyrate causes histone modification in HeLa and Friend erythroleukaemia cells. Nature 268, 462–464 (1977).

Kim, D. S. et al. Attenuation of rheumatoid inflammation by sodium butyrate through reciprocal targeting of HDAC2 in osteoclasts and HDAC8 in T cells. Front. Immunol. 9, 1525 (2018).

Rahman, M. M. et al. Two histone deacetylase inhibitors, trichostatin A and sodium butyrate, suppress differentiation into osteoclasts but not into macrophages. Blood 101, 3451–3459 (2003).

Kim, H. N. et al. Trichostatin A inhibits osteoclastogenesis and bone resorption by suppressing the induction of c-Fos by RANKL. Eur. J. Pharmacol. 623, 22–29 (2009).

Chen, T. H., Chen, W. M., Hsu, K. H., Kuo, C. D. & Hung, S. C. Sodium butyrate activates ERK to regulate differentiation of mesenchymal stem cells. Biochem. Biophys. Res. Commun. 355, 913–918 (2007).

Katono, T. et al. Sodium butyrate stimulates mineralized nodule formation and osteoprotegerin expression by human osteoblasts. Arch. Oral. Biol. 53, 903–909 (2008).

Marsh, A. G., Sanchez, T. V., Midkelsen, O., Keiser, J. & Mayor, G. Cortical bone density of adult lacto-ovo-vegetarian and omnivorous women. J. Am. Diet. Assoc. 76, 148–151 (1980).

Rivas, A. et al. Mediterranean diet and bone mineral density in two age groups of women. Int. J. Food Sci. Nutr. 64, 155–161 (2013).

Lee, M. J. et al. Exogenous polyamines promote osteogenic differentiation by reciprocally regulating osteogenic and adipogenic gene expression. J. Cell. Biochem. 114, 2718–2728 (2013).

Pegg, A. E. Mammalian polyamine metabolism and function. Iubmb. Life. 61, 880–894 (2009).

Zhao, Q. et al. Polyamine metabolism links gut microbiota and testicular dysfunction. Microbiome 9, 224 (2021).

Tofalo, R., Cocchi, S. & Suzzi, G. Polyamines and gut microbiota. Front. Nutr. 6, 16 (2019).

Ramos-Molina, B., Queipo-Ortuño, M. I., Lambertos, A., Tinahones, F. J. & Peñafiel, R. Dietary and gut microbiota polyamines in obesity- and age-related diseases. Front. Nutr. 6, 24 (2019).

Tjabringa, G. S. et al. Polyamines modulate nitric oxide production and COX-2 gene expression in response to mechanical loading in human adipose tissue-derived mesenchymal stem cells. Stem. Cells 24, 2262–2269 (2006).

Tjabringa, G. S. et al. The polymine spermine regulates osteogenic differentiation in adipose stem cells. J. Cell. Mol. Med. 12, 1710–1717 (2008).

Yamamoto, T. et al. The natural polyamines spermidine and spermine prevent bone loss through preferential disruption of osteoclastic activation in ovariectomized mice. Br. J. Pharm. 166, 1084–1096 (2012).

Yamada, T. et al. Daily intake of polyamine-rich Saccharomyces cerevisiae S631 prevents osteoclastic activation and bone loss in ovariectomized mice. Food Sci. Biotechnol. 28, 1241–1245 (2019).

Kong, S. H., Kim, J. H. & Shin, C. S. Serum spermidine as a novel potential predictor for fragility fractures. J. Clin. Endocrinol. Metab. 106, e582–e591 (2021).

Albert, J. S. et al. Impaired osteoblast and osteoclast function characterize the osteoporosis of Snyder - Robinson syndrome. Orphanet J. Rare Dis. 10, 27 (2015).

Murray-Stewart, T., Dunworth, M., Foley, J. R., Schwartz, C. E. & Casero, R. A., Jr. Polyamine homeostasis in Snyder-Robinson syndrome. Med. Sci. 6, 112 (2018).

Shen, X. et al. Microbial regulation of host hydrogen sulfide bioavailability and metabolism. Free Radic. Biol. Med. 60, 195–200 (2013).

Linden, D. R. Hydrogen sulfide signaling in the gastrointestinal tract. Antioxid. Redox Signal. 20, 818–830 (2014).

Guo, F. F., Yu, T. C., Hong, J. & Fang, J. Y. Emerging roles of hydrogen sulfide in inflammatory and neoplastic colonic diseases. Front. Physiol. 7, 156 (2016).

Liu, Y. et al. Hydrogen sulfide maintains mesenchymal stem cell function and bone homeostasis via regulation of Ca(2+) channel sulfhydration. Cell. Stem. Cell. 15, 66–78 (2014).

Gambari, L. et al. Sodium hydrosulfide inhibits the differentiation of osteoclast progenitor cells via NRF2-dependent mechanism. Pharmacol. Res. 87, 99–112 (2014).

Grassi, F. et al. Hydrogen sulfide is a novel regulator of bone formation implicated in the bone loss induced by estrogen deficiency. J. Bone Miner. Res. 31, 949–963 (2016).

Behera, J. et al. Hydrogen sulfide promotes bone homeostasis by balancing inflammatory cytokine signaling in CBS-deficient mice through an epigenetic mechanism. Sci. Rep. 8, 15226 (2018).

Kim, J. H., Lee, J., Park, J. & Gho, Y. S. Gram-negative and Gram-positive bacterial extracellular vesicles. Semin. Cell Dev. Biol. 40, 97–104 (2015).

Kulp, A. & Kuehn, M. J. Biological functions and biogenesis of secreted bacterial outer membrane vesicles. Annu. Rev. Microbiol. 64, 163–184 (2010).

Molina-Tijeras, J. A., Gálvez, J. & Rodríguez-Cabezas, M. E. The immunomodulatory properties of extracellular vesicles derived from probiotics: a novel approach for the management of gastrointestinal diseases. Nutrients. 11, 1038 (2019).

Tong, L. et al. Lactobacillus rhamnosus GG derived extracellular vesicles modulate gut microbiota and attenuate inflammatory in DSS-induced colitis mice. Nutrients. 13, 3319 (2021).

Hu, R. et al. Lactobacillus reuteri-derived extracellular vesicles maintain intestinal immune homeostasis against lipopolysaccharide-induced inflammatory responses in broilers. J. Anim. Sci. Biotechnol. 12, 25 (2021).

Yamasaki-Yashiki, S., Miyoshi, Y., Nakayama, T., Kunisawa, J. & Katakura, Y. IgA-enhancing effects of membrane vesicles derived from Lactobacillus sakei subsp. sakei NBRC15893. Biosci. Microbiota. Food Health 38, 23–29 (2019).

Kang, C. S. et al. Extracellular vesicles derived from gut microbiota, especially Akkermansia muciniphila, protect the progression of dextran sulfate sodium-induced colitis. PLoS One 8, e76520 (2013).

Ashrafian, F. et al. Akkermansia muciniphila-derived extracellular vesicles as a mucosal delivery vector for amelioration of obesity in mice. Front. Microbiol. 10, 2155 (2019).

Ashrafian, F. et al. Extracellular vesicles and pasteurized cells derived from Akkermansia muciniphila protect against high-fat induced obesity in mice. Microb. Cell. Fact. 20, 219 (2021).

Liu, J. H. et al. Extracellular vesicles from child gut microbiota enter into bone to preserve bone mass and strength. Adv. Sci. 8, 2004831 (2021).

Klimentová, J. & Stulík, J. Methods of isolation and purification of outer membrane vesicles from gram-negative bacteria. Microbiol. Res. 170, 1–9 (2015).

Jones, R. M., Mulle, J. G. & Pacifici, R. Osteomicrobiology: the influence of gut microbiota on bone in health and disease. Bone 115, 59–67 (2018).

O’Toole, P. W., Marchesi, J. R. & Hill, C. Next-generation probiotics: the spectrum from probiotics to live biotherapeutics. Nat. Microbiol. 2, 17057 (2017).

Pandey, K. R., Naik, S. R. & Vakil, B. V. Probiotics, prebiotics and synbiotics- a review. J. Food Sci. Technol. 52, 7577–7587 (2015).

McFarland, L. V. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease. Am. J. Gastroenterol. 101, 812–822 (2006).

Hsu, C. L. et al. Antiobesity and uric acid-lowering effect of Lactobacillus plantarum GKM3 in high-fat-diet-induced obese rats. J. Am. Coll. Nutr. 38, 623–632 (2019).

Hatakka, K. et al. The influence of Lactobacillus rhamnosus LC705 together with Propionibacterium freudenreichii ssp. shermanii JS on potentially carcinogenic bacterial activity in human colon. Int. J. Food Microbiol. 128, 406–410 (2008).

Hao, H. et al. Effect of extracellular vesicles derived from Lactobacillus plantarum Q7 on gut microbiota and ulcerative colitis in mice. Front. Immunol. 12, 777147 (2021).

Chiang, S. S. & Pan, T. M. Antiosteoporotic effects of Lactobacillus -fermented soy skim milk on bone mineral density and the microstructure of femoral bone in ovariectomized mice. J. Agric. Food Chem. 59, 7734–7742 (2011).

Ong, A. M., Kang, K., Weiler, H. A. & Morin, S. N. Fermented milk products and bone health in postmenopausal women: a systematic review of randomized controlled trials, prospective cohorts, and case-control studies. Adv. Nutr. 11, 251–265 (2020).

Tu, M. Y. et al. Kefir peptides prevent estrogen deficiency-induced bone loss and modulate the structure of the gut microbiota in ovariectomized mice. Nutrients. 12, 3432 (2020).

Lee, C. S. et al. Lactobacillus-fermented milk products attenuate bone loss in an experimental rat model of ovariectomy-induced post-menopausal primary osteoporosis. J. Appl. Microbiol. 130, 2041–2062 (2021).

Tu, M. Y. et al. Short-term effects of kefir-fermented milk consumption on bone mineral density and bone metabolism in a randomized clinical trial of osteoporotic patients. PLoS One 10, e0144231 (2015).

Britton, R. A. et al. Probiotic L. reuteri treatment prevents bone loss in a menopausal ovariectomized mouse model. J. Cell. Physiol. 229, 1822–1830 (2014).

Dar, H. Y. et al. Lactobacillus acidophilus inhibits bone loss and increases bone heterogeneity in osteoporotic mice via modulating Treg-Th17 cell balance. Bone Rep. 8, 46–56 (2018).

Liu, X. et al. Lactobacillus Fermentum ZS40 prevents secondary osteoporosis in Wistar Rat. Food Sci. Nutr. 8, 5182–5191 (2020).

Liu, X. et al. Lactobacillus Plantarum HFY15 Helps prevent retinoic acid-induced secondary osteoporosis in Wistar rats. Evid. Based Complement. Altern. Med. 2020, 2054389 (2020).

Parvaneh, M. et al. Lactobacillus helveticus (ATCC 27558) upregulates Runx2 and Bmp2 and modulates bone mineral density in ovariectomy-induced bone loss rats. Clin. Interv. Aging 13, 1555–1564 (2018).

Jang, A. R. et al. Cell-free culture supernatant of Lactobacillus curvatus Wikim38 inhibits RANKL-induced osteoclast differentiation and ameliorates bone loss in ovariectomized mice. Lett. Appl. Microbiol. 73, 383–391 (2021).

Ohlsson, C. et al. Probiotics protect mice from ovariectomy-induced cortical bone loss. PLoS One 9, e92368 (2014).

Jhun, J. et al. Lactobacillus sakei suppresses collagen-induced arthritis and modulates the differentiation of T helper 17 cells and regulatory B cells. J. Transl. Med. 18, 317 (2020).

Collins, F. L. et al. Beneficial effects of Lactobacillus reuteri 6475 on bone density in male mice is dependent on lymphocytes. Sci. Rep. 9, 14708 (2019).

Li, L. et al. Fructus Ligustri Lucidi preserves bone quality through the regulation of gut microbiota diversity, oxidative stress, TMAO and Sirt6 levels in aging mice. Aging 11, 9348–9368 (2019).

Ai, T. et al. Konjac oligosaccharides modulate the gut environment and promote bone health in calcium-deficient mice. J. Agric. Food Chem. 69, 4412–4422 (2021).

Parvaneh, K. et al. Probiotics (Bifidobacterium longum) increase bone mass density and upregulate sparc and Bmp-2 genes in rats with bone loss resulting from ovariectomy. Biomed. Res. Int. 2015, 897639 (2015).

Fernández-Murga, M. L., Olivares, M. & Sanz, Y. Bifidobacterium pseudocatenulatum CECT 7765 reverses the adverse effects of diet-induced obesity through the gut-bone axis. Bone 141, 115580 (2020).

Wallimann, A. et al. An exopolysaccharide produced by Bifidobacterium longum 35624® inhibits osteoclast formation via a TLR2-dependent mechanism. Calcif. Tissue Int. 108, 654–666 (2021).

Roberts, J. L. et al. Bifidobacterium adolescentis supplementation attenuates fracture-induced systemic sequelae. Biomed. Pharmacother. 132, 110831 (2020).

Jansson, P.-A. et al. Probiotic treatment using a mix of three Lactobacillus strains for lumbar spine bone loss in postmenopausal women: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet Rheumatol. 1, e154–e162 (2019).

Nilsson, A. G., Sundh, D., Bäckhed, F. & Lorentzon, M. Lactobacillus reuteri reduces bone loss in older women with low bone mineral density: a randomized, placebo-controlled, double-blind, clinical trial. J. Intern. Med. 284, 307–317 (2018).

Lei, M., Hua, L. M. & Wang, D. W. The effect of probiotic treatment on elderly patients with distal radius fracture: a prospective double-blind, placebo-controlled randomised clinical trial. Benef. Microbes 7, 631–637 (2016).

Motta, J. P. et al. Food-grade bacteria expressing elafin protect against inflammation and restore colon homeostasis. Sci. Transl. Med. 4, 158ra44 (2012).

Hamady, Z. Z. et al. Treatment of colitis with a commensal gut bacterium engineered to secrete human TGF-β1 under the control of dietary xylan 1. Inflamm. Bowel Dis. 17, 1925–1935 (2011).

Frossard, C. P., Steidler, L. & Eigenmann, P. A. Oral administration of an IL-10-secreting Lactococcus lactis strain prevents food-induced IgE sensitization. J. Allergy Clin. Immunol. 119, 952–959 (2007).

Naito, Y., Uchiyama, K. & Takagi, T. A next-generation beneficial microbe: Akkermansia muciniphila. J. Clin. Biochem. Nutr. 63, 33–35 (2018).

Derrien, M., Belzer, C. & de Vos, W. M. Akkermansia muciniphila and its role in regulating host functions. Microb. Pathog. 106, 171–181 (2017).

Schneeberger, M. et al. Akkermansia muciniphila inversely correlates with the onset of inflammation, altered adipose tissue metabolism and metabolic disorders during obesity in mice. Sci. Rep. 5, 16643 (2015).

Everard, A. et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc. Natl. Acad. Sci. USA 110, 9066–9071 (2013).

Cani, P. D. & de Vos, W. M. Next-generation beneficial microbes: the case of Akkermansia muciniphila. Front. Microbiol. 8, 1765 (2017).

Zhai, Q., Feng, S., Arjan, N. & Chen, W. A next generation probiotic, Akkermansia muciniphila. Crit. Rev. Food Sci. Nutr. 59, 3227–3236 (2019).

Depommier, C. et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nat. Med. 25, 1096–1103 (2019).

Mulhall, H. et al. Akkermansia muciniphila and its Pili-like protein Amuc_1100 modulate macrophage polarization in experimental periodontitis. Infect. Immun. 89, e00500–20 (2020).

Huck, O. et al. Akkermansia muciniphila reduces Porphyromonas gingivalis-induced inflammation and periodontal bone destruction. J. Clin. Periodontol. 47, 202–212 (2020).

Liu, J. H. et al. Akkermansia muciniphila promotes type H vessel formation and bone fracture healing by reducing gut permeability and inflammation. Dis. Model. Mech. 13, dmm043620 (2020).

Depommier, C. et al. Pasteurized Akkermansia muciniphila increases whole-body energy expenditure and fecal energy excretion in diet-induced obese mice. Gut. microbes 11, 1231–1245 (2020).

Wang, L. et al. A purified membrane protein from Akkermansia muciniphila or the pasteurised bacterium blunts colitis associated tumourigenesis by modulation of CD8(+) T cells in mice. Gut 69, 1988–1997 (2020).

Druart, C. et al. Toxicological safety evaluation of pasteurized Akkermansia muciniphila. J. Appl. Toxicol. 41, 276–290 (2021).

Mulhall, H., DiChiara, J. M., Huck, O. & Amar, S. Pasteurized Akkermansia muciniphila reduces periodontal and systemic inflammation induced by Porphyromonas gingivalis in lean and obese mice. J. Clin. Periodontol. 49, 717–729 (2022).

Wu, Z. et al. Pasteurized Akkermansia muciniphila reduces fat accumulation via nhr-49-mediated nuclear hormone signaling pathway in Caenorhabditis elegans. Molecules. 27, 6159 (2022).

Lawenius, L. et al. Pasteurized Akkermansia muciniphila protects from fat mass gain but not from bone loss. Am. J. Physiol. Endocrinol. Metab. 318, E480–e91 (2020).

Stoeva, M. K. et al. Butyrate-producing human gut symbiont, Clostridium butyricum, and its role in health and disease. Gut. microbes 13, 1–28 (2021).

Isa, K. et al. Safety assessment of the Clostridium butyricum MIYAIRI 588® probiotic strain including evaluation of antimicrobial sensitivity and presence of Clostridium toxin genes in vitro and teratogenicity in vivo. Hum. Exp. Toxicol. 35, 818–832 (2016).

Seki, H. et al. Prevention of antibiotic-associated diarrhea in children by Clostridium butyricum MIYAIRI. Pediatr. Int. 45, 86–90 (2003).

Sokol, H. et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc. Natl. Acad. Sci. USA 105, 16731–16736 (2008).

Rossi, O. et al. Faecalibacterium prausnitzii A2-165 has a high capacity to induce IL-10 in human and murine dendritic cells and modulates T cell responses. Sci. Rep. 6, 18507 (2016).

Zhang, M. et al. Faecalibacterium prausnitzii inhibits interleukin-17 to ameliorate colorectal colitis in rats. PLoS One 9, e109146 (2014).

Scher, J. U. et al. Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease. Arthritis Rheumatol. 67, 128–139 (2015).

Knip, M. & Siljander, H. The role of the intestinal microbiota in type 1 diabetes mellitus. Nat. Rev. Endocrinol. 12, 154–167 (2016).

Huang, R. 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 23, 1002–1013 (2022).

Liu, X. et al. Blautia-a new functional genus with potential probiotic properties? Gut. microbes 13, 1–21 (2021).

Rey, F. E. et al. Dissecting the in vivo metabolic potential of two human gut acetogens. J. Biol. Chem. 285, 22082–22090 (2010).

Polansky, O. et al. Important metabolic pathways and biological processes expressed by chicken cecal microbiota. Appl. Environ. Microbiol. 82, 1569–1576 (2015).

Oliphant, K. & Allen-Vercoe, E. Macronutrient metabolism by the human gut microbiome: major fermentation by-products and their impact on host health. Microbiome 7, 91 (2019).

Dziarski, R., Park, S. Y., Kashyap, D. R., Dowd, S. E. & Gupta, D. Pglyrp-regulated gut microflora Prevotella falsenii, Parabacteroides distasonis and Bacteroides eggerthii enhance and Alistipes finegoldii attenuates colitis in mice. PLoS One 11, e0146162 (2016).

Bui, T. P. N. et al. Conversion of dietary inositol into propionate and acetate by commensal Anaerostipes associates with host health. Nat. Commun. 12, 4798 (2021).

Schwiertz, A. et al. Anaerostipes caccae gen. nov., sp. nov., a new saccharolytic, acetate-utilising, butyrate-producing bacterium from human faeces. Syst. Appl. Microbiol. 25, 46–51 (2002).

Hernandez, C. J., Beaupré, G. S. & Carter, D. R. A theoretical analysis of the relative influences of peak BMD, age-related bone loss and menopause on the development of osteoporosis. Osteoporos. Int. 14, 843–847 (2003).