CC BY-NC-ND 4.0 · Planta Med 2025; 91(03): 127-141
DOI: 10.1055/a-2462-4844
Original Papers

Extracts of Drynariae Rhizoma Promote Bone Formation in OVX Rats through Modulating the Gut Microbiota

Qing Lin
1   College of Traditional Chinese Medicine, Jinan University, Guangzhou, Guangdong, China
2   Guangdong Provincial Key Laboratory of Traditional Chinese Medicine Informatization, Guangzhou, Guangdong, China
,
Xinchen Ouyang
1   College of Traditional Chinese Medicine, Jinan University, Guangzhou, Guangdong, China
,
Qi Pan
1   College of Traditional Chinese Medicine, Jinan University, Guangzhou, Guangdong, China
,
Jiajia Huang
3   The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China
,
Zhifen Zhang
4   College of Pharmacy, Jinan University, Guangzhou, Guangdong, China
,
Yumei Yang
4   College of Pharmacy, Jinan University, Guangzhou, Guangdong, China
,
Haoyu Wang
1   College of Traditional Chinese Medicine, Jinan University, Guangzhou, Guangdong, China
,
Li Yang
4   College of Pharmacy, Jinan University, Guangzhou, Guangdong, China
,
Xiaofeng Zhu
1   College of Traditional Chinese Medicine, Jinan University, Guangzhou, Guangdong, China
2   Guangdong Provincial Key Laboratory of Traditional Chinese Medicine Informatization, Guangzhou, Guangdong, China
3   The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China
,
Xiaoyun Li
4   College of Pharmacy, Jinan University, Guangzhou, Guangdong, China
,
Ronghua Zhang
2   Guangdong Provincial Key Laboratory of Traditional Chinese Medicine Informatization, Guangzhou, Guangdong, China
4   College of Pharmacy, Jinan University, Guangzhou, Guangdong, China
› Institutsangaben
This research was funded by the National Natural Science Foundation of China (No. U24A6013, 82405121, 82274232, 82274376, and 82074287), National Key Research and Development Program of China (No. 2018YFC2 002 500), Guangdong Provincial Key laboratory of Traditional Chinese Medicine Informatization (No. 2021B1 212 040 007), Basic and Applied Basic Research Fund of Guangdong Province (2022B1 515 120 022), Fundamental Research Funds for the Central Universities (21 622 329, 21 623 115, 21 624 225), Basic and Applied Basic Research Fund of Guangzhou (SL2022A04J00516), and Construction project of Guangdong Famous Traditional Chinese Medicine Inheritance Studio of Ronghua Zhang (Guangdong Traditional Chinese Medicine Letter (2023) No. 108).

Abstract

Drynariae Rhizoma has been commonly used as a preventive and therapeutic agent for bone diseases. However, its pharmacological mechanisms have not been fully elucidated. Here, we aimed to investigate the effects of Drynariae Rhizoma in a bilateral ovariectomized rat model and explore the correlation with gut microbiome. We established an ovariectomized rat model, which we treated with different doses of Drynariae Rhizoma (Drynariae Rhizoma-Low, 0.27 g/kg/day; Drynariae Rhizoma-Middle, 0.81 g/kg/day; Drynariae Rhizoma-High, 2.43 g/kg/day) through intragastric administration for 12 weeks. Results showed that Drynariae Rhizoma alleviated body weight, moderated bone microstructure, and promoted the expression of bone formation-related factors in ovariectomized rats, in which Drynariae Rhizoma-High showed the most significant effects among the three doses. Furthermore, the effects of Drynariae Rhizoma on promoting bone formation were correlated to the changes in microbial richness and the restorations of several genera, among which Ruminiclostridium and Ruminococcaceae_UCG_007 were positively correlated with the bone formation-related factors, and both were enriched in the Drynariae Rhizoma-High group as biomarkers. Moreover, CMP-legionaminate biosynthesis I might be a crucial pathway of Drynariae Rhizoma to regulate gut microbiota. The content of serum short-chain fatty acids in the ovariectomized rats were regulated by Drynariae Rhizoma. Our results demonstrate that Drynariae Rhizoma promotes bone formation in ovariectomized rats, and is related to the regulation of the gut microbiota structure.

Supporting Information



Publikationsverlauf

Eingereicht: 07. Mai 2024

Angenommen nach Revision: 04. November 2024

Accepted Manuscript online:
05. November 2024

Artikel online veröffentlicht:
17. Januar 2025

© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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  • References

  • 1 Xiao PL, Cui AY, Hsu CJ, Peng R, Jiang N, Xu XH, Ma YG, Liu D, Lu HD. Global, regional prevalence, and risk factors of osteoporosis according to the World Health Organization diagnostic criteria: A systematic review and meta-analysis. Osteoporos Int 2022; 33: 2137-2153
  • 2 Harris K, Zagar CA, Lawrence KV. Osteoporosis: Common questions and answers. Am Fam Physician 2023; 107: 238-246
  • 3 Gao ZR, Feng YZ, Zhao YQ, Zhao J, Zhou YH, Ye Q, Chen Y, Tan L, Zhang SH, Feng Y, Hu J, Ou-Yang ZY, Dusenge MA, Guo Y. Traditional Chinese medicine promotes bone regeneration in bone tissue engineering. Chin Med 2022; 17: 86
  • 4 Duan Y, Su YT, Ren J, Zhou Q, Tang M, Li J, Li SX. Kidney tonifying traditional Chinese medicine: Potential implications for the prevention and treatment of osteoporosis. Front Pharmacol 2023; 13: 106389
  • 5 Wu L, Ling Z, Feng X, Mao C, Xu Z. Herb medicines against osteoporosis: Active compounds & relevant biological mechanisms. Curr Top Med Chem 2017; 17: 1670-1691
  • 6 Xu ZL, Xu MY, Wang HT, Xu QX, Liu MY, Jia CP, Geng F, Zhang N. Pharmacokinetics of eight flavonoids in rats assayed by UPLC-MS/MS after oral administration of Drynariae rhizoma extract. J Anal Methods Chem 2018; 2018: 4789196
  • 7 Su H, Xue H, Gao S, Yan B, Wang R, Tan G, Xu Z, Zeng L. Effect of Rhizoma Drynariae on differential gene expression in ovariectomized rats with osteoporosis based on transcriptome sequencing. Front Endocrinol (Lausanne) 2022; 13: 930912
  • 8 Liu X, Zhang S, Lu X, Zheng S, Li F, Xiong Z. Metabonomic study on the anti-osteoporosis effect of Rhizoma Drynariae and its action mechanism using ultra-performance liquid chromatography-tandem mass spectrometry. J Ethnopharmacol 2012; 139: 311-317
  • 9 Kang SN, Lee JS, Park JH, Cho KK, Lee OH, Kim IS. In vitro anti-osteoporosis properties of diverse Korean Drynariae rhizoma phenolic extracts. Nutrients 2014; 6: 1737-1751
  • 10 Jeong JC, Lee JW, Yoon CH, Kim HM, Kim CH. Drynariae Rhizoma promotes osteoblast differentiation and mineralization in MC3 T3-E1 cells through regulation of bone morphogenetic protein-2, alkaline phosphatase, type I collagen and collagenase-1. Toxicol In Vitro 2004; 18: 829-834
  • 11 Villa CR, Ward WE, Comelli EM. Gut microbiota-bone axis. Crit Rev Food Sci Nutr 2017; 57: 1664-1672
  • 12 Feng Q, Chen WD, Wang YD. Gut microbiota: An integral moderator in health and disease. Front Microbiol 2018; 9: 151
  • 13 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: 3635-3646
  • 14 Qaseem A, Forciea MA, McLean RM, Denberg TD. Treatment of low bone density or osteoporosis to prevent fractures in men and women: A clinical practice guideline update from the American college of physicians. Ann Intern Med 2017; 166: 818-839
  • 15 Ni J, Au M, Kong H, Wang X, Wen C. Lycium barbarum polysaccharides in ageing and its potential use for prevention and treatment of osteoarthritis: A systematic review. BMC Complement Med Ther 2021; 21: 212
  • 16 Zhao P, Zhao C, Li X, Gao Q, Huang L, Xiao P, Gao W. The genus Polygonatum: A review of ethnopharmacology, phytochemistry and pharmacology. J Ethnopharmacol 2018; 214: 274-291
  • 17 Zhang F, Li Q, Wu J, Ruan H, Sun C, Zhu J, Song Q, Wei X, Shi Y, Zhu L. Total flavonoids of drynariae rhizoma improve glucocorticoid-induced osteoporosis of rats: UHPLC-MS-based qualitative analysis, network pharmacology strategy and pharmacodynamic validation. Front Endocrinol (Lausanne) 2022; 13: 920931
  • 18 Fang XH, Zhou GE, Lin N. Total flavonoids from Rhizoma Drynariae (Gusuibu) alleviates diabetic osteoporosis by activating BMP2/Smad signaling pathway. Comb Chem High Throughput Screen 2023; 26: 2401-2409
  • 19 Lupo M, Dains JE, Madsen LT. Hormone replacement therapy: An increased risk of recurrence and mortality for breast cancer patients?. J Adv Pract Oncol 2015; 6: 322-330
  • 20 Anderson GL, Judd HL, Kaunitz AM, Barad DH, Beresford SA, Pettinger M, Liu J, McNeeley SG, Lopez AM. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: The Womenʼs Health Initiative randomized trial. JAMA 2003; 290: 1739-1748
  • 21 Zhou L, Wong KY, Poon CC, Yu W, Xiao H, Chan CO, Mok DK, Wong MS. Water extract of Rhizoma Drynaria selectively exerts estrogenic activities in ovariectomized rats and estrogen receptor-positive cells. Front Endocrinol (Lausanne) 2022; 13: 817146
  • 22 Wei M, Li C, Dai Y, Zhou H, Cui Y, Zeng Y, Huang Q, Wang Q. High-throughput absolute quantification sequencing revealed osteoporosis-related gut microbiota alterations in Han Chinese elderly. Front Cell Infect Microbiol 2021; 11: 630372
  • 23 Li L, Chen B, Zhu R, Li R, Tian Y, Liu C, Jia Q, Wang L, Tang J, Zhao D, Mo F, Liu Y, Li Y, Orekhov AN, Brömme D, Zhang D, Gao S. Fructus Ligustri Lucidi preserves bone quality through the regulation of gut microbiota diversity, oxidative stress, TMAO and Sirt6 levels in aging mice. Aging (Albany NY) 2019; 11: 9348-9368
  • 24 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: 1145-1154
  • 25 Li JY, Chassaing B, Tyagi AM, Talezadeh P, Koohpeyma F, Gholami A. Sex steroid deficiency-associated bone loss is microbiota dependent and prevented by probiotics. J Clin Invest 2016; 126: 2049-2063
  • 26 Zhao X, Wang Y, Nie Z, Han L, Zhong X, Yan X, Gao X. Eucommia ulmoides leaf extract alters gut microbiota composition, enhances short-chain fatty acids production, and ameliorates osteoporosis in the senescence-accelerated mouse P6 (SAMP6) model. Food Sci Nutr 2020; 8: 4897-4906
  • 27 Tang XY, Gao MX, Xiao HH, Dai ZQ, Yao ZH, Dai Y, Yao XS. Effects of Xian-Ling-Gu-Bao capsule on the gut microbiota in ovariectomized rats: Metabolism and modulation. J Chromatogr B Analyt Technol Biomed Life Sci 2021; 1176: 122771
  • 28 Li M, Zhao Y, Wang Y, Geng R, Fang J, Kang SG, Huang K, Tong T. Eugenol, a major component of clove oil, attenuates adiposity, and modulates gut microbiota in high-fat diet-fed mice. Mol Nutr Food Res 2022; 66: e2200387
  • 29 Li X, Wu X, Wang Q, Xu W, Zhao Q, Xu N, Hu X, Ye Z, Yu S, Liu J, He X, Shi F, Zhang Q, Li W. Sanguinarine ameliorates DSS induced ulcerative colitis by inhibiting NLRP3 inflammasome activation and modulating intestinal microbiota in C57BL/6 mice. Phytomedicine 2022; 104: 154321
  • 30 Zhang M, Yang L, Zhu M, Yang B, Yang Y, Jia X, Feng L. Moutan Cortex polysaccharide ameliorates diabetic kidney disease via modulating gut microbiota dynamically in rats. Int J Biol Macromol 2022; 206: 849-860
  • 31 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: 1116-1131.e7
  • 32 Li X, Lin Q, Cui Y, Wang H, Wang P, Yang L, Ye Q, Zhang R, Zhu X. Glycine acts through estrogen receptor alpha to mediate estrogen receptor signaling, stimulating osteogenesis and attenuating adipogenesis in ovariectomized rats. Mol Nutr Food Res 2022; 66: e2100857
  • 33 Yu J, Hang Y, Sun W, Wang G, Xiong Z, Ai L, Xia Y. Anti-osteoporotic effect of Lactobacillus brevis AR281 in an ovariectomized mouse model mediated by inhibition of osteoclast differentiation. Biology (Basel) 2022; 11: 359
  • 34 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: 2190304
  • 35 Lee YM, Kim IS, Lim BO. Black rice (Oryza sativa L.) fermented with Lactobacillus casei attenuates osteoclastogenesis and ovariectomy-induced osteoporosis. Biomed Res Int 2019; 2019: 5073085
  • 36 Chen R, Wang J, Zhan R, Zhang L, Wang X. Fecal metabonomics combined with 16S rRNA gene sequencing to analyze the changes of gut microbiota in rats with kidney-yang deficiency syndrome and the intervention effect of You-Gui Pill. J Ethnopharmacol 2019; 244: 112139
  • 37 Yan S, Chen J, Zhu L, Guo T, Qin D, Hu Z, Han S, Wang J, Matias FB, Wen L, Luo F, Lin Q. Oryzanol alleviates high fat and cholesterol diet-induced hypercholesterolemia associated with the modulation of the gut microbiota in hamsters. Food Funct 2022; 13: 4486-4501
  • 38 Mo Z, Wang J, Meng X, Li A, Li Z, Que W, Wang T, Tarnue KF, Ma X, Liu Y, Yan S, Wu L, Zhang R, Pei J, Wang X. The dose-response effect of fluoride exposure on the gut microbiome and its functional pathways in rats. Metabolites 2023; 13: 1159
  • 39 Zhang J, Zhang J, Wang R. Gut microbiota modulates drug pharmacokinetics. Drug Metab Rev 2018; 50: 357-368
  • 40 Xiao HH, Yu X, Yang C, Chan CO, Lu L, Cao S, Wan SW, Lan ZJ, Mok DK, Chen S, Wong M. Prenylated isoflavonoids-rich extract of erythrinae cortex exerted bone protective effects by modulating gut microbial compositions and metabolites in ovariectomized rats. Nutrients 2021; 13: 2943
  • 41 Schoenhofen IC, Vinogradov E, Whitfield DM, Brisson JR, Logan SM. The CMP-legionaminic acid pathway in Campylobacter: biosynthesis involving novel GDP-linked precursors. Glycobiology 2009; 19: 715-725
  • 42 Tsvetkov YE, Shashkov AS, Knirel YA, Zähringer U. Synthesis and identification in bacterial lipopolysaccharides of 5, 7-diacetamido-3, 5, 7, 9-tetradeoxy-D-glycero-D-galacto- and -D-glycero-D-talo-non-2-ulosonic acids. Carbohydr Res 2001; 331: 233-237
  • 43 Fu X, Sun X, Zhang C, Lv N, Guo H, Xing C, Lv J, Wu J, Zhu X, Liu M, Su L. Genkwanin prevents lipopolysaccharide-induced inflammatory bone destruction and ovariectomy-induced bone loss. Front Nutr 2022; 9: 921037
  • 44 Kim HJ, Lee J, Lee GR, Kim N, Lee HI, Kwon M, Kim NY, Park JH, Kang YH, Song HJ, Kim T, Shin DM, Jeong W. Flunarizine inhibits osteoclastogenesis by regulating calcium signaling and promotes osteogenesis. J Cell Physiol 2021; 236: 8239-8252
  • 45 Morrison DJ, Preston T. Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut Microbes 2016; 7: 189-200
  • 46 Chinese Pharmacopoeia Commission. Pharmacopoeia of the Peopleʼs Republic of China. Beijing, China: Peopleʼs Medical Publishing House and Chemical Industry Press; 2020
  • 47 Zhao Y, Xu Y, Zheng H, Lin N. QingYan formula extracts protect against postmenopausal osteoporosis in ovariectomized rat model via active ER-dependent MEK/ERK and PI3K/Akt signal pathways. J Ethnopharmacol 2021; 268: 113644
  • 48 Liu F, Tan F, Tong W, Fan Q, Ye S, Lu S, Teng Z, Han M, Zhang M, Chai Y. Effect of Zuoguiwan on osteoporosis in ovariectomized rats through RANKL/OPG pathway mediated by β2AR. Biomed Pharmacother 2018; 103: 1052-1060