{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T17:35:57Z","timestamp":1793036157084,"version":"4.5.0"},"reference-count":44,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2023,11,2]],"date-time":"2023-11-02T00:00:00Z","timestamp":1698883200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82273753"],"award-info":[{"award-number":["82273753"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81703177"],"award-info":[{"award-number":["81703177"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2017M623198"],"award-info":[{"award-number":["2017M623198"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the General Financial Grant from the China Postdoctoral Science Foundation","award":["82273753"],"award-info":[{"award-number":["82273753"]}]},{"name":"the General Financial Grant from the China Postdoctoral Science Foundation","award":["81703177"],"award-info":[{"award-number":["81703177"]}]},{"name":"the General Financial Grant from the China Postdoctoral Science Foundation","award":["2017M623198"],"award-info":[{"award-number":["2017M623198"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Kashin\u2013Beck disease (KBD) is a distinct osteoarthropathy in China with an unclear pathogenesis. This study aims to explore whether perturbations in the intestine metabolome could be linked to KBD individuals. Methods: An investigation was conducted in KBD endemic villages and fecal samples were collected. After applying inclusion and exclusion criteria, a total of 75 subjects were enrolled for this study, including 46 KBD (including 19 Grade I KBD and 27 Grade II KBD) and 29 controls. Untargeted metabolomics analysis was performed on the platform of UHPLC-MS. PLS-DA and OPLS-DA were conducted to compare the groups and identify the differential metabolites (DMs). Pathway analysis was conducted on MPaLA platform to explore the functional implication of the DMs. Results: Metabolomics analysis showed that compared with the control group, KBD individuals have a total of 584 differential metabolites with dysregulated levels such as adrenic acid (log2FC = \u22121.87, VIP = 4.84, p = 7.63 \u00d7 10\u22127), hydrogen phosphate (log2FC = \u22122.57, VIP = 1.27, p = 1.02 \u00d7 10\u22123), taurochenodeoxycholic acid (VIP = 1.16, log2FC = \u22123.24, p = 0.03), prostaglandin E3 (VIP = 1.17, log2FC = 2.67, p = 5.61 \u00d7 10\u22124), etc. Pathway analysis revealed several significantly perturbed pathways associated with KBD such as selenium micronutrient network (Q value = 3.11 \u00d7 10\u22123, Wikipathways), metabolism of lipids (Q value = 8.43 \u00d7 10\u22124, Reactome), free fatty acid receptors (Q value = 3.99 \u00d7 10\u22123, Reactome), and recycling of bile acids and salts (Q value = 2.98 \u00d7 10\u22123, Reactome). Subgroup comparisons found a total of 267 differential metabolites were shared by KBD vs. control, KBD II vs. control, and KBD I vs. control, while little difference was found between KBD II and KBD I (only one differential metabolite detected). Conclusions: KBD individuals showed distinct metabolic features characterized by perturbations in lipid metabolism and selenium-related bioprocesses. Our findings suggest that the loss of nutrients metabolism balance in intestine was involved in KBD pathogenesis. Linking the nutrients metabolism (especially selenium and lipid) to KBD cartilage damage should be a future direction of KBD study.<\/jats:p>","DOI":"10.3390\/nu15214651","type":"journal-article","created":{"date-parts":[[2023,11,2]],"date-time":"2023-11-02T09:28:13Z","timestamp":1698917293000},"page":"4651","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A Metabolomics Study of Feces Revealed That a Disturbance of Selenium-Centered Metabolic Bioprocess Was Involved in Kashin\u2013Beck Disease, an Osteoarthropathy Endemic to China"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5317-4387","authenticated-orcid":false,"given":"Yan","family":"Wen","sequence":"first","affiliation":[{"name":"Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, School of Public Health, Health Science Center, Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingyi","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, School of Public Health, Health Science Center, Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panxing","family":"Shi","sequence":"additional","affiliation":[{"name":"Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, School of Public Health, Health Science Center, Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoge","family":"Chu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, School of Public Health, Health Science Center, Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sirong","family":"Shi","sequence":"additional","affiliation":[{"name":"Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, School of Public Health, Health Science Center, Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Yao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, School of Public Health, Health Science Center, Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"},{"name":"Key Laboratory for Tumor Precision Medicine of Shaanxi Province, Department of Endocrinology, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, School of Public Health, Health Science Center, Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"},{"name":"Medical Department, The First Affiliated Hospital of Air Force Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, School of Public Health, Health Science Center, Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s13075-018-1531-1","article-title":"Integrating genome-wide DNA methylation and mRNA expression profiles identified different molecular features between Kashin-Beck disease and primary osteoarthritis","volume":"20","author":"Wen","year":"2018","journal-title":"Arthritis Res. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1016\/j.joca.2014.07.023","article-title":"Recent advances in the research of an endemic osteochondropathy in China: Kashin-Beck disease","volume":"22","author":"Guo","year":"2014","journal-title":"Osteoarthr. Cartil."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1007\/s12011-019-01759-7","article-title":"Serious Selenium Deficiency in the Serum of Patients with Kashin-Beck Disease and the Effect of Nano-Selenium on Their Chondrocytes","volume":"194","author":"Wang","year":"2020","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"144103","DOI":"10.1016\/j.scitotenv.2020.144103","article-title":"Status and risks of selenium deficiency in a traditional selenium-deficient area in Northeast China","volume":"762","author":"Yang","year":"2021","journal-title":"Sci. Total Environ."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s12011-015-0463-8","article-title":"Selenium and Iodine Levels in Subjects with Kashin-Beck Disease: A Meta-analysis","volume":"170","author":"Yang","year":"2016","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"113419","DOI":"10.1016\/j.ecoenv.2022.113419","article-title":"Animal models of Kashin-Beck disease exposed to environmental risk factors: Methods and comparisons","volume":"234","author":"Yu","year":"2022","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2765","DOI":"10.1007\/s12011-022-03387-0","article-title":"The Role of Selenium-Mediated Notch\/Hes1 Signaling Pathway in Kashin-Beck Disease Patients and Cartilage Injury Models","volume":"201","author":"Zhang","year":"2023","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1007\/s12011-021-02772-5","article-title":"Dysregulation of Transcription Profile of Selenoprotein in Patients with Kashin-Beck Disease and Its Effect on Se Deficiency-Induced Chondrocyte Apoptosis","volume":"200","author":"Yang","year":"2022","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e017883","DOI":"10.1136\/bmjopen-2017-017883","article-title":"Effects of five types of selenium supplementation for treatment of Kashin-Beck disease in children: A systematic review and network meta-analysis","volume":"8","author":"Xie","year":"2018","journal-title":"BMJ Open"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.semarthrit.2019.07.014","article-title":"Endemic Kashin-Beck disease: A food-sourced osteoarthropathy","volume":"50","author":"Wang","year":"2020","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"259","DOI":"10.3109\/03009740903270599","article-title":"Heritability estimates and linkage analysis of 23 short tandem repeat loci on chromosomes 2, 11, and 12 in an endemic osteochondropathy in China","volume":"39","author":"Shi","year":"2010","journal-title":"Scand. J. Rheumatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1007\/s12011-021-02705-2","article-title":"Meta-analysis of Association Studies of Selenoprotein Gene Polymorphism and Kashin-Beck Disease: An Updated Systematic Review","volume":"200","author":"Yu","year":"2022","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.14336\/AD.2021.1228","article-title":"The Metabolic Landscape in Osteoarthritis","volume":"13","author":"Wu","year":"2022","journal-title":"Aging Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1038\/s41419-021-04322-2","article-title":"Alterations in the gut microbiota and metabolite profiles of patients with Kashin-Beck disease, an endemic osteoarthritis in China","volume":"12","author":"Wang","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"9191","DOI":"10.1038\/s41598-019-45640-y","article-title":"An untargeted fecal and urine metabolomics analysis of the interplay between the gut microbiome, diet and human metabolism in Indian and Chinese adults","volume":"9","author":"Jain","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e13807","DOI":"10.1111\/acel.13807","article-title":"The gut microbiota metabolite capsiate regulate SLC2A1 expression by targeting HIF-1\u03b1 to inhibit knee osteoarthritis-induced ferroptosis","volume":"22","author":"Guan","year":"2023","journal-title":"Aging Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1016\/j.bbrc.2020.08.102","article-title":"Adrenic acid induces oxidative stress in hepatocytes","volume":"532","author":"Zhao","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2840","DOI":"10.4049\/jimmunol.1801653","article-title":"Anti-Inflammatory and Proresolving Effects of the Omega-6 Polyunsaturated Fatty Acid Adrenic Acid","volume":"205","author":"Brouwers","year":"2020","journal-title":"J. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4065","DOI":"10.1039\/D3FO00775H","article-title":"Prebiotics alleviate cartilage degradation and inflammation in post-traumatic osteoarthritic mice by modulating the gut barrier and fecal metabolomics","volume":"14","author":"Mi","year":"2023","journal-title":"Food Funct."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3201","DOI":"10.1039\/C9FO02882J","article-title":"Untargeted metabolomics revealed therapeutic mechanisms of icariin on low bone mineral density in older caged laying hens","volume":"11","author":"Huang","year":"2020","journal-title":"Food Funct."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1007\/s00296-013-2862-5","article-title":"Increased levels of IL-6, IL-1\u03b2, and TNF-\u03b1 in Kashin-Beck disease and rats induced by T-2 toxin and selenium deficiency","volume":"34","author":"Zhou","year":"2014","journal-title":"Rheumatol. Int."},{"key":"ref_22","first-page":"941","article-title":"[Serum hyaluronic acid, tumor necrosis factor -alpha, vascular endothelial growth factor, NO, and Se levels in adult patients with Kashin-Beck disease]","volume":"27","author":"Li","year":"2007","journal-title":"Nan Fang Yi Ke Da Xue Xue Bao = J. South. Med. Univ."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1007\/s00198-015-3364-y","article-title":"Integrative analysis of genome-wide association studies and gene expression profiles identified candidate genes for osteoporosis in Kashin-Beck disease patients","volume":"27","author":"Wen","year":"2016","journal-title":"Osteoporos. Int."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/s00018-010-0527-z","article-title":"The emergence of phosphate as a specific signaling molecule in bone and other cell types in mammals","volume":"68","author":"Khoshniat","year":"2011","journal-title":"Cell. Mol. Life Sci. CMLS"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7460","DOI":"10.1039\/C9TB02011J","article-title":"Critical and diverse roles of phosphates in human bone formation","volume":"7","author":"Hughes","year":"2019","journal-title":"J. Mater. Chem. B"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Wen, Y., Zhang, F., Li, C., He, S., Tan, W., Lei, Y., Zhang, Q., Yu, H., Zheng, J., and Guo, X. (2014). Gene expression analysis suggests bone development-related genes GDF5 and DIO2 are involved in the development of Kashin-Beck disease in children rather than adults. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0103618"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Di Ciaula, A., Bonfrate, L., Khalil, M., and Portincasa, P. (2023). The interaction of bile acids and gut inflammation influences the pathogenesis of inflammatory bowel disease. Intern. Emerg. Med., 1\u201317.","DOI":"10.1007\/s11739-023-03343-3"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"817437","DOI":"10.3389\/fendo.2022.817437","article-title":"The Association of Serum Total Bile Acids with Bone Mineral Density in Chinese Adults Aged 20-59: A Retrospective Cross-Sectional Study","volume":"13","author":"Liu","year":"2022","journal-title":"Front. Endocrinol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Wen, K., Tao, L., Tao, Z., Meng, Y., Zhou, S., Chen, J., Yang, K., Da, W., and Zhu, Y. (2020). Fecal and Serum Metabolomic Signatures and Microbial Community Profiling of Postmenopausal Osteoporosis Mice Model. Front. Cell. Infect. Microbiol., 10.","DOI":"10.3389\/fcimb.2020.535310"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.3892\/ijmm.2015.2295","article-title":"Tauroursodeoxycholic acid suppresses endoplasmic reticulum stress in the chondrocytes of patients with osteoarthritis","volume":"36","author":"Liu","year":"2015","journal-title":"Int. J. Mol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Ahn, T.K., Kim, K.T., Joshi, H.P., Park, K.H., Kyung, J.W., Choi, U.Y., Sohn, S., Sheen, S.H., Shin, D.E., and Lee, S.H. (2020). Therapeutic Potential of Tauroursodeoxycholic Acid for the Treatment of Osteoporosis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21124274"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"780149","DOI":"10.1155\/2015\/780149","article-title":"Therapeutic Effect of Chenodeoxycholic Acid in an Experimental Rabbit Model of Osteoarthritis","volume":"2015","author":"Yan","year":"2015","journal-title":"Mediat. Inflamm."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5167","DOI":"10.1007\/s12035-020-02087-x","article-title":"The Role of Brain Cyclooxygenase-2 (Cox-2) Beyond Neuroinflammation: Neuronal Homeostasis in Memory and Anxiety","volume":"57","author":"Ballaz","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.joca.2012.11.012","article-title":"Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!)","volume":"21","author":"Berenbaum","year":"2013","journal-title":"Osteoarthr. Cartil."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1111\/jvp.12983","article-title":"Grapiprant: A snapshot of the current knowledge","volume":"44","author":"Sartini","year":"2021","journal-title":"J. Vet. Pharmacol. Ther."},{"key":"ref_36","first-page":"86","article-title":"Thyroid Hormone Concentrations in Preschool Children in Kashin-Beck Disease Endemic Area","volume":"8","author":"Wu","year":"2008","journal-title":"Chin. J. Evid.-Based Med."},{"key":"ref_37","first-page":"67","article-title":"Determination of Thyroxine Levels in the Serum of Patients with Hypertrophic Osteoarthropathy","volume":"1","author":"Yuan","year":"1984","journal-title":"J. Chengde Med. Univ."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e3123","DOI":"10.1002\/jgm.3123","article-title":"Association between DIO2 polymorphism and the risk of Kashin-Beck disease in the Tibetan population","volume":"21","author":"Jin","year":"2019","journal-title":"J. Gene Med."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Su, Z., Zong, Z., Deng, J., Huang, J., Liu, G., Wei, B., Cui, L., Li, G., Zhong, H., and Lin, S. (2022). Lipid Metabolism in Cartilage Development, Degeneration, and Regeneration. Nutrients, 14.","DOI":"10.3390\/nu14193984"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"46457","DOI":"10.1038\/srep46457","article-title":"Saturated fatty acids induce development of both metabolic syndrome and osteoarthritis in rats","volume":"7","author":"Sekar","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"13092","DOI":"10.1038\/srep13092","article-title":"Stearic acid induces proinflammatory cytokine production partly through activation of lactate-HIF1\u03b1 pathway in chondrocytes","volume":"5","author":"Miao","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1002\/ar.1092240210","article-title":"Role of lipids in calcification of cartilage","volume":"224","author":"Boyan","year":"1989","journal-title":"Anat. Rec."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"116076","DOI":"10.1016\/j.bone.2021.116076","article-title":"Cholesterol metabolism related genes in osteoarthritis","volume":"152","author":"Papathanasiou","year":"2021","journal-title":"Bone"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.bone.2010.09.015","article-title":"Kashin-Beck disease and Sayiwak disease in China: Prevalence and a comparison of the clinical manifestations, familial aggregation, and heritability","volume":"48","author":"Guo","year":"2011","journal-title":"Bone"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/21\/4651\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:16:05Z","timestamp":1760130965000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/21\/4651"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,2]]},"references-count":44,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["nu15214651"],"URL":"https:\/\/doi.org\/10.3390\/nu15214651","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,2]]}}}