{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:52:30Z","timestamp":1790790750469,"version":"4.1.0"},"reference-count":52,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,5,24]],"date-time":"2021-05-24T00:00:00Z","timestamp":1621814400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Japan Food Chemical Research Foundation","award":["2021"],"award-info":[{"award-number":["2021"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Background: Erythritol, a sugar alcohol, is widely used as a substitute for sugar in diets for patients with diabetes or obesity. Methods: In this study, we aimed to investigate the effects of erythritol on metabolic disorders induced by a high-fat diet in C57BL\/6J mice, while focusing on changes in innate immunity. Results: Mice that were fed a high-fat diet and administered water containing 5% erythritol (Ery group) had markedly lower body weight, improved glucose tolerance, and markedly higher energy expenditure than the control mice (Ctrl group) (n = 6). Furthermore, compared with the Ctrl group, the Ery group had lesser fat deposition in the liver, smaller adipocytes, and significantly better inflammatory findings in the small intestine. The concentrations of short-chain fatty acids (SCFAs), such as acetic acid, propanoic acid, and butanoic acid, in the serum, feces, and white adipose tissue of the Ery group were markedly higher than those in the Ctrl group. In flow cytometry experiments, group 3 innate lymphoid cell (ILC3) counts in the lamina propria of the small intestine and ILC2 counts in the white adipose tissue of the Ery group were markedly higher than those in the Ctrl group. Quantitative real-time reverse transcription polymerase chain reaction analyses showed that the Il-22 expression in the small intestine of the Ery group was markedly higher than that in the Ctrl group. Conclusions: Erythritol markedly decreased metabolic disorders such as diet-induced obesity, glucose intolerance, dyslipidemia, and fat accumulation in the mouse liver by increasing SCFAs and modulating innate immunity.<\/jats:p>","DOI":"10.3390\/ijms22115558","type":"journal-article","created":{"date-parts":[[2021,5,24]],"date-time":"2021-05-24T12:38:01Z","timestamp":1621859881000},"page":"5558","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Erythritol Ameliorates Small Intestinal Inflammation Induced by High-Fat Diets and Improves Glucose Tolerance"],"prefix":"10.3390","volume":"22","author":[{"given":"Rena","family":"Kawano","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7269-1697","authenticated-orcid":false,"given":"Takuro","family":"Okamura","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8794-0550","authenticated-orcid":false,"given":"Yoshitaka","family":"Hashimoto","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saori","family":"Majima","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takafumi","family":"Senmaru","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1031-4380","authenticated-orcid":false,"given":"Emi","family":"Ushigome","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai","family":"Asano","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Yamazaki","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Takakuwa","sequence":"additional","affiliation":[{"name":"Agilent Technologies, Chromatography Mass Spectrometry Sales Department, Life Science and Applied Markets Group, Tokyo 192-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryoichi","family":"Sasano","sequence":"additional","affiliation":[{"name":"AiSTI Science Co., Ltd., Wakayama 640-8341, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoko","family":"Nakanishi","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8651-4445","authenticated-orcid":false,"given":"Masahide","family":"Hamaguchi","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0903-1797","authenticated-orcid":false,"given":"Michiaki","family":"Fukui","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"277","DOI":"10.3177\/jnsv.38.277","article-title":"Effect of maltitol intake on intestinal calcium absorption in the rat","volume":"38","author":"Goda","year":"1992","journal-title":"J. Nutr. Sci. Vitaminol."},{"key":"ref_2","first-page":"2186","article-title":"Intestinal calcium absorption in rats is stimulated by dietary lactulose and other resistant sugars","volume":"123","author":"Brommage","year":"1993","journal-title":"J. Nutr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S31","DOI":"10.1093\/advances\/nmy037","article-title":"Effects of sweeteners on the gut microbiota: A review of experimental studies and Clinical Trials","volume":"10","author":"Gil","year":"2019","journal-title":"Adv. Nutr."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S59","DOI":"10.1111\/j.1753-4887.1996.tb03820.x","article-title":"Oligosaccharides with beneficial health Effects: A Japanese perspective","volume":"54","author":"Oku","year":"1996","journal-title":"Nutr. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1079\/NRR200371","article-title":"Health potential of polyols as sugar replacers, with emphasis on low glycaemic properties","volume":"16","author":"Livesey","year":"2003","journal-title":"Nutr. Res. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1093\/clinchem\/30.10.1611","article-title":"Determination of polyols in serum by selected ion monitoring","volume":"30","author":"Roboz","year":"1984","journal-title":"Clin. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"111","DOI":"10.3177\/jnsv.32.111","article-title":"Influence of chronic intake of new sweetener fructooligosaccharide (neosugar) on growth and gastrointestinal function of the rat","volume":"32","author":"Tokunaga","year":"1986","journal-title":"J. Nutr. Sci. Vitaminol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1093\/jn\/122.6.1266","article-title":"Metabolism and disposition of erythritol after oral administration to rats","volume":"122","author":"Noda","year":"1992","journal-title":"J. Nutr."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Lee, D., Han, Y., Kwon, E.Y., and Choi, M.S. (2020). D-allulose ameliorates metabolic dysfunction in C57BL\/KsJ-Db\/Db mice. Molecules, 25.","DOI":"10.3390\/molecules25163656"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1038\/nature08636","article-title":"Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells","volume":"463","author":"Moro","year":"2010","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1038\/nature14115","article-title":"Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity","volume":"519","author":"Brestoff","year":"2015","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1084\/jem.20121964","article-title":"Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages","volume":"210","author":"Molofsky","year":"2013","journal-title":"J. Exp. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1038\/ni.3447","article-title":"IL-1 is a critical regulator of group 2 innate lymphoid cell function and plasticity","volume":"17","author":"Ohne","year":"2016","journal-title":"Nat. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1538\/expanim.60.481","article-title":"Effect of three types of mixed anesthetic agents alternate to ketamine in mice","volume":"60","author":"Kawai","year":"2011","journal-title":"Exp. Anim."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"Design and validation of a histological scoring system for nonalcoholic fatty liver disease","volume":"41","author":"Kleiner","year":"2005","journal-title":"Hepatology"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Hamaguchi, M., Okamura, T., Fukuda, T., Nishida, K., Yoshimura, Y., Hashimoto, Y., Ushigome, E., Nakanishi, N., Majima, S., and Asano, M. (2021). Group 3 innate lymphoid cells protect steatohepatitis from high-fat diet induced toxicity. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.648754"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.lfs.2017.09.014","article-title":"Sulfate-reducing bacteria stimulate gut immune responses and contribute to inflammation in experimental colitis","volume":"189","author":"Figliuolo","year":"2017","journal-title":"Life Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.molmed.2016.01.002","article-title":"Sulfide as a mucus barrier-breaker in inflammatory bowel disease?","volume":"22","author":"Ijssennagger","year":"2016","journal-title":"Trends Mol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.cmet.2016.07.009","article-title":"Colonic pro-inflammatory macrophages cause insulin resistance in an intestinal Ccl2\/Ccr2-dependent manner","volume":"24","author":"Kawano","year":"2016","journal-title":"Cell Metab."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Fachi, J.L., S\u00e9cca, C., Rodrigues, P.B., Mato, F.C.P.d., di Luccia, B., Felipe, J.d.S., Pral, L.P., Rungue, M., Rocha, V.d.M., and Sato, F.T. (2020). Acetate coordinates neutrophil and ILC3 responses against C. difficile through FFAR2. J. Exp. Med., 217.","DOI":"10.1084\/jem.20190489"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Wang, N., Liang, H., and Zen, K. (2014). Molecular mechanisms that influence the macrophage M1-M2 polarization balance. Front. Immunol., 5.","DOI":"10.3389\/fimmu.2014.00614"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1038\/ni.2025","article-title":"Border patrol: Regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22","volume":"12","author":"Sonnenberg","year":"2011","journal-title":"Nat. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1038\/nature07537","article-title":"A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity","volume":"457","author":"Cella","year":"2009","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.1038\/ismej.2012.27","article-title":"Structural resilience of the gut microbiota in adult mice under high-fat dietary perturbations","volume":"6","author":"Zhang","year":"2012","journal-title":"ISME J."},{"key":"ref_25","first-page":"534","article-title":"IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis","volume":"118","author":"Sugimoto","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2325","DOI":"10.1194\/jlr.R036012","article-title":"The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism","volume":"54","author":"Groen","year":"2013","journal-title":"J. Lipid Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2839","DOI":"10.3390\/nu7042839","article-title":"Dietary gut microbial metabolites, short-chain fatty acids, and host metabolic regulation","volume":"7","author":"Kasubuchi","year":"2015","journal-title":"Nutrients"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Kimura, I., Ozawa, K., Inoue, D., Imamura, T., Kimura, K., Maeda, T., Terasawa, K., Kashihara, D., Hirano, K., and Tani, T. (2013). The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat. Commun., 4.","DOI":"10.1038\/ncomms2852"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"8030","DOI":"10.1073\/pnas.1016088108","article-title":"Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41)","volume":"108","author":"Kimura","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Lu, Y., Fan, C., Li, P., Lu, Y., Chang, X., and Qi, K. (2016). Short chain fatty acids prevent high-fat-diet-induced obesity in mice by regulating G protein-coupled receptors and gut microbiota. Sci. Rep., 6.","DOI":"10.1038\/srep37589"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2398","DOI":"10.2337\/db14-1213","article-title":"Short-chain fatty acids protect against high-fat diet-induced obesity via a PPAR\u03b3-dependent switch from lipogenesis to fat oxidation","volume":"64","author":"Bleeker","year":"2015","journal-title":"Diabetes"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"7514","DOI":"10.4049\/jimmunol.0900063","article-title":"G protein-coupled receptor 43 is essential for neutrophil recruitment during intestinal inflammation","volume":"183","author":"Sina","year":"2009","journal-title":"J. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1016\/j.pharep.2019.07.010","article-title":"Dietary fatty acid content influences the expression of genes involved in the lipid turnover and inflammation in mouse colon and spleen","volume":"71","author":"Tarasiuk","year":"2019","journal-title":"Pharmacol. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1016\/j.cmet.2017.04.013","article-title":"A specific gut microbiota dysbiosis of type 2 diabetic mice induces GLP-1 resistance through an enteric NO-dependent and gut-brain axis mechanism","volume":"25","author":"Grasset","year":"2017","journal-title":"Cell Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"187","DOI":"10.2337\/db11-1029","article-title":"Na+-D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion","volume":"61","author":"Gorboulev","year":"2012","journal-title":"Diabetes"},{"key":"ref_36","first-page":"82","article-title":"CD36 deficiency impairs the small intestinal barrier and induces subclinical inflammation in mice","volume":"3","author":"Cifarelli","year":"2017","journal-title":"CMGH"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.immuni.2019.09.014","article-title":"Metabolite-sensing receptor Ffar2 regulates colonic group 3 innate lymphoid cells and gut immunity","volume":"51","author":"Chun","year":"2019","journal-title":"Immunity"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Gulhane, M., Murray, L., Lourie, R., Tong, H., Sheng, Y.H., Wang, R., Kang, A., Schreiber, V., Wong, K.Y., and Magor, G. (2016). High fat diets induce colonic epithelial cell stress and inflammation that is reversed by IL-22. Sci. Rep., 6.","DOI":"10.1038\/srep28990"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5349","DOI":"10.4049\/jimmunol.1301176","article-title":"Cutting edge: IL-25 elicits innate lymphoid type 2 and type II NKT cells that regulate obesity in mice","volume":"191","author":"Hams","year":"2013","journal-title":"J. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.coi.2015.07.003","article-title":"Type 2 responses at the interface between immunity and fat metabolism","volume":"36","author":"Odegaard","year":"2015","journal-title":"Curr. Opin. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1016\/j.cmet.2018.04.006","article-title":"Toward an understanding of how immune cells control brown and beige adipobiology","volume":"27","author":"Villarroya","year":"2018","journal-title":"Cell Metab."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"E4233","DOI":"10.1073\/pnas.1620079114","article-title":"Erythritol is a pentose-phosphate pathway metabolite and associated with adiposity gain in young adults","volume":"114","author":"Hootman","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1007\/s12016-017-8648-x","article-title":"Sexual dimorphism in innate immunity","volume":"56","author":"Jaillon","year":"2019","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1182\/blood-2009-05-219923","article-title":"Adipose tissue is an extramedullary reservoir for functional hematopoietic stem and progenitor cells","volume":"115","author":"Han","year":"2010","journal-title":"Blood"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2565","DOI":"10.1042\/CS20180482","article-title":"Type 3 innate lymphoid cell: A new player in liver fibrosis progression","volume":"132","author":"Wang","year":"2018","journal-title":"Clin. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/B978-0-12-411619-1.00006-9","article-title":"Quantifying size and number of adipocytes in adipose tissue","volume":"Volume 537","author":"Parlee","year":"2014","journal-title":"Methods in Enzymology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"8171","DOI":"10.1038\/s41598-018-25837-3","article-title":"CD11c+ M1-like macrophages (M\u03a6s) but not CD206+ M2-like M\u03a6 are involved in folliculogenesis in mice ovary","volume":"8","author":"Ono","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-\u2206\u2206 C(T)) method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Wang, H., Shen, L., Sun, X., Liu, F., Feng, W., Jiang, C., Chu, X., Ye, X., Jiang, C., and Wang, Y. (2019). Adipose group 1 innate lymphoid cells promote adipose tissue fibrosis and diabetes in obesity. Nat. Commun., 10.","DOI":"10.1038\/s41467-019-11270-1"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/j.immuni.2016.06.016","article-title":"Adipose-resident group 1 innate lymphoid cells promote obesity-associated insulin resistance","volume":"45","author":"Rapp","year":"2016","journal-title":"Immunity"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"G989","DOI":"10.1152\/ajpgi.00310.2019","article-title":"Immune modulating effects of additional supplementation of estradiol combined with testosterone in murine testosterone-deficient NAFLD model","volume":"318","author":"Okamura","year":"2020","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"B\u00e9n\u00e9zech, C., and Jackson-Jones, L.H. (2019). ILC2 orchestration of local immune function in adipose tissue. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.00171"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/11\/5558\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:07:09Z","timestamp":1760162829000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/11\/5558"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,24]]},"references-count":52,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["ijms22115558"],"URL":"https:\/\/doi.org\/10.3390\/ijms22115558","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,24]]}}}