{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T06:01:43Z","timestamp":1777442503842,"version":"3.51.4"},"reference-count":24,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T00:00:00Z","timestamp":1639612800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Suntory Global Innovation Center Ltd., a company affiliated with Suntory Holdings Ltd.","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>A leaky gut can trigger chronic inflammation and poses a primary risk for metabolic diseases. This study established a relationship between intestinal integrity (leaky gut) and metabolic health in a general population. Leaky-gut markers (LGMs) were studied in a large population of Dutch adults with a broad spectrum of metabolic health. This study enrolled 500 individuals selected within the NQplus cohort study (n = 2048) by stratified randomization, based on waist circumference, fasting glucose, and high-density lipoprotein (HDL) cholesterol to obtain a representative and balanced population in terms of metabolic health parameters, sex (male\/female), and age (&lt;54\/\u226554 years). LGMs\u2014zonulin, lipopolysaccharide-binding protein (LBP), and soluble CD14 (sCD14)\u2014were measured in EDTA plasma or serum. Zonulin was most strongly associated with metabolic health. Zonulin and LBP were most strongly associated with the inflammatory marker C-reactive protein (CRP). The quartile analysis for zonulin and LBP showed that most metabolic health parameters and CRP levels increased from Q1 to Q4, with significant differences between quartiles, except for markers related to glucose homeostasis (glucose and glycated hemoglobin A1c (HbA1c)). Associations between LGMs and metabolic health parameters in this large Dutch adult population indicate that LGMs are valuable markers for identifying people at risk of a leaky gut and subsequent chronic inflammation linked to metabolic disorders.<\/jats:p>","DOI":"10.3390\/metabo11120877","type":"journal-article","created":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T21:32:40Z","timestamp":1639690360000},"page":"877","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Exploring the Link between Leaky-Gut-Related Markers and Metabolic Health in a Large Dutch Adult Population"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4449-6808","authenticated-orcid":false,"given":"Hiroyuki","family":"Hoshiko","sequence":"first","affiliation":[{"name":"HE Center, Suntory MONOZUKURI Expert Ltd., Kyoto 619-0284, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edith J. M.","family":"Feskens","sequence":"additional","affiliation":[{"name":"Human Nutrition and Health, Department of Agrotechnology and Food Sciences, Wageningen University, 6708 WE Wageningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Els","family":"Oosterink","sequence":"additional","affiliation":[{"name":"Wageningen Food and Biobased Research, Wageningen University & Research, 6708 WG Wageningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9846-4257","authenticated-orcid":false,"given":"Renata M. C.","family":"Ariens","sequence":"additional","affiliation":[{"name":"Wageningen Food and Biobased Research, Wageningen University & Research, 6708 WG Wageningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jurriaan J.","family":"Mes","sequence":"additional","affiliation":[{"name":"Wageningen Food and Biobased Research, Wageningen University & Research, 6708 WG Wageningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole J. W.","family":"de Wit","sequence":"additional","affiliation":[{"name":"Wageningen Food and Biobased Research, Wageningen University & Research, 6708 WG Wageningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1038\/oby.2006.83","article-title":"Waist circumference correlates with metabolic syndrome indicators better than percentage fat","volume":"14","author":"Shen","year":"2006","journal-title":"Obesity (Silver Spring)"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2294","DOI":"10.2337\/dc12-1654","article-title":"Metabolically healthy obesity and risk of mortality: Does the definition of metabolic health matter?","volume":"36","author":"Hinnouho","year":"2013","journal-title":"Diabetes Care"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"136584","DOI":"10.1155\/2013\/136584","article-title":"Mechanisms of chronic state of inflammation as mediators that link obese adipose tissue and metabolic syndrome","volume":"2013","author":"Fuentes","year":"2013","journal-title":"Mediators Inflamm."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Hoshiko, H., Feskens, E.J.M., Oosterink, E., Ariens, R.M.C., Mes, J.J., and de Wit, N.J.W. (2021). Identification of leaky gut-related markers as indicators of metabolic health in Dutch adults: The Nutrition Questionnaires plus (NQplus) study. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0252936"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"R51","DOI":"10.1530\/JME-13-0079","article-title":"Metabolic endotoxemia: A molecular link between obesity and cardiovascular risk","volume":"51","author":"Neves","year":"2013","journal-title":"J. Mol. Endocrinol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3","DOI":"10.3389\/fcimb.2013.00003","article-title":"Recognition of lipid A variants by the TLR4-MD-2 receptor complex","volume":"3","author":"Maeshima","year":"2013","journal-title":"Front. Cell Infect. Microbiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/s13098-018-0360-3","article-title":"Markers of metabolic endotoxemia as related to metabolic syndrome in an elderly male population at high cardiovascular risk: A cross-sectional study","volume":"10","author":"Awoyemi","year":"2018","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_8","first-page":"141","article-title":"Intestinal permeability in non-alcoholic fatty liver disease: The gut-liver axis","volume":"9","author":"Scarpellini","year":"2014","journal-title":"Rev. Recent Clin. Trials"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Hoshiko, H., Zeinstra, G.G., Lenaerts, K., Oosterink, E., Ariens, R.M.C., Mes, J.J., and de Wit, N.J.W. (2021). An Observational Study to Evaluate the Association between Intestinal Permeability, Leaky Gut Related Markers, and Metabolic Health in Healthy Adults. Healthcare, 9.","DOI":"10.3390\/healthcare9111583"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Moreno-Navarrete, J.M., Sabater, M., Ortega, F., Ricart, W., and Fernandez-Real, J.M. (2012). Circulating zonulin, a marker of intestinal permeability, is increased in association with obesity-associated insulin resistance. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0037160"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"107766","DOI":"10.1016\/j.jdiacomp.2020.107766","article-title":"Impaired intestinal barrier function in type 2 diabetic patients measured by serum LPS, Zonulin, and IFABP","volume":"35","author":"Yuan","year":"2021","journal-title":"J. Diabetes Complicat."},{"key":"ref_12","unstructured":"(2021, November 17). International Diabetes Federation: The IDF Consensus Worldwide Definition of the Metabolic Syndrome. Available online: https:\/\/www.idf.org\/component\/attachments\/attachments.html?id=705&task=download."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1016\/j.cgh.2012.08.012","article-title":"Intestinal permeability and its regulation by zonulin: Diagnostic and therapeutic implications","volume":"10","author":"Fasano","year":"2012","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Ohlsson, B., Orho-Melander, M., and Nilsson, P.M. (2017). Higher Levels of Serum Zonulin May Rather Be Associated with Increased Risk of Obesity and Hyperlipidemia, Than with Gastrointestinal Symptoms or Disease Manifestations. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18030582"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Fasano, A. (2020). All disease begins in the (leaky) gut: Role of zonulin-mediated gut permeability in the pathogenesis of some chronic inflammatory diseases. F1000Res, 9.","DOI":"10.12688\/f1000research.20510.1"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1002\/mnfr.201400044","article-title":"Overfeeding increases postprandial endotoxemia in men: Inflammatory outcome may depend on LPS transporters LBP and sCD14","volume":"58","author":"Laugerette","year":"2014","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.2337\/dc10-0340","article-title":"A marker of endotoxemia is associated with obesity and related metabolic disorders in apparently healthy Chinese","volume":"33","author":"Sun","year":"2010","journal-title":"Diabetes Care"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1194\/jlr.M800156-JLR200","article-title":"Chylomicrons promote intestinal absorption of lipopolysaccharides","volume":"50","author":"Ghoshal","year":"2009","journal-title":"J. Lipid. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1194\/jlr.P020909","article-title":"Endotoxin increase after fat overload is related to postprandial hypertriglyceridemia in morbidly obese patients","volume":"53","author":"Murri","year":"2012","journal-title":"J. Lipid. Res."},{"key":"ref_20","first-page":"D306","article-title":"Dietary lipid emulsions and endotoxemia","volume":"23","author":"Michalski","year":"2016","journal-title":"Oilseeds Fats Crops Lipids"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/1743-7075-10-6","article-title":"Dietary oil composition differentially modulates intestinal endotoxin transport and postprandial endotoxemia","volume":"10","author":"Mani","year":"2013","journal-title":"Nutr. Metab. (Lond.)"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/S1357-2725(98)00153-8","article-title":"CD14","volume":"31","year":"1999","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1002\/mnfr.201500102","article-title":"Contrasting association of circulating sCD14 with insulin sensitivity in non-obese and morbidly obese subjects","volume":"60","author":"Lyons","year":"2016","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e020228","DOI":"10.1136\/bmjopen-2017-020228","article-title":"Nutrition Questionnaires plus (NQplus) study, a prospective study on dietary determinants and cardiometabolic health in Dutch adults","volume":"8","author":"Streppel","year":"2018","journal-title":"BMJ Open"}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/11\/12\/877\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:50:05Z","timestamp":1760169005000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/11\/12\/877"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,16]]},"references-count":24,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["metabo11120877"],"URL":"https:\/\/doi.org\/10.3390\/metabo11120877","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,16]]}}}