{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T22:16:17Z","timestamp":1791324977343,"version":"4.3.1"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,7,6]],"date-time":"2023-07-06T00:00:00Z","timestamp":1688601600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Nutr."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Coeliac disease is a lifelong immune-mediated enteropathy manifested as gluten intolerance in individuals carrying specific human leukocyte antigen (HLA) molecules. Other factors than genetics and gluten intake, however, may play a role in triggering the disease. The gut internal environment is thought to be one of these potential contributing factors, and it can be influenced throughout life.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We examine the impact of Lactiplantibacillus plantarum HEAL9 and Lacticaseibacillus paracasei 8700:2 supplementation on the faecal metabolome in genetically predisposed children having tissue transglutaminase autoantibodies, i.e., coeliac disease autoimmunity. Probiotic strains were selected based on their beneficial properties, including mucosal permeability and immune modulation effects. The intervention group (<jats:italic>n<\/jats:italic> = 40) and control group (<jats:italic>n<\/jats:italic> = 38) took the probiotics or placebo daily for 6 months in a double-blinded randomised trial. Faecal samples were collected at baseline and after 3 and 6 months and analysed using the 1H NMR for metabolome. The incorporation of 16S rRNA sequencing as a supportive dataset complemented the analysis of the metabolome data.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>During the 6 months of intervention, the stool concentrations of 4-hydroxyphenylacetate increased in the intervention group as compared to controls, whereas concentrations of threonine, valine, leucine, isoleucine, methionine, phenylalanine, aspartate, and fumarate decreased. Additionally, a noteworthy effect on the glycine, serine, and threonine metabolic pathway has been observed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The findings suggest a modest yet significant impact of the probiotics on the faecal metabolome, primarily influencing proteolytic processes in the gut.<\/jats:p><\/jats:sec><jats:sec><jats:title>Clinical trial registration<\/jats:title><jats:p><jats:ext-link>ClinicalTrials.gov<\/jats:ext-link>, NCT03176095.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnut.2023.1183963","type":"journal-article","created":{"date-parts":[[2023,7,6]],"date-time":"2023-07-06T19:15:45Z","timestamp":1688670945000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Effects of Lactiplantibacillus plantarum and Lacticaseibacillus paracasei supplementation on the faecal metabolome in children with coeliac disease autoimmunity: a randomised, double-blinded placebo-controlled clinical trial"],"prefix":"10.3389","volume":"10","author":[{"given":"Eliska","family":"Jenickova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carin","family":"Andr\u00e9n Aronsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Mascellani Bergo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ondrej","family":"Cinek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaroslav","family":"Havlik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Agardh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,7,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1038\/nm0797-797","article-title":"Identification of tissue transglutaminase as the autoantigen of celiac disease","volume":"3","author":"Dieterich","year":"1997","journal-title":"Nat Med."},{"key":"B2","doi-asserted-by":"publisher","first-page":"818","DOI":"10.1038\/ajg.2013.60","article-title":"Increasing incidence of celiac disease in a North American population","volume":"108","author":"Ludvigsson","year":"2013","journal-title":"Am J Gastroenterol."},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2021-324209","article-title":"Two waves of coeliac disease incidence in Sweden: a nationwide population-based cohort study from 1990 to 2015","author":"Bergman","year":"2021","journal-title":"Gut"},{"key":"B4","doi-asserted-by":"publisher","first-page":"2403","DOI":"10.3390\/nu11102403","article-title":"Celiac disease and the microbiome","volume":"11","author":"Valitutti","year":"2019","journal-title":"Nutrients."},{"key":"B5","doi-asserted-by":"publisher","first-page":"2969","DOI":"10.1016\/j.ajpath.2015.07.018","article-title":"Intestinal microbiota modulates gluten-induced immunopathology in humanized mice","volume":"185","author":"Galipeau","year":"2015","journal-title":"Am J Pathol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"e33387","DOI":"10.1371\/journal.pone.0033387","article-title":"Proof of concept of microbiome-metabolome analysis and delayed gluten exposure on celiac disease autoimmunity in genetically at-risk infants","volume":"7","author":"Sellitto","year":"2012","journal-title":"PLoS ONE."},{"key":"B7","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1136\/jcp.2008.061366","article-title":"Specific duodenal and faecal bacterial groups associated with paediatric coeliac disease","volume":"62","author":"Collado","year":"2008","journal-title":"J Clin Pathol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"5316","DOI":"10.1128\/AEM.00365-11","article-title":"Influence of environmental and genetic factors linked to celiac disease risk on infant gut colonization by bacteroides species","volume":"77","author":"S\u00e1nchez","year":"2011","journal-title":"Appl Environ Microbiol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1824","DOI":"10.3390\/nu10121824","article-title":"Probiotics in celiac disease","volume":"10","author":"Cristofori","year":"2018","journal-title":"Nutrients."},{"key":"B10","doi-asserted-by":"publisher","first-page":"93","DOI":"10.2478\/rjim-2022-0002","article-title":"Systematic approach to celiac disease: a comprehensive review for primary providers","volume":"60","author":"Cort\u00e9s","year":"2022","journal-title":"Roman J Int Med."},{"key":"B11","doi-asserted-by":"publisher","first-page":"2674","DOI":"10.3390\/nu12092674","article-title":"Probiotics, prebiotics and other dietary supplements for gut microbiota modulation in celiac disease patients","volume":"12","author":"Marasco","year":"2020","journal-title":"Nutrients."},{"key":"B12","doi-asserted-by":"publisher","first-page":"957","DOI":"10.3389\/fimmu.2020.00957","article-title":"Gut microbiota in celiac disease: is there any role for probiotics?","volume":"11","author":"Pecora","year":"2020","journal-title":"Front Immunol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1373","DOI":"10.1016\/j.clnu.2018.06.931","article-title":"Clinical intervention using Bifidobacterium strains in celiac disease children reveals novel microbial modulators of TNF-\u03b1 and short-chain fatty acids","volume":"38","author":"Primec","year":"2019","journal-title":"Clin Nutr."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1080\/1744666X.2021.1840354","article-title":"Gut microbiota in celiac disease: microbes, metabolites, pathways and therapeutics","volume":"16","author":"Olshan","year":"2020","journal-title":"Expert Rev Clin Immunol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"925","DOI":"10.3390\/nu11081925","article-title":"Effects of Lactobacillus plantarum and Lactobacillus paracasei on the peripheral immune response in children with celiac disease autoimmunity: a randomized, double-blind, placebo-controlled clinical trial","volume":"11","author":"H\u00e5kansson","year":"2019","journal-title":"Nutrients"},{"key":"B16","doi-asserted-by":"publisher","first-page":"771","DOI":"10.3389\/fnut.2021.680771","article-title":"Effects of probiotic bacteria lactobacillaceae on the gut microbiota in children with celiac disease autoimmunity: a placebo-controlled and randomized clinical trial","volume":"8","author":"Oscarsson","year":"2021","journal-title":"Front Nutri"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.aca.2018.05.031","article-title":"A review on human fecal metabolomics: methods, applications and the human fecal metabolome database","volume":"1030","author":"Karu","year":"2018","journal-title":"Anal Chim Acta."},{"key":"B18","doi-asserted-by":"publisher","first-page":"906","DOI":"10.1186\/s40168-020-00906-w","article-title":"Multi-omics analysis reveals the influence of genetic and environmental risk factors on developing gut microbiota in infants at risk of celiac disease","volume":"8","author":"Leonard","year":"2020","journal-title":"Microbiome"},{"key":"B19","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1126\/science.1241165","article-title":"The microbial metabolites, short-chain fatty acids, regulate colonic treg cell","volume":"341","author":"Smith","year":"2013","journal-title":"Homeos Sci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1186\/1471-2180-10-175","article-title":"A distinctive \u201cmicrobial signature\u201d in celiac pediatric patients","volume":"10","author":"Schippa","year":"2010","journal-title":"BMC Microbiol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"894","DOI":"10.1111\/j.1572-0241.2004.04157.x","article-title":"Presence of bacteria and innate immunity of intestinal epithelium in childhood celiac disease","volume":"99","author":"Forsberg","year":"2004","journal-title":"Am J Gastroenterol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"2784","DOI":"10.1111\/j.1572-0241.2005.00313.x","article-title":"Gut microflora associated characteristics in children with celiac disease","volume":"100","author":"Tjellstr\u00f6m","year":"2005","journal-title":"Am J Gastroenterol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1017\/S0029665114000196","article-title":"The metabolic activity of the gut microbiota and the impact of gluten free diet in children with coeliac disease","volume":"73","author":"Makinder","year":"2014"},{"key":"B24","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1046\/j.1440-1711.2003.t01-1-01177.x","article-title":"Tryptophan and the immune response","volume":"81","author":"Moffett","year":"2003","journal-title":"Immunol Cell Biol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1564","DOI":"10.3390\/nu10111564","article-title":"Glutamine: metabolism and immune function, supplementation and clinical translation","volume":"10","author":"Cruzat","year":"2018","journal-title":"Nutrients."},{"key":"B26","doi-asserted-by":"publisher","first-page":"113083","DOI":"10.1016\/j.physbeh.2020.113083","article-title":"Intake of Lactiplantibacillus plantarum HEAL9 reduces the inflammatory markers soluble fractalkine and CD163 during acute stress: a randomized, double blind, placebo-controlled study","volume":"225","author":"\u00d6nning","year":"2020","journal-title":"Physiol Behav."},{"key":"B27","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1111\/cei.12055","article-title":"Differential effect on cell-mediated immunity in human volunteers after intake of different lactobacilli","volume":"172","author":"Rask","year":"2013","journal-title":"Clin Exp Immunol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1038\/nmeth.3869","article-title":"DADA2: high-resolution sample inference from Illumina amplicon data","volume":"13","author":"Callahan","year":"2016","journal-title":"Nat Methods."},{"key":"B29","doi-asserted-by":"publisher","first-page":"D590","DOI":"10.1093\/nar\/gks1219","article-title":"The SILVA ribosomal RNA gene database project: improved data processing and web-based tools","volume":"41","author":"Quast","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"e0247378","DOI":"10.1371\/journal.pone.0247378","article-title":"Stool metabolome-microbiota evaluation among children and adolescents with obesity, overweight, and normal-weight using 1H NMR and 16S rRNA gene profiling. Ishaq SL, editor","volume":"16","author":"Jaimes","year":"2021","journal-title":"PLOS ONE."},{"key":"B31","doi-asserted-by":"publisher","first-page":"9944","DOI":"10.1021\/jf5031218","article-title":"Impact of dietary polydextrose fiber on the human gut metabolome","volume":"62","author":"Lamichhane","year":"2014","journal-title":"J Agric Food Chem."},{"key":"B32","doi-asserted-by":"publisher","first-page":"5079","DOI":"10.1021\/acs.jproteome.1c00617","article-title":"Practical and robust NMR-based metabolic phenotyping of gut health in early life","volume":"20","author":"Bervoets","year":"2021","journal-title":"J Proteome Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"9546","DOI":"10.1021\/acs.analchem.0c00606","article-title":"Human Faecal 1H NMR Metabolomics: evaluation of solvent and sample processing on coverage and reproducibility of signature metabolites","volume":"92","author":"Cui","year":"2020","journal-title":"Anal Chem."},{"key":"B34","doi-asserted-by":"publisher","first-page":"4281","DOI":"10.1021\/ac051632c","article-title":"Probabilistic quotient normalization as robust method to account for dilution of complex biological mixtures. Application in 1H NMR metabonomics","volume":"78","author":"Dieterle","year":"2006","journal-title":"Anal Chem."},{"key":"B35","doi-asserted-by":"publisher","first-page":"13","DOI":"10.18637\/jss.v082.i13","article-title":"lmerTest package: tests in linear mixed effects models","volume":"82","author":"Kuznetsova","year":"2017","journal-title":"J Stat Software"},{"key":"B36","unstructured":"R: A Language and Environment for Statistical Computing2022"},{"key":"B37","doi-asserted-by":"publisher","first-page":"W652","DOI":"10.1093\/nar\/gkp356","article-title":"MetaboAnalyst: a web server for metabolomic data analysis and interpretation","volume":"37","author":"Xia","year":"2009","journal-title":"Nuc Acids Res"},{"key":"B38","doi-asserted-by":"publisher","first-page":"W127","DOI":"10.1093\/nar\/gkab382","article-title":"MetaboAnalyst 50: narrowing the gap between raw spectra and functional insights","volume":"49","author":"Pang","year":"2021","journal-title":"Nuc Acids Res."},{"key":"B39","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1111\/nbu.12396","article-title":"Diet-derived microbial metabolites in health and disease","volume":"44","author":"Roager","year":"2019","journal-title":"Nutri Bullet."},{"key":"B40","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1080\/19490976.2018.1526580","article-title":"Balance of saccharolysis and proteolysis underpins improvements in stool quality induced by adding a fiber bundle containing bound polyphenols to either hydrolyzed meat or grain-rich foods","volume":"10","author":"Jackson","year":"2018","journal-title":"Gut Microbes."},{"key":"B41","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1002\/mnfr.201100542","article-title":"Relevance of protein fermentation to gut health","volume":"56","author":"Windey","year":"2011","journal-title":"Mol Nutr Food Res."},{"key":"B42","doi-asserted-by":"publisher","first-page":"G1","DOI":"10.1152\/ajpgi.00048.2011","article-title":"Functional analysis of colonic bacterial metabolism: relevant to health?","volume":"302","author":"Hamer","year":"2012","journal-title":"Am J Physiol Gastroint Liver Physiol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1021\/pr060470d","article-title":"Rapid and non-invasive metabonomic characterization of inflammatory bowel disease","volume":"6","author":"Marchesi","year":"2007","journal-title":"J Proteome Res."},{"key":"B44","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1186\/1471-2180-11-219","article-title":"Duodenal and faecal microbiota of celiac children: molecular, phenotype and metabolome characterization","volume":"11","author":"Di Cagno","year":"2011","journal-title":"BMC Microbiol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/j.ijfoodmicro.2016.07.025","article-title":"Salivary and fecal microbiota and metabolome of celiac children under gluten-free diet","volume":"239","author":"De Angelis","year":"2016","journal-title":"Int J Food Microbiol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.tifs.2016.08.011","article-title":"Gut microbiota role in dietary protein metabolism and health-related outcomes: the two sides of the coin","volume":"57","author":"Portune","year":"2016","journal-title":"Trends Food Sci Technol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"e16876","DOI":"10.1371\/journal.pone.0016876","article-title":"The genome of akkermansia muciniphila, a dedicated intestinal mucin degrader, and its use in exploring intestinal metagenomes","volume":"6","author":"van Passel","year":"2011","journal-title":"PLoS ONE."},{"key":"B48","doi-asserted-by":"publisher","first-page":"8696","DOI":"10.1038\/s41467-020-18696-y","article-title":"Structural basis of mammalian mucin processing by the human gut O-glycopeptidase OgpA from Akkermansia muciniphila","volume":"11","author":"Trastoy","year":"2020","journal-title":"Nature Commun"},{"key":"B49","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/j.cocis.2005.11.001","article-title":"Mucin structure, aggregation, physiological functions and biomedical applications","volume":"11","author":"Bansil","year":"2006","journal-title":"Curr Opin Colloid Interface Sci."},{"key":"B50","doi-asserted-by":"publisher","first-page":"2232","DOI":"10.1136\/gutjnl-2020-322260","article-title":"Mucus barrier, mucins and gut microbiota: the expected slimy partners?","volume":"69","author":"Paone","year":"2020","journal-title":"Gut."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1414","DOI":"10.3390\/biom11101414","article-title":"Gut microbiota as the link between elevated BCAA serum levels and insulin resistance","volume":"11","author":"Gojda","year":"2021","journal-title":"Biomolecules."},{"key":"B52","doi-asserted-by":"publisher","first-page":"653","DOI":"10.3389\/fphar.2018.00653","article-title":"4-hydroxyphenylacetic acid prevents acute APAP-induced liver injury by increasing phase II and antioxidant enzymes in mice","volume":"9","author":"Zhao","year":"2018","journal-title":"Front Pharmacol"},{"key":"B53","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1038\/nature09944","article-title":"Enterotypes of the human gut microbiome","volume":"473","author":"Arumugam","year":"2011","journal-title":"Nature."},{"key":"B54","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1038\/nmicrobiol.2016.88","article-title":"Species\u2013function relationships shape ecological properties of the human gut microbiome","volume":"1","author":"Vieira-Silva","year":"2016","journal-title":"Nat Microbiol"},{"key":"B55","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/19490976.2020.1848158","article-title":"Gut Bacteroides species in health and disease","volume":"13","author":"Zafar","year":"2021","journal-title":"Gut Microbes."}],"container-title":["Frontiers in Nutrition"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2023.1183963\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,6]],"date-time":"2023-07-06T19:15:49Z","timestamp":1688670949000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2023.1183963\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,6]]},"references-count":55,"alternative-id":["10.3389\/fnut.2023.1183963"],"URL":"https:\/\/doi.org\/10.3389\/fnut.2023.1183963","relation":{},"ISSN":["2296-861X"],"issn-type":[{"value":"2296-861X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,6]]},"article-number":"1183963"}}