{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T15:49:47Z","timestamp":1787500187757,"version":"build-2736575974"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,2,12]],"date-time":"2024-02-12T00:00:00Z","timestamp":1707696000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>The presented study protocol outlines a comprehensive investigation into the interplay among the human microbiota, volatilome, and disease biomarkers, with a specific focus on Beh\u00e7et\u2019s disease (BD) using methods based on explainable artificial intelligence. The protocol is structured in three phases. During the initial three-month clinical study, participants will be divided into control and experimental groups. The experimental groups will receive a soluble fiber-based dietary supplement alongside standard therapy. Data collection will encompass oral and fecal microbiota, breath samples, clinical characteristics, laboratory parameters, and dietary habits. The subsequent biological data analysis will involve gas chromatography, mass spectrometry, and metagenetic analysis to examine the volatilome and microbiota composition of salivary and fecal samples. Additionally, chemical characterization of breath samples will be performed. The third phase introduces Explainable Artificial Intelligence (XAI) for the analysis of the collected data. This novel approach aims to evaluate eubiosis and dysbiosis conditions, identify markers associated with BD, dietary habits, and the supplement. Primary objectives include establishing correlations between microbiota, volatilome, phenotypic BD characteristics, and identifying patient groups with shared features. The study aims to identify taxonomic units and metabolic markers predicting clinical outcomes, assess the supplement\u2019s impact, and investigate the relationship between dietary habits and patient outcomes. This protocol contributes to understanding the microbiome\u2019s role in health and disease and pioneers an XAI-driven approach for personalized BD management. With 70 recruited BD patients, XAI algorithms will analyze multi-modal clinical data, potentially revolutionizing BD management and paving the way for improved patient outcomes.<\/jats:p>","DOI":"10.3389\/fmicb.2024.1341152","type":"journal-article","created":{"date-parts":[[2024,2,11]],"date-time":"2024-02-11T23:46:39Z","timestamp":1707695199000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Unraveling the microbiome-metabolome nexus: a comprehensive study protocol for personalized management of Beh\u00e7et\u2019s disease using explainable artificial intelligence"],"prefix":"10.3389","volume":"15","author":[{"given":"Sabina","family":"Tangaro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Lopalco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Sabella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Venerito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierfrancesco","family":"Novielli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donato","family":"Romano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Di Gilio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolanda","family":"Palmisani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluigi","family":"de Gennaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasquale","family":"Filannino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosanna","family":"Latronico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Bellotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"De Angelis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florenzo","family":"Iannone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,2,12]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"620","DOI":"10.1111\/1346-8138.13381","article-title":"Beh\u00e7et\u2019s disease: a comprehensive review with a focus on epidemiology, etiology and clinical features, and management of mucocutaneous lesions","volume":"43","author":"Alpsoy","year":"2016","journal-title":"J. Dermatol."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"e0259724","DOI":"10.1371\/journal.pone.0259724","article-title":"A ma chine and deep learning approach to predict pulmo nary hyperte NsIon in newborn S with congenital diaphragmatic hernia (CLANNISH): protocol for a retrospective study","volume":"16","author":"Amodeo","year":"2021","journal-title":"PLoS One"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1161\/CIRCULATIONAHA.115.017738","article-title":"Neutrophil activation promotes fibrinogen oxidation and thrombus formation in Beh\u00e7et disease","volume":"133","author":"Becatti","year":"2016","journal-title":"Circulation"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"625","DOI":"10.3390\/jpm11070625","article-title":"Exploring the oral microbiome in rheumatic diseases, state of art and future prospective in personalized medicine with an AI approach","volume":"11","author":"Bellando-Randone","year":"2021","journal-title":"J. Pers. Med."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1027783","DOI":"10.3389\/fdata.2022.1027783","article-title":"Worldwide impact of lifestyle predictors of dementia prevalence: an eXplainable artificial intelligence analysis","volume":"5","author":"Bellantuono","year":"2022","journal-title":"Front. Big Data"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"16590","DOI":"10.1038\/s41598-023-43856-7","article-title":"An eXplainable artificial intelligence analysis of Raman spectra for thyroid cancer diagnosis","volume":"13","author":"Bellantuono","year":"2023","journal-title":"Sci. Rep."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"3325","DOI":"10.1007\/s00394-020-02282-5","article-title":"Prebiotic effect of inulin-type fructans on faecal microbiota and short-chain fatty acids in type 2 diabetes: a randomised controlled trial","volume":"59","author":"Birkeland","year":"2020","journal-title":"Eur. J. Nutr."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1093\/jn\/129.1.113","article-title":"Short-chain fructo-oligosaccharide administration dose-dependently increases fecal bifidobacteria in healthy humans","volume":"129","author":"Bouhnik","year":"1999","journal-title":"J. Nutr."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1773","DOI":"10.3390\/nu14091773","article-title":"A low glycemic index Mediterranean diet combined with aerobic physical activity rearranges the gut microbiota signature in NAFLD patients","volume":"14","author":"Calabrese","year":"2022","journal-title":"Nutrients"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"1236","DOI":"10.3945\/ajcn.2009.28095","article-title":"Gut microbiota fermentation of prebiotics increases satietogenic and incretin gut peptide production with consequences for appetite sensation and glucose response after a meal","volume":"90","author":"Cani","year":"2009","journal-title":"Am. J. Clin. Nutr."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/j.autrev.2014.11.009","article-title":"Beh\u00e7et's syndrome patients exhibit specific microbiome signature","volume":"14","author":"Consolandi","year":"2015","journal-title":"Autoimmun. Rev."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1109\/MSP.2017.2765202","article-title":"Generative adversarial networks: an overview","volume":"35","author":"Creswell","year":"2018","journal-title":"IEEE Signal Process. Mag."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1262","DOI":"10.3390\/cancers12051262","article-title":"Breath analysis for early detection of malignant pleural mesothelioma: volatile organic compounds (VOCs) determination and possible biochemical pathways","volume":"12","author":"Di Gilio","year":"","journal-title":"Cancers"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"5823","DOI":"10.3390\/molecules25245823","article-title":"Breath analysis: comparison among methodological approaches for breath sampling","volume":"25","author":"Di Gilio","year":"","journal-title":"Molecules"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s12602-017-9329-z","article-title":"Gut microbiota and IL-17A: physiological and pathological responses","volume":"11","author":"Douzandeh-Mobarrez","year":"2019","journal-title":"Probiotic Antimicro. Prot."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1161\/CIRCRESAHA.120.317789","article-title":"Butyrate-rich diets improve redox status and fibrin lysis in Beh\u00e7et\u2019s syndrome","volume":"128","author":"Emmi","year":"2021","journal-title":"Circ. Res."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"S10","DOI":"10.1111\/j.1753-4887.2012.00499.x","article-title":"The impact of nutrition on the human microbiome","volume":"70","author":"Flint","year":"2012","journal-title":"Nutr. Rev."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"13780","DOI":"10.1073\/pnas.0706625104","article-title":"Molecular\u2013phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases","volume":"104","author":"Frank","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1002\/jpen.1682","article-title":"Relationship between dietary fiber intake and short-chain fatty acid producing bacteria during critical illness: a prospective cohort study","volume":"44","author":"Fu","year":"2020","journal-title":"J. Parenter. Enter. Nutr."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1038\/nature12721","article-title":"Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells","volume":"504","author":"Furusawa","year":"2013","journal-title":"Nature"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1016\/j.chom.2014.02.005","article-title":"The treatment-naive microbiome in new-onset Crohn\u2019s disease","volume":"15","author":"Gevers","year":"2014","journal-title":"Cell Host Microbe"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"975","DOI":"10.1016\/0016-5085(95)90192-2","article-title":"Selective stimulation of bifidobacteria in the human colon by oligofructose and inulin","volume":"108","author":"Gibson","year":"1995","journal-title":"Gastroenterology"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1038\/nm.4517","article-title":"Current understanding of the human microbiome","volume":"24","author":"Gilbert","year":"2018","journal-title":"Nat. Med."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"101350","DOI":"10.1016\/j.xcrm.2023.101350","article-title":"Microbiome preterm birth DREAM challenge: crowdsourcing machine learning approaches to advance preterm birth research","volume":"5","author":"Golob","year":"2023","journal-title":"Cell Reports Medicine"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1146\/annurev-genom-090711-163814","article-title":"The human microbiome: our second genome","volume":"13","author":"Grice","year":"2012","journal-title":"Annu. Rev. Genomics Hum. Genet."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.neuron.2017.06.011","article-title":"Neuroscience-Inspired Artificial Intelligence","volume":"95","author":"Hassabis","year":"2017","journal-title":"Neuron"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1080\/14737175.2018.1400909","article-title":"Protective roles of intestinal microbiota derived short chain fatty acids in Alzheimer\u2019s disease-type beta-amyloid neuropathological mechanisms","volume":"18","author":"Ho","year":"2018","journal-title":"Expert. Rev. Neurother."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1016\/j.bbi.2015.03.016","article-title":"Altered fecal microbiota composition in patients with major depressive disorder","volume":"48","author":"Jiang","year":"2015","journal-title":"Brain Behav. Immun."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"1189","DOI":"10.1038\/sj.ejcn.1602636","article-title":"A double-blind placebo-controlled study to establish the bifidogenic dose of inulin in healthy humans","volume":"61","author":"Kolida","year":"2007","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/j.chom.2013.07.007","article-title":"Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment","volume":"14","author":"Kostic","year":"2013","journal-title":"Cell Host Microbe"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"271","DOI":"10.3233\/FI-2010-288","article-title":"Boruta\u2013a system for feature selection","volume":"101","author":"Kursa","year":"2010","journal-title":"Fundamenta Informat."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1016\/j.copbio.2012.08.005","article-title":"Bacteria as vitamins suppliers to their host: a gut microbiota perspective","volume":"24","author":"LeBlanc","year":"2013","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1002\/art.41169","article-title":"Interleukin-17 inhibition in spondyloarthritis is associated with subclinical gut microbiome perturbations and a distinctive interleukin-25-driven intestinal inflammation","volume":"72","author":"Manasson","year":"2020","journal-title":"Arthritis Rheumatol."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.3389\/fneur.2019.01021","article-title":"FETR-ALS study protocol: a randomized clinical trial of fecal microbiota transplantation in amyotrophic lateral sclerosis","volume":"10","author":"Mandrioli","year":"2019","journal-title":"Front. Neurol."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"3820","DOI":"10.1002\/jps.21271","article-title":"An investigation into the digestion of chitosan (noncrosslinked and crosslinked) by human colonic Bacteria","volume":"97","author":"McConnell","year":"2008","journal-title":"J. Pharm. Sci."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1007\/s10151-019-01963-6","article-title":"Colorectal cancer and adenoma screening using urinary volatile organic compound (VOC) detection: early results from a single-Centre bowel screening population (UK BCSP)","volume":"23","author":"Mozdiak","year":"2019","journal-title":"Tech. Coloproctol."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1186\/s12934-020-01477-z","article-title":"Anti-cancer and anti-inflammatory effects elicited by short chain fatty acids produced by Escherichia coli, isolated from healthy human gut microbiota","volume":"20","author":"Nakkarach","year":"2021","journal-title":"Microb. Cell Factories"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1126\/scitranslmed.aah6888","article-title":"A role for bacterial urease in gut dysbiosis and Crohn\u2019s disease","volume":"9","author":"Ni","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref39","first-page":"2024","article-title":"Explainable artificial intelligence for microbiome data analysis in colorectal cancer biomarker identification","author":"Novielli","year":"2023"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13063-020-04444-6","article-title":"Modulation of gut microbiota through nutritional interventions in Beh\u00e7et\u2019s syndrome patients (the MAMBA study): study protocol for a randomized controlled trial","volume":"21","author":"Pagliai","year":"2020","journal-title":"Trials"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"1261889","DOI":"10.3389\/fmicb.2023.1261889","article-title":"Machine learning approaches in microbiome research: challenges and best practices","volume":"14","author":"Papoutsoglou","year":"2023","journal-title":"Front. Microbiol."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1017\/S0007114508019880","article-title":"Effect of inulin on the human gut microbiota: stimulation of Bifidobacterium adolescentis and Faecalibacterium prausnitzii","volume":"101","author":"Ramirez-Farias","year":"2008","journal-title":"Br. J. Nutr."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"105593","DOI":"10.1016\/j.phrs.2021.105593","article-title":"Beh\u00e7et disease: from pathogenesis to novel therapeutic options","volume":"167","author":"Rodr\u00ecguez-Carrio","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1093\/ajcn\/52.4.675","article-title":"Fructans of Jerusalem arichokes: intestinal transport, absorption, fermentation, and influence on blood glucose, insulin, and C-peptide responses in healthy subjects","volume":"52","author":"Rumessen","year":"1990","journal-title":"Am. J. Clin. Nutr."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1016\/j.cell.2016.01.013","article-title":"Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans","volume":"164","author":"Sender","year":"2016","journal-title":"Cell"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"2374","DOI":"10.1109\/JBHI.2021.3088832","article-title":"Guest editorial explainable AI: towards fairness, accountability, transparency and trust in healthcare","volume":"25","author":"Shaban-Nejad","year":"2021","journal-title":"IEEE J. Biomed. Health Inform."},{"key":"ref47","doi-asserted-by":"crossref","DOI":"10.1109\/ICSEM.2010.14","article-title":"Feature selection using principal component analysis","author":"Song","year":"2010"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"1215836","DOI":"10.3389\/fnut.2023.1215836","article-title":"In vivo evaluation of an innovative synbiotics on stage IIIb-IV chronic kidney disease patients","volume":"10","author":"Vacca","year":"2023","journal-title":"Front. Nutr."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"2517","DOI":"10.1007\/s00394-022-02822-1","article-title":"The establishment of the gut microbiota in 1-year-aged infants: from birth to family food","volume":"61","author":"Vacca","year":"2022","journal-title":"Eur. J. Nutr."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"8730","DOI":"10.3390\/ijms21228730","article-title":"Network analysis of gut microbiome and metabolome to discover microbiota-linked biomarkers in patients affected by non-small cell lung cancer","volume":"21","author":"Vernocchi","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1203\/PDR.0b013e318155a422","article-title":"Butyrate regulates the expression of pathogen-triggered IL-8 in intestinal epithelia","volume":"62","author":"Weng","year":"2007","journal-title":"Pediatr. Res."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1038\/mp.2016.44","article-title":"Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host\u2019s metabolism","volume":"21","author":"Zheng","year":"2016","journal-title":"Mol. Psychiatry"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"718","DOI":"10.1007\/s13238-010-0093-z","article-title":"Human gut microbiome: the second genome of human body","volume":"1","author":"Zhu","year":"2010","journal-title":"Protein Cells"}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2024.1341152\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,11]],"date-time":"2024-02-11T23:46:42Z","timestamp":1707695202000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2024.1341152\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,12]]},"references-count":53,"alternative-id":["10.3389\/fmicb.2024.1341152"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2024.1341152","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,12]]},"article-number":"1341152"}}