{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T18:29:35Z","timestamp":1767205775474,"version":"build-2238731810"},"reference-count":94,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T00:00:00Z","timestamp":1753747200000},"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>Parkinson\u2019s disease (PD) is a prevalent neurodegenerative disorder with complex pathogenesis and limited treatment options. The current reliance on clinical evaluation for diagnosis, due to the absence of reliable non-invasive methods, presents significant challenges. Traditional diagnostic approaches, including cerebrospinal fluid or blood sampling, are invasive, pose risks of infection, are costly, and often require complex procedures. Tongue coating sampling presents a non-invasive, cost-effective, and repeatable alternative, indicating that it could be a valuable tool for early detection and monitoring of PD, warranting further investigation. This study explores the feasibility of using tongue coating samples as a diagnostic tool for PD through microbiome analysis, with metabolomics data providing additional context and validation via machine learning models. A cohort of 36 PD patients and 31 controls was recruited. 16S rRNA sequencing was used for microbiome analysis, revealing significant alterations in the relative abundances of various microbial taxa, including Firmicutes, Bacteroidetes, and Actinobacteria. Concurrent metabolomics analysis using UPLC-Q\/TOF-MS revealed a decrease in palmitoylethanolamide (PEA) levels in Parkinson\u2019s disease (PD) patients, and also showed reduced carnitine levels specifically in the severe Hoehn-Yahr (H-Y) stage and mild cognitive impairment (MCI) subgroups. These findings provide preliminary evidence suggesting a potential link between specific microbial alterations and PD progression, which may warrant further investigation. Additionally, the analysis indicates a correlation between certain microbial and metabolomic changes and the advancement of PD. Our results also suggest that tongue coating may serve as a potential non-invasive tool for PD diagnosis, with a particular emphasis on the combined role of the microbiome and metabolome in the pathogenesis of the disease.<\/jats:p>","DOI":"10.3389\/fmicb.2025.1621468","type":"journal-article","created":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T05:20:50Z","timestamp":1753766450000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Microbiome and metabolome integrated analysis: exploring potential diagnostic approaches for Parkinson\u2019s disease using tongue coating samples"],"prefix":"10.3389","volume":"16","author":[{"given":"Runjuan","family":"Yang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengqi","family":"Jia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhenghua","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongying","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaxing","family":"Gui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,29]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"2945","DOI":"10.1002\/mds.28779","article-title":"Neurofilament light chain as a biomarker for cognitive decline in Parkinson disease","volume":"36","author":"Aamodt","year":"2021","journal-title":"Mov. Disord."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1212\/WNL.0b013e31823ed101","article-title":"Cerebrospinal fluid amyloid \u03b2 and tau in LRRK2 mutation carriers","volume":"78","author":"Aasly","year":"2012","journal-title":"Neurology"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1002\/mds.27284","article-title":"Relationship between cerebrospinal fluid biomarkers and structural brain network properties in Parkinson\u2019s disease","volume":"33","author":"Abbasi","year":"2018","journal-title":"Mov. Disord."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1038\/s41575-023-00890-0","article-title":"Gastrointestinal and brain barriers: unlocking gates of communication across the microbiota-gut-brain axis","volume":"21","author":"Aburto","year":"2024","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"e94416","DOI":"10.1172\/jci.insight.94416","article-title":"Microbiota, cirrhosis, and the emerging oral-gut-liver axis","volume":"2","author":"Acharya","year":"2017","journal-title":"JCI Insight"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.biopha.2017.02.007","article-title":"Acetyl-L-carnitine protects dopaminergic nigrostriatal pathway in 6-hydroxydopamine-induced model of Parkinson\u2019s disease in the rat","volume":"89","author":"Afshin-Majd","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"10","DOI":"10.4161\/19490976.2014.990790","article-title":"Antibiotic-induced dysbiosis alters host-bacterial interactions and leads to colonic sensory and motor changes in mice","volume":"6","author":"Aguilera","year":"2015","journal-title":"Gut Microbes"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1111\/jcpe.12474","article-title":"Prevalence estimation of halitosis and its association with oral health-related parameters in an adult population of a city in North Italy","volume":"42","author":"Aimetti","year":"2015","journal-title":"J. Clin. Periodontol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"105271","DOI":"10.1016\/j.archoralbio.2021.105271","article-title":"Tongue-coating microbiome as a cancer predictor: a scoping review","volume":"132","author":"Ali Mohammed","year":"2021","journal-title":"Arch. Oral Biol."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1001\/jama.2019.22360","article-title":"Diagnosis and treatment of Parkinson disease: a review","volume":"323","author":"Armstrong","year":"2020","journal-title":"JAMA"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1257","DOI":"10.1016\/S1474-4422(16)30230-7","article-title":"The epidemiology of Parkinson\u2019s disease: risk factors and prevention","volume":"15","author":"Ascherio","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1016\/j.phrs.2016.09.004","article-title":"Palmitoylethanolamide protects mice against 6-OHDA-induced neurotoxicity and endoplasmic reticulum stress: in vivo and in vitro evidence","volume":"113","author":"Avagliano","year":"2016","journal-title":"Pharmacol. Res."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/S0140-6736(23)01419-8","article-title":"The epidemiology of Parkinson\u2019s disease","volume":"403","author":"Ben-Shlomo","year":"2024","journal-title":"Lancet"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41380-024-02862-5","article-title":"Sex differences in mitochondrial free-carnitine levels in subjects at-risk and with Alzheimer\u2019s disease in two independent study cohorts","volume":"30","author":"Bigio","year":"2025","journal-title":"Mol. Psychiatry"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"2284","DOI":"10.1016\/S0140-6736(21)00218-X","article-title":"Parkinson\u2019s disease","volume":"397","author":"Bloem","year":"2021","journal-title":"Lancet"},{"key":"ref16","first-page":"12","article-title":"Palmitoylethanolamide\/luteolin as adjuvant therapy to improve an unusual case of camptocormia in a patient with Parkinson\u2019s disease: a case report","volume":"18","author":"Brotini","year":"2021","journal-title":"Innov. Clin. Neurosci."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"705","DOI":"10.2174\/1871527316666170321124949","article-title":"Ultra-micronized palmitoylethanolamide: an efficacious adjuvant therapy for Parkinson\u2019s disease","volume":"16","author":"Brotini","year":"2017","journal-title":"CNS Neurol. Disord."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1279","DOI":"10.1007\/s40520-016-0533-6","article-title":"PEALut efficacy in mild cognitive impairment: evidence from a SPECT case study! Aging Clin","volume":"28","author":"Calabr\u00f2","year":"2016","journal-title":"Exp. Res."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"758","DOI":"10.3390\/biom12060758","article-title":"Classical and unexpected effects of ultra-micronized PEA in neuromuscular function","volume":"12","author":"Cifelli","year":"2022","journal-title":"Biomolecules"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1038122","DOI":"10.3389\/fpsyt.2022.1038122","article-title":"Therapeutic effect of palmitoylethanolamide in cognitive decline: a systematic review and preliminary meta-analysis of preclinical and clinical evidence","volume":"13","author":"Colizzi","year":"2022","journal-title":"Front. Psych."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1977","DOI":"10.3390\/nu14091977","article-title":"Intestinal microbiota-derived short chain fatty acids in host health and disease","volume":"14","author":"Cong","year":"2022","journal-title":"Nutrients"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"216","DOI":"10.3390\/antiox9030216","article-title":"An update of palmitoylethanolamide and luteolin effects in preclinical and clinical studies of neuroinflammatory events","volume":"9","author":"Cordaro","year":"2020","journal-title":"Antioxidants"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"9251","DOI":"10.1007\/s12035-018-1064-2","article-title":"2-Pentadecyl-2-Oxazoline reduces neuroinflammatory environment in the MPTP model of Parkinson disease","volume":"55","author":"Cordaro","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1016\/j.pain.2008.06.003","article-title":"The endogenous fatty acid amide, palmitoylethanolamide, has anti-allodynic and anti-hyperalgesic effects in a murine model of neuropathic pain: involvement of CB1, TRPV1 and PPAR\u03b3 receptors and neurotrophic factors","volume":"139","author":"Costa","year":"2008","journal-title":"Pain"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"8455","DOI":"10.1007\/s12035-018-0959-2","article-title":"N-palmitoylethanolamide prevents parkinsonian phenotypes in aged mice","volume":"55","author":"Crupi","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1007\/s13238-018-0596-6","article-title":"Tongue coating microbiome as a potential biomarker for gastritis including precancerous cascade","volume":"10","author":"Cui","year":"2019","journal-title":"Protein Cell"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"772","DOI":"10.1002\/mas.21562","article-title":"Challenges and emergent solutions for LC-MS\/MS based untargeted metabolomics in diseases","volume":"37","author":"Cui","year":"2018","journal-title":"Mass Spectrom. Rev."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1038\/s41592-022-01520-4","article-title":"Emu: species-level microbial community profiling of full-length 16S rRNA Oxford Nanopore sequencing data","volume":"19","author":"Curry","year":"2022","journal-title":"Nat. Methods"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1034\/j.1601-5037.2003.00034.x","article-title":"Tongue coating and tongue brushing: a literature review","volume":"1","author":"Danser","year":"2003","journal-title":"Int. J. Dent. Hyg."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"e41880","DOI":"10.1371\/journal.pone.0041880","article-title":"Neuroprotective activities of Palmitoylethanolamide in an animal model of Parkinson\u2019s disease","volume":"7","author":"Esposito","year":"2012","journal-title":"PLoS One"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"288","DOI":"10.55730\/1300-0152.2617","article-title":"Influence of aerobic exercise training on mice gut microbiota in Parkinson\u2019s disease","volume":"46","author":"Fan","year":"2022","journal-title":"Turk. J. Biol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1016\/S0140-6736(23)01429-0","article-title":"Medical, surgical, and physical treatments for Parkinson\u2019s disease","volume":"403","author":"Foltynie","year":"2024","journal-title":"Lancet"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1186\/s12903-018-0689-x","article-title":"Clinical observation of tongue coating of perioperative patients: factors related to the number of bacteria on the tongue before and after surgery","volume":"18","author":"Funahara","year":"2018","journal-title":"BMC Oral Health"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1021\/acschemneuro.7b00468","article-title":"L-carnitine inhibits lipopolysaccharide-induced nitric oxide production of SIM-A9 microglia cells","volume":"9","author":"Gill","year":"2018","journal-title":"ACS Chem. Neurosci."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"814","DOI":"10.1111\/jcpe.12280","article-title":"Volatile Sulphur compound levels and related factors in patients with chronic renal failure","volume":"41","author":"Gulsahi","year":"2014","journal-title":"J. Clin. Periodontol."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"813790","DOI":"10.3389\/fcimb.2022.813790","article-title":"Relationships between diurnal changes of tongue coating microbiota and intestinal microbiota","volume":"12","author":"Guo","year":"2022","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"4106293","DOI":"10.1155\/2019\/4106293","article-title":"Metabolomic markers in tongue-coating samples from damp phlegm pattern patients of coronary heart disease and chronic renal failure","volume":"2019","author":"Hao","year":"2019","journal-title":"Dis. Markers"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1080\/17474124.2021.1850259","article-title":"Metabolome and microbiome alterations in tongue coating of gastric precancerous lesion patients","volume":"15","author":"Hao","year":"2021","journal-title":"Expert Rev. Gastroenterol. Hepatol."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1186\/s40168-022-01295-y","article-title":"Phylogenies of the 16S rRNA gene and its hypervariable regions lack concordance with core genome phylogenies","volume":"10","author":"Hassler","year":"2022","journal-title":"Microbiome"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"e38645","DOI":"10.1016\/j.heliyon.2024.e38645","article-title":"Retrospective analysis of diet and gut microbiota diversity and clinical pharmacology outcomes in patients with Parkinsonism syndrome","volume":"10","author":"Hu","year":"2024","journal-title":"Heliyon"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1016\/j.jtcme.2022.04.001","article-title":"Exploring the pivotal variables of tongue diagnosis between patients with acute ischemic stroke and health participants","volume":"12","author":"Huang","year":"2022","journal-title":"J. Tradit. Complement. Med."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"108273","DOI":"10.1016\/j.pharmthera.2022.108273","article-title":"Short-chain fatty acid receptors and gut microbiota as therapeutic targets in metabolic, immune, and neurological diseases","volume":"239","author":"Ikeda","year":"2022","journal-title":"Pharmacol. Ther."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1136\/jnnp.2007.131045","article-title":"Parkinson\u2019s disease: clinical features and diagnosis","volume":"79","author":"Jankovic","year":"2008","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1111\/prd.12398","article-title":"Oral health\u2019s inextricable connection to systemic health: special populations bring to bear multimodal relationships and factors connecting periodontal disease to systemic diseases and conditions","volume":"87","author":"Kapila","year":"2021","journal-title":"Periodontol."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"e2020007","DOI":"10.23750\/abm.v91i13-S.10582","article-title":"Food supplements based on palmitoylethanolamide plus hydroxytyrosol from olive tree or Bacopa monnieri extracts for neurological diseases","volume":"91","author":"Kiani","year":"2020","journal-title":"Acta Biomed."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"ECAM 2017, 6435702","DOI":"10.1155\/2017\/6435702","article-title":"Differences in the tongue features of primary dysmenorrhea patients and controls over a normal menstrual cycle","volume":"2017","author":"Kim","year":"2017","journal-title":"Evid. Based Complement. Alternat. Med."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"348272","DOI":"10.1155\/2013\/348272","article-title":"Availability of tongue diagnosis system for assessing tongue coating thickness in patients with functional dyspepsia","volume":"2013","author":"Kim","year":"2013","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"4592","DOI":"10.1073\/pnas.1011383107","article-title":"Human oral, gut, and plaque microbiota in patients with atherosclerosis","volume":"108","author":"Koren","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1055\/s-2007-995614","article-title":"Tongue coating, mouth odor, gustatory sense disorder - earlier and new treatment options by means of tongue scraper","volume":"87","author":"Kostka","year":"2008","journal-title":"Laryngorhinootologie"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"1986","DOI":"10.1002\/art.41780","article-title":"Differences in the Oral microbiome in patients with early rheumatoid arthritis and individuals at risk of rheumatoid arthritis compared to healthy individuals","volume":"73","author":"Kroese","year":"2021","journal-title":"Arthritis Rheumatol."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"667","DOI":"10.3390\/biom12050667","article-title":"Effects of Palmitoylethanolamide on neurodegenerative diseases: a review from rodents to humans","volume":"12","author":"Landolfo","year":"2022","journal-title":"Biomolecules"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1161\/CIRCRESAHA.119.316448","article-title":"Gut microbiota-derived short-chain fatty acids promote Poststroke recovery in aged mice","volume":"127","author":"Lee","year":"2020","journal-title":"Circ. Res."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"203","DOI":"10.3389\/fcvm.2021.730203","article-title":"Oral, tongue-coating microbiota, and metabolic disorders: a novel area of interactive research","volume":"8","author":"Li","year":"2021","journal-title":"Front. Cardiovasc. Med."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"1203","DOI":"10.1136\/gutjnl-2021-325189","article-title":"Integrative metabolomic characterisation identifies altered portal vein serum metabolome contributing to human hepatocellular carcinoma","volume":"71","author":"Liu","year":"2022","journal-title":"Gut"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1111\/j.1600-051X.2005.00862.x","article-title":"Oral malodor-related parameters in the Chinese general population","volume":"33","author":"Liu","year":"2006","journal-title":"J. Clin. Periodontol."},{"key":"ref56","doi-asserted-by":"publisher","first-page":"2422","DOI":"10.1016\/j.bbamcr.2016.01.023","article-title":"Carnitine transport and fatty acid oxidation","volume":"1863","author":"Longo","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"148271","DOI":"10.1016\/j.brainres.2023.148271","article-title":"Association of serum neurofilament light chain and glial fibrillary acidic protein levels with cognitive decline in Parkinson\u2019s disease","volume":"1805","author":"Mao","year":"2023","journal-title":"Brain Res."},{"key":"ref58","doi-asserted-by":"publisher","first-page":"51","DOI":"10.3390\/metabo11010051","article-title":"L-carnitine and Acylcarnitines: mitochondrial biomarkers for precision medicine","volume":"11","author":"McCann","year":"2021","journal-title":"Metabolites"},{"key":"ref59","doi-asserted-by":"publisher","first-page":"111661","DOI":"10.1016\/j.biopha.2021.111661","article-title":"Role of microbiota-derived short-chain fatty acids in nervous system disorders","volume":"139","author":"Mirzaei","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref60","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1016\/j.jpba.2019.06.025","article-title":"Non-targeted metabolomics reveals diagnostic biomarker in the tongue coating of patients with chronic gastritis","volume":"174","author":"Mu","year":"2019","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref61","doi-asserted-by":"publisher","first-page":"7363","DOI":"10.1038\/s41598-017-07519-8","article-title":"A novel crosstalk within the endocannabinoid system controls GABA transmission in the striatum","volume":"7","author":"Musella","year":"2017","journal-title":"Sci. Rep."},{"key":"ref62","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/s13024-020-00385-5","article-title":"Utility of plasma Neurofilament light as a diagnostic and prognostic biomarker of the postural instability gait disorder motor subtype in early Parkinson\u2019s disease","volume":"15","author":"Ng","year":"2020","journal-title":"Mol. Neurodegener."},{"key":"ref63","doi-asserted-by":"publisher","first-page":"106338","DOI":"10.1016\/j.phrs.2022.106338","article-title":"Targeting NAAA counters dopamine neuron loss and symptom progression in mouse models of Parkinsonism","volume":"182","author":"Palese","year":"2022","journal-title":"Pharmacol. Res."},{"key":"ref64","doi-asserted-by":"publisher","first-page":"106475","DOI":"10.1016\/j.rmed.2021.106475","article-title":"The role of oral microbiome in respiratory health and diseases","volume":"185","author":"Pathak","year":"2021","journal-title":"Respir. Med."},{"key":"ref65","doi-asserted-by":"publisher","first-page":"e54","DOI":"10.1590\/1807-3107bor-2018.vol32.0054","article-title":"Comparative study of oral and salivary parameters in patients with and without loss of bone mass","volume":"32","author":"Pereira","year":"2018","journal-title":"Braz. Oral Res."},{"key":"ref66","doi-asserted-by":"publisher","first-page":"9526","DOI":"10.3390\/ijms21249526","article-title":"Palmitoylethanolamide: a nutritional approach to keep Neuroinflammation within physiological boundaries-a systematic review","volume":"21","author":"Petrosino","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"ref67","doi-asserted-by":"publisher","first-page":"1591","DOI":"10.1002\/mds.26424","article-title":"MDS clinical diagnostic criteria for Parkinson\u2019s disease","volume":"30","author":"Postuma","year":"2015","journal-title":"Mov. Disord."},{"key":"ref68","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1902\/jop.2005.76.6.1025","article-title":"A combined therapeutic approach to manage oral halitosis: a 3-month prospective case series","volume":"76","author":"Rold\u00e1n","year":"2005","journal-title":"J. Periodontol."},{"key":"ref69","doi-asserted-by":"publisher","first-page":"174","DOI":"10.23736\/S0026-4970.19.04186-4","article-title":"Etiology and characteristics of halitosis in patients of a halitosis center in northern Italy","volume":"69","author":"Romano","year":"2020","journal-title":"Minerva Stomatol."},{"key":"ref70","doi-asserted-by":"publisher","first-page":"3930","DOI":"10.2174\/0929867324666170216113756","article-title":"Gut-brain Axis: role of lipids in the regulation of inflammation, pain and CNS diseases","volume":"25","author":"Russo","year":"2018","journal-title":"Curr. Med. Chem."},{"key":"ref71","doi-asserted-by":"publisher","first-page":"034001","DOI":"10.1088\/1752-7163\/aaa3a1","article-title":"Tongue coating: its characteristics and role in intra-oral halitosis and general health-a review","volume":"12","author":"Seerangaiyan","year":"2018","journal-title":"J. Breath Res."},{"key":"ref72","doi-asserted-by":"publisher","first-page":"760542","DOI":"10.3389\/fmedt.2021.760542","article-title":"Construction of a standardized tongue image database for diagnostic education: development of a tongue diagnosis e-learning system","volume":"3","author":"Segawa","year":"2021","journal-title":"Front. Med. Technol."},{"key":"ref73","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1007\/s40520-017-0770-3","article-title":"Effects of acetyl-L-carnitine in diabetic neuropathy and other geriatric disorders","volume":"30","author":"Sergi","year":"2018","journal-title":"Aging Clin. Exp. Res."},{"key":"ref74","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/s13024-021-00425-8","article-title":"Comprehensive metabolic profiling of Parkinson\u2019s disease by liquid chromatography-mass spectrometry","volume":"16","author":"Shao","year":"2021","journal-title":"Mol. Neurodegener."},{"key":"ref75","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1212\/WNL.0b013e3181f39a78","article-title":"CSF amyloid {beta} 1-42 predicts cognitive decline in Parkinson disease","volume":"75","author":"Siderowf","year":"2010","journal-title":"Neurology"},{"key":"ref76","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.cger.2019.08.002","article-title":"Parkinson disease epidemiology, pathology, genetics, and pathophysiology","volume":"36","author":"Simon","year":"2020","journal-title":"Clin. Geriatr. Med."},{"key":"ref77","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1007\/s12035-016-0293-5","article-title":"Acetyl-L-carnitine via Upegulating dopamine D1 receptor and attenuating microglial activation prevents neuronal loss and improves memory functions in parkinsonian rats","volume":"55","author":"Singh","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref78","doi-asserted-by":"publisher","first-page":"1350","DOI":"10.2174\/1871527314666150821102823","article-title":"The association of Palmitoylethanolamide with luteolin decreases neuroinflammation and stimulates autophagy in Parkinson\u2019s disease model","volume":"14","author":"Siracusa","year":"2015","journal-title":"CNS Neurol. Disord."},{"key":"ref79","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1007\/s12035-015-9253-8","article-title":"N-Palmitoylethanolamine and Neuroinflammation: a novel therapeutic strategy of resolution","volume":"52","author":"Skaper","year":"2015","journal-title":"Mol. Neurobiol."},{"key":"ref80","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.eswa.2019.05.028","article-title":"A comparison of random forest variable selection methods for classification prediction modeling","volume":"134","author":"Speiser","year":"2019","journal-title":"Expert Syst. Appl."},{"key":"ref81","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1007\/s11655-011-0702-6","article-title":"Objectified study on tongue images of patients with lung cancer of different syndromes","volume":"17","author":"Su","year":"2011","journal-title":"Chin. J. Integr. Med."},{"key":"ref82","doi-asserted-by":"publisher","first-page":"1050","DOI":"10.1111\/j.1532-5415.2010.02867.x","article-title":"Microfloral characterization of the tongue coating and associated risk for pneumonia-related health problems in institutionalized older adults","volume":"58","author":"Takeshita","year":"2010","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref83","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/S1474-4422(05)70285-4","article-title":"The diagnosis of Parkinson\u2019s disease","volume":"5","author":"Tolosa","year":"2006","journal-title":"Lancet Neurol."},{"key":"ref84","doi-asserted-by":"publisher","first-page":"1874","DOI":"10.1111\/febs.12152","article-title":"Metabolism of endocannabinoids and related -acylethanolamines: canonical and alternative pathways","volume":"280","author":"Ueda","year":"2013","journal-title":"FEBS J."},{"key":"ref85","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1111\/jcpe.12031","article-title":"Tongue coating: related factors","volume":"40","author":"Van Tornout","year":"2013","journal-title":"J. Clin. Periodontol."},{"key":"ref86","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1016\/S1474-4422(21)00061-2","article-title":"Progress towards therapies for disease modification in Parkinson\u2019s disease","volume":"20","author":"Vijiaratnam","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref87","doi-asserted-by":"publisher","first-page":"2717","DOI":"10.3390\/ijms23052717","article-title":"The role of l-carnitine in mitochondria, prevention of metabolic inflexibility and disease initiation","volume":"23","author":"Virmani","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"ref88","doi-asserted-by":"publisher","first-page":"5515325","DOI":"10.1155\/2021\/5515325","article-title":"Metabolite characteristics in tongue coating from damp phlegm pattern in patients with gastric precancerous lesion","volume":"2021","author":"Xu","year":"2021","journal-title":"Evid. Based Complement. Alternat. Med."},{"key":"ref89","doi-asserted-by":"publisher","first-page":"874021","DOI":"10.3389\/fimmu.2022.874021","article-title":"Comprehensive analysis of the relationships between the gut microbiota and fecal metabolome in individuals with primary Sjogren\u2019s syndrome by 16S rRNA sequencing and LC-MS-based metabolomics","volume":"13","author":"Yang","year":"2022","journal-title":"Front. Immunol."},{"key":"ref90","doi-asserted-by":"publisher","first-page":"101834","DOI":"10.1016\/j.eclinm.2023.101834","article-title":"Development of a tongue image-based machine learning tool for the diagnosis of gastric cancer: a prospective multicentre clinical cohort study","volume":"57","author":"Yuan","year":"2023","journal-title":"EClinicalMedicine"},{"key":"ref91","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1177\/00220345241230067","article-title":"Tongue-coating microbial and metabolic characteristics in halitosis","volume":"103","author":"Zhang","year":"2024","journal-title":"J. Dent. Res."},{"key":"ref92","doi-asserted-by":"publisher","first-page":"725284","DOI":"10.3389\/fcimb.2021.725284","article-title":"Specific gut microbiome and serum metabolome changes in lung Cancer patients","volume":"11","author":"Zhao","year":"2021","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref93","doi-asserted-by":"publisher","first-page":"265","DOI":"10.19852\/j.cnki.jtcm.2000.04.007","article-title":"Acupuncture treatment of Parkinson\u2019s disease--a report of 29 cases","volume":"20","author":"Zhuang","year":"2000","journal-title":"J. Tradit. Chin. Med."},{"key":"ref94","doi-asserted-by":"publisher","first-page":"e13213","DOI":"10.1111\/cpr.13213","article-title":"In situ analysis of acupuncture protecting dopaminergic neurons from lipid peroxidative damage in mice of Parkinson\u2019s disease","volume":"55","author":"Zuo","year":"2022","journal-title":"Cell Prolif."}],"updated-by":[{"DOI":"10.3389\/fmicb.2025.1721341","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T00:00:00Z","timestamp":1762387200000}}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2025.1621468\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T18:21:58Z","timestamp":1762453318000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2025.1621468\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,29]]},"references-count":94,"alternative-id":["10.3389\/fmicb.2025.1621468"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2025.1621468","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,29]]},"article-number":"1621468"}}