{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T09:06:50Z","timestamp":1784192810759,"version":"3.55.0"},"reference-count":112,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Minister of Health","award":["PNRR-POC-2023-12377354"],"award-info":[{"award-number":["PNRR-POC-2023-12377354"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Periodontitis is a chronic inflammatory disease increasingly recognized as a manifestation of complex microbial dysbiosis extending beyond the oral cavity. Recent advances in spatial metagenomics provide unprecedented resolution to investigate microbial community structure, function, and localization within periodontal niches and along the oral\u2013gut axis. This review aims to explore how spatially resolved metagenomic approaches refine our understanding of the ecological and functional shifts in bacterial populations associated with periodontitis and their systemic implications. By integrating spatial mapping with shotgun metagenomics, we highlight distinct microenvironmental signatures within periodontal pockets, characterized by anaerobic pathobionts, metabolic reprogramming, and localized inflammatory gradients. Furthermore, we examine evidence supporting bidirectional interactions between oral and gut microbiota, suggesting that oral-derived taxa may contribute to gut dysbiosis through translocation and ecological disruption. From a basic science perspective, spatial metagenomics reveals niche-specific microbial functions and interspecies interactions that are not captured by bulk sequencing. Clinically, these insights open avenues for precision diagnostics and targeted therapeutics, including microbiome modulation strategies tailored to spatial microbial organization. Overall, this work underscores the importance of spatial context in metagenomic analyses and advances the conceptual framework linking periodontal disease to systemic microbial dysbiosis.<\/jats:p>","DOI":"10.3390\/metabo16070502","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T08:08:34Z","timestamp":1784189314000},"page":"502","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metagenomics in the Interplay Among Oral and Gut Dysbiosis"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-7262-5594","authenticated-orcid":false,"given":"Morena","family":"Munzone","sequence":"first","affiliation":[{"name":"Unit of Periodontology, Department of General Surgery and Surgical-Medical Specialties, School of Dentistry, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7131-5883","authenticated-orcid":false,"given":"Giorgia Maria","family":"Marmo","sequence":"additional","affiliation":[{"name":"Unit of Periodontology, Department of General Surgery and Surgical-Medical Specialties, School of Dentistry, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6717-8899","authenticated-orcid":false,"given":"Alessandro","family":"Polizzi","sequence":"additional","affiliation":[{"name":"Unit of Periodontology, Department of General Surgery and Surgical-Medical Specialties, School of Dentistry, University of Catania, 95123 Catania, Italy"},{"name":"International Research Center on Periodontal and Systemic Health \u201cPerioHealth\u201d, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Jovanova","sequence":"additional","affiliation":[{"name":"Unit of Periodontology, Department of General Surgery and Surgical-Medical Specialties, School of Dentistry, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3231-0704","authenticated-orcid":false,"given":"Angela","family":"Angjelova","sequence":"additional","affiliation":[{"name":"Unit of Periodontology, Department of General Surgery and Surgical-Medical Specialties, School of Dentistry, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3165-0631","authenticated-orcid":false,"given":"Saturnino Marco","family":"Lupi","sequence":"additional","affiliation":[{"name":"Department of Clinical Surgical, Diagnostic and Paediatric Sciences, School of Dentistry, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4267-6992","authenticated-orcid":false,"given":"Gaetano","family":"Isola","sequence":"additional","affiliation":[{"name":"Unit of Periodontology, Department of General Surgery and Surgical-Medical Specialties, School of Dentistry, University of Catania, 95123 Catania, Italy"},{"name":"International Research Center on Periodontal and Systemic Health \u201cPerioHealth\u201d, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1021\/acs.biochem.0c00033","article-title":"From Metagenomes to Molecules: Innovations in Functional Metagenomics Unlock Hidden Chemistry in the Human Microbiome","volume":"59","author":"Chevrette","year":"2020","journal-title":"Biochemistry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"fuad051","DOI":"10.1093\/femsre\/fuad051","article-title":"Illuminating the oral microbiome and its host interactions: Recent advancements in omics and bioinformatics technologies in the context of oral microbiome research","volume":"47","author":"Baker","year":"2023","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"86","DOI":"10.17135\/jdhs.2019.19.2.86","article-title":"Oral Metagenomic Analysis Techniques","volume":"19","author":"Chung","year":"2019","journal-title":"J. Dent. Hyg. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1177\/0022034512449466","article-title":"Next-generation sequencing approaches to understanding the oral microbiome","volume":"24","author":"Zaura","year":"2012","journal-title":"Adv. Dent. Res."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Saxena, R. (2016). A Metagenomic Insight into Human Microbiome: Its Implications in Health and Disease, Academic Press.","DOI":"10.1016\/B978-0-12-420196-5.00009-5"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"122","DOI":"10.4103\/jomfp.JOMFP_304_18","article-title":"Oral microbiome: Unveiling the fundamentals","volume":"23","author":"Deo","year":"2019","journal-title":"J. Oral Maxillofac. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"9","DOI":"10.5604\/17331331.1234988","article-title":"Application of Metagenomic Analyses in Dentistry as a Novel Strategy Enabling Complex Insight into Microbial Diversity of the Oral Cavity","volume":"66","author":"Burczynska","year":"2017","journal-title":"Pol. J. Microbiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.micinf.2015.03.014","article-title":"Beyond microbial community composition: Functional activities of the oral microbiome in health and disease","volume":"17","year":"2015","journal-title":"Microbes Infect."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Huang, Y., Zhao, X., Cui, L., and Huang, S. (2021). Metagenomic and Metatranscriptomic Insight Into Oral Biofilms in Periodontitis and Related Systemic Diseases. Front. Microbiol., 12.","DOI":"10.3389\/fmicb.2021.728585"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"278","DOI":"10.5005\/jp-journals-10005-3413","article-title":"Metagenomics as an Effective Diagnostic Approach for Exploring Oral Microbial Diversity and Dental Diseases: A Narrative Review","volume":"19","author":"Walia","year":"2026","journal-title":"Int. J. Clin. Pediatr. Dent."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1111\/jre.13408","article-title":"Metagenomic Insights Into the Subgingival Microbiome in Periodontal Health and Different Grades of Periodontitis","volume":"60","author":"Zhao","year":"2025","journal-title":"J. Periodontal. Res."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Willis, J.R., and Gabald\u00f3n, T. (2020). The Human Oral Microbiome in Health and Disease: From Sequences to Ecosystems. Microorganisms, 8.","DOI":"10.3390\/microorganisms8020308"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Wirth, R., Pap, B., Mar\u00f3ti, G., V\u00e1lyi, P., Koml\u00f3si, L., Barta, N., Strang, O., Min\u00e1rovits, J., and Kov\u00e1cs, K.L. (2021). Toward Personalized Oral Diagnosis: Distinct Microbiome Clusters in Periodontitis Biofilms. Front. Cell. Infect. Microbiol., 11.","DOI":"10.3389\/fcimb.2021.747814"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1111\/prd.12393","article-title":"The oral microbiome: Role of key organisms and complex networks in oral health and disease","volume":"87","author":"Sedghi","year":"2021","journal-title":"Periodontol. 2000"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Lee, Y.H., Chung, S.W., Auh, Q.S., Hong, S.J., Lee, Y.A., Jung, J., Lee, G.J., Park, H.J., Shin, S.I., and Hong, J.Y. (2021). Progress in Oral Microbiome Related to Oral and Systemic Diseases: An Update. Diagnostics, 11.","DOI":"10.20944\/preprints202106.0529.v1"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/s41579-023-00963-6","article-title":"The oral microbiome: Diversity, biogeography and human health","volume":"22","author":"Baker","year":"2024","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"100289","DOI":"10.1016\/j.cobme.2021.100289","article-title":"Recent advances in tools to map the microbiome","volume":"19","author":"Shi","year":"2021","journal-title":"Curr. Opin. Biomed. Eng."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1038\/s44222-025-00346-x","article-title":"Multi-dimensional metagenomics","volume":"3","author":"Peng","year":"2025","journal-title":"Nat. Rev. Bioeng."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s41894-025-00154-x","article-title":"A comprehensive review of microbial spatial organization in periodontal pathogenesis","volume":"9","author":"Gonal","year":"2025","journal-title":"Periodontal Implant Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2640344","DOI":"10.1080\/20002297.2026.2640344","article-title":"Interrogation of imaging-based interspecies dynamics in the oral microbiome","volume":"18","author":"Xiang","year":"2026","journal-title":"J. Oral Microbiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"fuac052","DOI":"10.1093\/femsre\/fuac052","article-title":"Illuminating the oral microbiome and its host interactions: Tools and approaches for molecular ecological studies","volume":"47","author":"Kreth","year":"2023","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Ferrillo, M., Giudice, A., Migliario, M., Ren\u00f3, F., Lippi, L., Calafiore, D., Marotta, N., de Sire, R., Fortunato, L., and Ammendolia, A. (2023). Oral-Gut Microbiota, Periodontal Diseases, and Arthritis: Literature Overview on the Role of Probiotics. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24054626"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Di Stefano, M., Santonocito, S., Polizzi, A., Mauceri, R., Troiano, G., Lo Giudice, A., Romano, A., Mascitti, M., and Isola, G. (2023). A Reciprocal Link between Oral, Gut Microbiota during Periodontitis: The Potential Role of Probiotics in Reducing Dysbiosis-Induced Inflammation. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021084"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.jdsr.2023.08.003","article-title":"Oral-gut axis as a novel biological mechanism linking periodontal disease and systemic diseases: A review","volume":"59","author":"Yamazaki","year":"2023","journal-title":"Jpn. Dent. Sci. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7351229","DOI":"10.1155\/agm3\/7351229","article-title":"Gut\u2013Oral Microbial Dysbiosis: A Correlated Ecosystem","volume":"2025","author":"Siddiqui","year":"2025","journal-title":"Adv. Gut Microbiome Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1093\/ibd\/izac241","article-title":"The Oral-Gut Axis: Periodontal Diseases and Gastrointestinal Disorders","volume":"29","author":"Lam","year":"2023","journal-title":"Inflamm. Bowel. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Harrandah, A.M. (2025). The Oral\u2013Gut\u2013Systemic Axis: Emerging Insights into Periodontitis, Microbiota Dysbiosis, and Systemic Disease Interplay. Diagnostics, 15.","DOI":"10.3390\/diagnostics15212784"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"10-1128","DOI":"10.1128\/mSphere.00460-18","article-title":"Oral Administration of Porphyromonas gingivalis Alters the Gut Microbiome and Serum Metabolome","volume":"3","author":"Kato","year":"2018","journal-title":"mSphere"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Sulaiman, Y., Pacauskien\u0117, I.M., \u0160adzevi\u010dien\u0117, R., and Anuzyte, R. (2024). Oral and Gut Microbiota Dysbiosis Due to Periodontitis: Systemic Implications and Links to Gastrointestinal Cancer: A Narrative Review. Medicina, 60.","DOI":"10.3390\/medicina60091416"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2197779","DOI":"10.1080\/20002297.2023.2197779","article-title":"Current concepts in the pathogenesis of periodontitis: From symbiosis to dysbiosis","volume":"15","author":"Abdulkareem","year":"2023","journal-title":"J. Oral Microbiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1586422","DOI":"10.1080\/20002297.2019.1586422","article-title":"Can oral bacteria affect the microbiome of the gut?","volume":"11","author":"Olsen","year":"2019","journal-title":"J. Oral Microbiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1038\/s41421-021-00356-0","article-title":"Metagenome-genome-wide association studies reveal human genetic impact on the oral microbiome","volume":"7","author":"Liu","year":"2021","journal-title":"Cell Discov."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1038\/s41579-024-01075-5","article-title":"The oral-gut microbiome axis in health and disease","volume":"22","author":"Kunath","year":"2024","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1177\/1099800420941606","article-title":"The Oral and Gut Bacterial Microbiomes: Similarities, Differences, and Connections","volume":"23","author":"Maki","year":"2021","journal-title":"Biol. Res. Nurs."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1093\/ecco-jcc\/jjae028","article-title":"Unravelling the Oral-Gut Axis: Interconnection Between Periodontitis and Inflammatory Bowel Disease, Current Challenges, and Future Perspective","volume":"18","author":"Tanwar","year":"2024","journal-title":"J. Crohns Colitis"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1093\/intimm\/dxac027","article-title":"Untangling the oral-gut axis in the pathogenesis of intestinal inflammation","volume":"34","author":"Kitamoto","year":"2022","journal-title":"Int. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Huang, X., Li, Y., Zhang, J., and Feng, Q. (2024). Linking Periodontitis with Inflammatory Bowel Disease through the Oral\u2013Gut Axis: The Potential Role of Porphyromonas gingivalis. Biomedicines, 12.","DOI":"10.3390\/biomedicines12030685"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1111\/odi.13843","article-title":"Shared microbiological and immunological patterns in periodontitis and IBD: A scoping review","volume":"28","author":"Baima","year":"2022","journal-title":"Oral Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1038\/s41368-023-00264-x","article-title":"Omics for deciphering oral microecology","volume":"16","author":"Lin","year":"2024","journal-title":"Int. J. Oral Sci."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Plachokova, A.S., Andreu-S\u00e1nchez, S., Noz, M.P., Fu, J., and Riksen, N.P. (2021). Oral Microbiome in Relation to Periodontitis Severity and Systemic Inflammation. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115876"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1628","DOI":"10.1093\/ecco-jcc\/jjac063","article-title":"Oral Microbiome of Crohn\u2019s Disease Patients With and Without Oral Manifestations","volume":"16","author":"Hu","year":"2022","journal-title":"J. Crohns Colitis"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1111\/prd.12350","article-title":"Metatranscriptomic analyses of the oral microbiome","volume":"85","year":"2021","journal-title":"Periodontol. 2000"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"424","DOI":"10.4161\/viru.28532","article-title":"Application of metagenomics in understanding oral health and disease","volume":"5","author":"Xu","year":"2014","journal-title":"Virulence"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"S159","DOI":"10.1002\/JPER.18-0006","article-title":"Staging and grading of periodontitis: Framework and proposal of a new classification and case definition","volume":"89","author":"Tonetti","year":"2018","journal-title":"J. Periodontol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1111\/prd.12621","article-title":"Relationship between periodontitis and systemic diseases: A bibliometric and visual study","volume":"98","author":"Isola","year":"2025","journal-title":"Periodontol. 2000"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1111\/jcpe.12732","article-title":"Impact of the global burden of periodontal diseases on health, nutrition and wellbeing of mankind: A call for global action","volume":"44","author":"Tonetti","year":"2017","journal-title":"J. Clin. Periodontol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Schaefer, A.S., Nibali, L., Zoheir, N., Moutsopoulos, N.M., and Loos, B.G. (2025). Genetic risk variants implicate impaired maintenance and repair of periodontal tissues as causal for periodontitis\u2014A synthesis of recent findings. Periodontol. 2000.","DOI":"10.1111\/prd.12622"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.1002\/JPER.23-0063","article-title":"Impact of N-terminal pro-B-type natriuretic peptide and related inflammatory biomarkers on periodontal treatment outcomes in patients with periodontitis: An explorative human randomized-controlled clinical trial","volume":"94","author":"Isola","year":"2023","journal-title":"J. Periodontol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1002\/JPER.21-0049","article-title":"Periodontitis activates the NLRP3 inflammasome in serum and saliva","volume":"93","author":"Isola","year":"2022","journal-title":"J. Periodontol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"112120","DOI":"10.1016\/j.celrep.2023.112120","article-title":"Periodontal disease is associated with increased gut colonization of pathogenic Haemophilus parainfluenzae in patients with Crohn\u2019s disease","volume":"42","author":"Sohn","year":"2023","journal-title":"Cell Rep."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Sun, B., Liu, B., Gao, X., Xing, K., Xie, L., and Guo, T. (2021). Metagenomic Analysis of Saliva Reveals Disease-Associated Microbiotas in Patients With Periodontitis and Crohn\u2019s Disease-Associated Periodontitis. Front. Cell. Infect. Microbiol., 11.","DOI":"10.3389\/fcimb.2021.719411"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Belibasakis, G.N., Belstr\u00f8m, D., Eick, S., Gursoy, U.K., Johansson, A., and K\u00f6n\u00f6nen, E. (2023). Periodontal microbiology and microbial etiology of periodontal diseases: Historical concepts and contemporary perspectives. Periodontol. 2000.","DOI":"10.1111\/prd.12473"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Basic, A., and Dahl\u00e9n, G. (2023). Microbial metabolites in the pathogenesis of periodontal diseases: A narrative review. Front. Oral Health, 4.","DOI":"10.3389\/froh.2023.1210200"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Cui, Z., Wang, P., and Gao, W. (2025). Microbial dysbiosis in periodontitis and peri-implantitis: Pathogenesis, immune responses, and therapeutic. Front. Cell. Infect. Microbiol., 15.","DOI":"10.3389\/fcimb.2025.1517154"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1515\/oncologie-2025-0205","article-title":"Periodontal inflammation as a negative stimulus for oral cancerization: The hidden role of periodontitis in oral cancerization","volume":"27","author":"Munzone","year":"2025","journal-title":"Oncologie"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1111\/j.1600-051X.2010.01622.x","article-title":"Oxygen tension modulates the cytokine response of oral epithelium to periodontal bacteria","volume":"37","author":"Grant","year":"2010","journal-title":"J. Clin. Periodontol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1111\/j.1600-051X.1998.tb02419.x","article-title":"Microbial complexes in subgingival plaque","volume":"25","author":"Socransky","year":"1998","journal-title":"J. Clin. Periodontol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1038\/nrmicro2381","article-title":"Oral multispecies biofilm development and the key role of cell-cell distance","volume":"8","author":"Kolenbrander","year":"2010","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.coemr.2021.04.005","article-title":"Recent progress in analyzing the spatial structure of the human microbiome: Distinguishing biogeography and architecture in the oral and gut communities","volume":"18","author":"Adade","year":"2021","journal-title":"Curr. Opin. Endocr. Metab. Res."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Yekani, M., Dastgir, M., Fattahi, S., Shahi, S., Maleki Dizaj, S., and Memar, M.Y. (2025). Microbiological and molecular aspects of periodontitis pathogenesis: An infection-induced inflammatory condition. Front. Cell. Infect. Microbiol., 15.","DOI":"10.3389\/fcimb.2025.1533658"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1111\/prd.12153","article-title":"The periodontal pocket: Pathogenesis, histopathology and consequences","volume":"76","author":"Bosshardt","year":"2018","journal-title":"Periodontol. 2000"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1111\/prd.12203","article-title":"The periodontal pocket","volume":"76","author":"Donos","year":"2018","journal-title":"Periodontol. 2000"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1177\/00220345950740070801","article-title":"Volatile Fatty Acids, Metabolic By-products of Periodontopathic Bacteria, Inhibit Lymphocyte Proliferation and Cytokine Production","volume":"74","author":"Fukushima","year":"1995","journal-title":"J. Dent. Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1034\/j.1600-051X.1999.260906.x","article-title":"Sulfate-reducing bacteria in periodontal pockets and in healthy oral sites","volume":"26","author":"Langendijk","year":"1999","journal-title":"J. Clin. Periodontol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1002\/JPER.23-0518","article-title":"Effects of minimally invasive non-surgical therapy on C-reactive protein, lipoprotein-associated phospholipase A(2), and clinical outcomes in periodontitis patients: A 1-year randomized, controlled clinical trial","volume":"95","author":"Isola","year":"2024","journal-title":"J. Periodontol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1111\/jre.13324","article-title":"Gut microbial dysbiosis and inflammation: Impact on periodontal health","volume":"60","author":"Zhao","year":"2025","journal-title":"J. Periodontal Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1487741","DOI":"10.1080\/20002297.2018.1487741","article-title":"Defining the gut microbiota in individuals with periodontal diseases: An exploratory study","volume":"10","author":"Spencer","year":"2018","journal-title":"J. Oral Microbiol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1111\/jcpe.13906","article-title":"Exploring the causal relationship between periodontitis and gut microbiome: Unveiling the oral\u2013gut and gut\u2013oral axes through bidirectional Mendelian randomization","volume":"51","author":"Chen","year":"2024","journal-title":"J. Clin. Periodontol."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Nakajima, M., Arimatsu, K., Kato, T., Matsuda, Y., Minagawa, T., Takahashi, N., Ohno, H., and Yamazaki, K. (2015). Oral Administration of P. gingivalis Induces Dysbiosis of Gut Microbiota and Impaired Barrier Function Leading to Dissemination of Enterobacteria to the Liver. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0134234"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1111\/prd.12540","article-title":"Periodontitis and risk of cancer: Mechanistic evidence","volume":"96","author":"Baima","year":"2024","journal-title":"Periodontol. 2000"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1111\/jcpe.70047","article-title":"Familial Patterns of Oral\u2013Gut Dysbiosis and Systemic Markers in Periodontitis","volume":"53","author":"Paz","year":"2026","journal-title":"J. Clin. Periodontol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1111\/jre.70055","article-title":"Multi-Omics Signatures of Periodontitis and Periodontal Therapy on the Oral and Gut Microbiome","volume":"60","author":"Baima","year":"2025","journal-title":"J. Periodontal Res."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Kamer, A.R., Pushalkar, S., Hamidi, B., Janal, M.N., Tang, V., Annam, K.R.C., Palomo, L., Gulivindala, D., Glodzik, L., and Saxena, D. (2024). Periodontal Inflammation and Dysbiosis Relate to Microbial Changes in the Gut. Microorganisms, 12.","DOI":"10.3390\/microorganisms12061225"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Di Pierro, F., Fornaini, C., Palazzi, C.M., Bertuccioli, A., Tagg, J., and Zerbinati, N. (2025). From periodontal infection to oral\u2013systemic dysbiosis: Re-framing the oral microbiome\u2019s role in systemic health and the prophylactic potential of Streptococcus salivarius probiotics. Front. Microbiol., 16.","DOI":"10.3389\/fmicb.2025.1685071"},{"key":"ref_75","unstructured":"Nagarajan, M. (2025). 11-Metagenomics: Implications in oral health and disease. Metagenomics, Academic Press. [2nd ed.]."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Kawamoto, D., Borges, R., Ribeiro, R.A., de Souza, R.F., Amado, P.P.P., Saraiva, L., Horliana, A., Faveri, M., and Mayer, M.P.A. (2021). Oral Dysbiosis in Severe Forms of Periodontitis Is Associated With Gut Dysbiosis and Correlated With Salivary Inflammatory Mediators: A Preliminary Study. Front. Oral Health, 2.","DOI":"10.3389\/froh.2021.722495"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"394","DOI":"10.5051\/jpis.2200680034","article-title":"Comparison of the oral microbial composition between healthy individuals and periodontitis patients in different oral sampling sites using 16S metagenome profiling","volume":"52","author":"Kim","year":"2022","journal-title":"J. Periodontal Implant Sci."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1111\/prd.12356","article-title":"Impact of systemic factors in shaping the periodontal microbiome","volume":"85","author":"Teles","year":"2021","journal-title":"Periodontol. 2000"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"967","DOI":"10.3748\/wjg.v29.i6.967","article-title":"Periodontal treatment and microbiome-targeted therapy in management of periodontitis-related nonalcoholic fatty liver disease with oral and gut dysbiosis","volume":"29","author":"Kuraji","year":"2023","journal-title":"World J. Gastroenterol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1038\/ismej.2011.191","article-title":"Distinct and complex bacterial profiles in human periodontitis and health revealed by 16S pyrosequencing","volume":"6","author":"Griffen","year":"2012","journal-title":"ISME J."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Ai, D., Huang, R., Wen, J., Li, C., Zhu, J., and Xia, L.C. (2017). Integrated metagenomic data analysis demonstrates that a loss of diversity in oral microbiota is associated with periodontitis. BMC Genom., 18.","DOI":"10.1186\/s12864-016-3254-5"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Liu, B., Faller, L.L., Klitgord, N., Mazumdar, V., Ghodsi, M., Sommer, D.D., Gibbons, T.R., Treangen, T.J., Chang, Y.C., and Li, S. (2012). Deep sequencing of the oral microbiome reveals signatures of periodontal disease. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0037919"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1038\/srep01843","article-title":"Metagenomic sequencing reveals microbiota and its functional potential associated with periodontal disease","volume":"3","author":"Wang","year":"2013","journal-title":"Sci. Rep."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s13073-015-0153-3","article-title":"Functional signatures of oral dysbiosis during periodontitis progression revealed by microbial metatranscriptome analysis","volume":"7","author":"Yost","year":"2015","journal-title":"Genome Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s13099-021-00409-5","article-title":"Ectopic gut colonization: A metagenomic study of the oral and gut microbiome in Crohn\u2019s disease","volume":"13","author":"Hu","year":"2021","journal-title":"Gut Pathog."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"102761","DOI":"10.1016\/j.xcrm.2026.102761","article-title":"Distinct signatures in the human gut and oral microbiomes of gastric cancer","volume":"7","author":"Qin","year":"2026","journal-title":"Cell Rep. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1053\/j.gastro.2022.03.054","article-title":"Metagenomic Identification of Microbial Signatures Predicting Pancreatic Cancer From a Multinational Study","volume":"163","author":"Nagata","year":"2022","journal-title":"Gastroenterology"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Pietroni, C., Wang, B., Bogri, A., Langa, J., Odriozola, I., Horisberger, Z., Contreras-Serrano, M., Lauritsen, J.G., Gaun, N., and Toffano, A. (2025). Micro-scale spatial metagenomics: Revealing high-resolution spatial biogeography of gut microbiomes. bioRxiv.","DOI":"10.1101\/2025.09.30.679663"},{"key":"ref_89","first-page":"E791","article-title":"Biogeography of a human oral microbiome at the micron scale","volume":"113","author":"Rossetti","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1111\/prd.12364","article-title":"Spatial scale in analysis of the dental plaque microbiome","volume":"86","author":"Borisy","year":"2000","journal-title":"Periodontology"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1146\/annurev-micro-090817-062503","article-title":"Biogeography of the Oral Microbiome: The Site-Specialist Hypothesis","volume":"73","author":"Dewhirst","year":"2019","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Rajasekaran, J., Krishnamurthy, H., Bosco, J., Jayaraman, V., Krishna, K., Wang, T., and Bei, K. (2024). Oral Microbiome: A Comprehensive Review of Its Impact on Oral and Systemic Health. Preprint.","DOI":"10.20944\/preprints202406.1923.v1"},{"key":"ref_93","first-page":"e78918","article-title":"The Oral Microbiome and Systemic Health: Bridging the Gap Between Dentistry and Medicine","volume":"17","author":"Nayak","year":"2025","journal-title":"Cureus"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Vil\u00e0-Quintana, L., Fort, E., Pardo, L., Albiol-Quer, M.T., Ortiz, M.R., Capdevila, M., Feliu, A., Bah\u00ed, A., Llir\u00f3s, M., and Garc\u00eda-Velasco, A. (2024). Metagenomic Study Reveals Phage-Bacterial Interactome Dynamics in Gut and Oral Microbiota in Pancreatic Diseases. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252010988"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"4240","DOI":"10.1158\/1078-0432.CCR-24-0875","article-title":"Oral and Gut Microbiome Alterations in Oral Chronic GVHD Disease: Results from Close Assessment and Testing for Chronic GVHD (CATCH Study)","volume":"30","author":"Rashidi","year":"2024","journal-title":"Clin. Cancer Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/s41597-024-02916-x","article-title":"Multi-cohort shotgun metagenomic analysis of oral and gut microbiota overlap in healthy adults","volume":"11","author":"Rashidi","year":"2024","journal-title":"Sci. Data"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.archoralbio.2019.05.025","article-title":"Whole metagenomic shotgun sequencing of the subgingival microbiome of diabetics and non-diabetics with different periodontal conditions","volume":"104","author":"Farina","year":"2019","journal-title":"Arch. Oral Biol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"e2412001","DOI":"10.4014\/jmb.2412.12001","article-title":"Advancing Gut Microbiome Research: The Shift from Metagenomics to Multi-Omics and Future Perspectives","volume":"35","author":"Yang","year":"2025","journal-title":"J. Microbiol. Biotechnol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1038\/s44320-025-00129-x","article-title":"From microbes to molecules: Unveiling host-microbe interactions with spatial metabolomics","volume":"21","author":"Petersen","year":"2025","journal-title":"Mol. Syst. Biol."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Zhang, M., Wang, X., Su, X., Yimamu, A., Li, L., and Sun, Z. (2025). Mass Spectrometry Imaging: Revolutionizing Molecular Insights in Infectious Diseases Research. Pathogens, 14.","DOI":"10.3390\/pathogens14070645"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1038\/s41587-023-01979-2","article-title":"Spatial metatranscriptomics resolves host-bacteria-fungi interactomes","volume":"42","author":"Shalev","year":"2024","journal-title":"Nat. Biotechnol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1111\/jre.13279","article-title":"Effect of quadrantwise versus full-mouth subgingival instrumentation on clinical and microbiological parameters in periodontitis patients: A randomized clinical trial","volume":"59","author":"Isola","year":"2024","journal-title":"J. Periodontal Res."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Caselli, E., Fabbri, C., D\u2019Accolti, M., Soffritti, I., Bassi, C., Mazzacane, S., and Franchi, M. (2020). Defining the oral microbiome by whole-genome sequencing and resistome analysis: The complexity of the healthy picture. BMC Microbiol., 20.","DOI":"10.1186\/s12866-020-01801-y"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1111\/jre.13059","article-title":"Oral-gut bacterial profiles discriminate between periodontal health and diseases","volume":"57","author":"Colombo","year":"2022","journal-title":"J. Periodontal Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"10086","DOI":"10.1038\/s41598-023-37246-2","article-title":"Factors influencing oral microbiome analysis: From saliva sampling methods to next-generation sequencing platforms","volume":"13","author":"Bang","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"McLean, J.S. (2014). Advancements toward a systems level understanding of the human oral microbiome. Front. Cell. Infect. Microbiol., 4.","DOI":"10.3389\/fcimb.2014.00098"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1177\/00220345231222800","article-title":"Effect of Periodontitis and Periodontal Therapy on Oral and Gut Microbiota","volume":"103","author":"Baima","year":"2024","journal-title":"J. Dent. Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1002\/JPER.24-0422","article-title":"Impact of nonsurgical periodontal treatment on arterial stiffness outcomes related to endothelial dysfunction: A systematic review and meta-analysis","volume":"96","author":"Polizzi","year":"2025","journal-title":"J. Periodontol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1002\/jper.70007","article-title":"Effectiveness of two supportive periodontal care protocols and outcome predictors during periodontitis: A randomized controlled trial","volume":"97","author":"Isola","year":"2026","journal-title":"J. Periodontol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1111\/clr.14405","article-title":"Effect of Nonsurgical Mechanical Debridement With or Without Chlorhexidine Formulations in the Treatment of Peri-Implant Mucositis. A Randomized Placebo-Controlled Clinical Trial","volume":"36","author":"Isola","year":"2025","journal-title":"Clin. Oral Implants Res."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Isola, G., Polizzi, A., Angjelova, A., Jovanova, E., Pizzo, G., and Sculean, A. (2026). Impact and efficacy of systemic antibiotics for peri-implant diseases treatment: A systematic review and meta-analysis on clinical and microbiological outcomes. Periodontol. 2000.","DOI":"10.1111\/prd.70033"},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Mora\u00efs, S., and Mizrahi, I. (2026). Micro-scale spatial metagenomics opens a new era in microbiome ecology. Trends Microbiol.","DOI":"10.1016\/j.tim.2026.03.005"}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/16\/7\/502\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T08:47:19Z","timestamp":1784191639000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/16\/7\/502"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,16]]},"references-count":112,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["metabo16070502"],"URL":"https:\/\/doi.org\/10.3390\/metabo16070502","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,16]]}}}