{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T13:01:01Z","timestamp":1791291661393,"version":"4.1.0"},"reference-count":48,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T00:00:00Z","timestamp":1694649600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"OPOS Foundation, St. Gallen, Switzerland","award":["CF10000044\u2014EPFL SCR0237812"],"award-info":[{"award-number":["CF10000044\u2014EPFL SCR0237812"]}]},{"name":"Foundation Bertarelli Catalyst Fund, EPFL","award":["CF10000044\u2014EPFL SCR0237812"],"award-info":[{"award-number":["CF10000044\u2014EPFL SCR0237812"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Although dry eye disease (DED) is one of the most common ocular surface diseases worldwide, its pathogenesis is incompletely understood, and treatment options are limited. There is growing evidence that complex interactions between the ocular surface microbiome (OSM) and tear fluid constituents, potentially leading to inflammatory processes, are associated with ocular surface diseases such as DED. In this study, we aimed to find unique compositional and functional features of the OSM associated with human and microbial tear proteins in patients with DED. Applying whole-metagenome shotgun sequencing of forty lid and conjunctival swabs, we identified 229 taxa, with Actinobacteria and Proteobacteria being the most abundant phyla and Propionibacterium acnes the dominating species in the cohort. When DED patients were compared to controls, the species Corynebacterium tuberculostearicum was more abundant in conjunctival samples, whereas the family Propionibacteriaceae was more abundant in lid samples. Functional analysis showed that genes of L-lysine biosynthesis, tetrapyrrole biosynthesis, 5-aminoimidazole ribonucleotide biosynthesis, and the super pathway of L-threonine biosynthesis were enriched in conjunctival samples of controls. The relative abundances of Acinetobacter johnsonii correlated with seven human tear proteins, including mucin-16. The three most abundant microbial tear proteins were the chaperone protein DnaK, the arsenical resistance protein ArsH, and helicase. Compositional and functional features of the OSM and the tear proteome are altered in patients with DED. Ultimately, this may help to design novel interventional therapeutics to target DED.<\/jats:p>","DOI":"10.3390\/ijms241814091","type":"journal-article","created":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T02:54:13Z","timestamp":1694746453000},"page":"14091","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["The Human Ocular Surface Microbiome and Its Associations with the Tear Proteome in Dry Eye Disease"],"prefix":"10.3390","volume":"24","author":[{"given":"Irina","family":"Schlegel","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire M. F.","family":"De Go\u00fcyon Matignon de Pontourade","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel-Benjamin","family":"Lincke","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Keller","sequence":"additional","affiliation":[{"name":"Department for BioMedical Research, University of Bern, 3010 Bern, Switzerland"},{"name":"Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, 3012 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin S.","family":"Zinkernagel","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland"},{"name":"Department for BioMedical Research, University of Bern, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4147-5374","authenticated-orcid":false,"given":"Denise C.","family":"Zysset-Burri","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland"},{"name":"Department for BioMedical Research, University of Bern, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.ajo.2019.01.026","article-title":"Estimated Prevalence and Incidence of Dry Eye Disease Based on Coding Analysis of a Large, All-age United States Health Care System","volume":"202","author":"Dana","year":"2019","journal-title":"Am. J. Ophthalmol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.jtos.2017.05.003","article-title":"TFOS DEWS II Epidemiology Report","volume":"15","author":"Stapleton","year":"2017","journal-title":"Ocul. Surf."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Zhang, X., Jeyalatha M., V., Qu, Y., He, X., Ou, S., Bu, J., Jia, C., Wang, J., Wu, H., and Liu, Z. (2017). Dry Eye Management: Targeting the Ocular Surface Microenvironment. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071398"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s40135-013-0009-1","article-title":"Dry Eye Disease: Impact on Quality of Life and Vision","volume":"1","author":"Uchino","year":"2013","journal-title":"Curr. Ophthalmol. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.jtos.2017.05.008","article-title":"TFOS DEWS II Definition and Classification Report","volume":"15","author":"Craig","year":"2017","journal-title":"Ocul. Surf."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1111\/imm.12716","article-title":"Mucosal immune tolerance at the ocular surface in health and disease","volume":"150","author":"Galletti","year":"2017","journal-title":"Immunology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"40826","DOI":"10.1038\/srep40826","article-title":"Association of the Intestinal Microbiome with the Development of Neovascular Age-Related Macular Degeneration","volume":"7","author":"Zinkernagel","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/s41525-020-00141-0","article-title":"Associations of the intestinal microbiome with the complement system in neovascular age-related macular degeneration","volume":"5","author":"Keller","year":"2020","journal-title":"NPJ Genom. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"15303","DOI":"10.1038\/s41598-019-51698-5","article-title":"Retinal artery occlusion is associated with compositional and functional shifts in the gut microbiome and altered trimethylamine-N-oxide levels","volume":"9","author":"Keller","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Moon, J., Choi, S.H., Yoon, C.H., and Kim, M.K. (2020). Gut dysbiosis is prevailing in Sjogren\u2019s syndrome and is related to dry eye severity. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0229029"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1080\/07853890.2021.1925150","article-title":"Influence of gut microbiota on eye diseases: An overview","volume":"53","author":"Napolitano","year":"2021","journal-title":"Ann. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"232","DOI":"10.3389\/fimmu.2019.00232","article-title":"Microbiome and Autoimmune Uveitis","volume":"10","author":"Horai","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1002\/ame2.12033","article-title":"The intestinal microbiome and Alzheimer\u2019s disease: A review","volume":"1","author":"Li","year":"2018","journal-title":"Anim. Model. Exp. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"432","DOI":"10.3389\/fmicb.2018.00432","article-title":"Intestinal Microbiota Influences Non-intestinal Related Autoimmune Diseases","volume":"9","author":"Opazo","year":"2018","journal-title":"Front. Microbiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1136\/gutjnl-2016-313235","article-title":"A microbial signature for Crohn\u2019s disease","volume":"66","author":"Pascal","year":"2017","journal-title":"Gut"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1038\/s41584-018-0152-z","article-title":"The microbiome in SLE pathogenesis","volume":"15","author":"Silverman","year":"2019","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1080\/19490976.2016.1273996","article-title":"Gut microbiota as a source of a surrogate antigen that triggers autoimmunity in an immune privileged site","volume":"8","author":"Horai","year":"2017","journal-title":"Gut Microbes"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1167\/iovs.62.10.8","article-title":"Understanding the Interactions between the Ocular Surface Microbiome and the Tear Proteome","volume":"62","author":"Schlegel","year":"2021","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e412","DOI":"10.1111\/aos.13526","article-title":"Dry eye disease and oxidative stress","volume":"96","author":"Seen","year":"2018","journal-title":"Acta Ophthalmol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Heidari, M., Noorizadeh, F., Wu, K., Inomata, T., and Mashaghi, A. (2019). Dry Eye Disease: Emerging Approaches to Disease Analysis and Therapy. J. Clin. Med., 8.","DOI":"10.3390\/jcm8091439"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/nar\/gkn923","article-title":"Bioinformatics enrichment tools: Paths toward the comprehensive functional analysis of large gene lists","volume":"37","author":"Sherman","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"643.e7\u2013643.e12","DOI":"10.1016\/j.cmi.2016.04.008","article-title":"Defining the normal core microbiome of conjunctival microbial communities","volume":"22","author":"Huang","year":"2016","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"19","DOI":"10.3109\/08830185.2012.748052","article-title":"Dry eye as a mucosal autoimmune disease","volume":"32","author":"Stern","year":"2013","journal-title":"Int. Rev. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1099\/ijs.0.02907-0","article-title":"Taxonomic characterization of nine strains isolated from clinical and environmental specimens, and proposal of Corynebacterium tuberculostearicum sp. nov","volume":"54","author":"Feurer","year":"2004","journal-title":"Int. J. Syst. Evol. Microbiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1002\/iid3.284","article-title":"Corynebacterium tuberculostearicum, a human skin colonizer, induces the canonical nuclear factor-kappaB inflammatory signaling pathway in human skin cells","volume":"8","author":"Altonsy","year":"2020","journal-title":"Immun. Inflamm. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"459","DOI":"10.3389\/fmicb.2016.00459","article-title":"Characterization of the Gut Microbiome Using 16S or Shotgun Metagenomics","volume":"7","author":"Jovel","year":"2016","journal-title":"Front. Microbiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4708","DOI":"10.1111\/bcp.15444","article-title":"L-lysine: Its antagonism with L-arginine in controlling viral infection. Narrative literature review","volume":"88","author":"Pedrazini","year":"2022","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1097\/01.ico.0000611404.04418.6c","article-title":"Phospholipase D in the Human Ocular Surface and in Pterygium","volume":"27","author":"Tong","year":"2008","journal-title":"Cornea"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4509","DOI":"10.1167\/iovs.07-0430","article-title":"Functions of MUC16 in corneal epithelial cells","volume":"48","author":"Blalock","year":"2007","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.aanat.2007.05.001","article-title":"Regulation of MUC16 by inflammatory mediators in ocular surface epithelial cell lines","volume":"190","author":"Paulsen","year":"2008","journal-title":"Ann. Anat."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1864","DOI":"10.1167\/iovs.07-1081","article-title":"Release of membrane-associated mucins from ocular surface epithelia","volume":"49","author":"Blalock","year":"2008","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4437","DOI":"10.1074\/jbc.M607667200","article-title":"Fatty acyl benzamido antibacterials based on inhibition of DnaK-catalyzed protein folding","volume":"282","author":"Liebscher","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Sedlacek, V., Kryl, M., and Kucera, I. (2022). The ArsH Protein Product of the Paracoccus denitrificans ars Operon Has an Activity of Organoarsenic Reductase and Is Regulated by a Redox-Responsive Repressor. Antioxid, 11.","DOI":"10.3390\/antiox11050902"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1016\/j.molcel.2013.11.016","article-title":"Nucleotide and partner-protein control of bacterial replicative helicase structure and function","volume":"52","author":"Strycharska","year":"2013","journal-title":"Mol. Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/j.str.2005.04.006","article-title":"The bacterial helicase-primase interaction: A common structural\/functional module","volume":"13","author":"Soultanas","year":"2005","journal-title":"Structure"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.18240\/ijo.2019.10.15","article-title":"New approaches for diagnosis of dry eye disease","volume":"12","author":"Elhusseiny","year":"2019","journal-title":"Int. J. Ophthalmol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1111\/aos.12012","article-title":"Correlations between commonly used objective signs and symptoms for the diagnosis of dry eye disease: Clinical implications","volume":"92","author":"Sullivan","year":"2014","journal-title":"Acta Ophthalmol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1111\/aos.12985","article-title":"Evidence of seasonality and effects of psychrometry in dry eye disease","volume":"94","author":"Labetoulle","year":"2016","journal-title":"Acta Ophthalmol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1167\/tvst.10.9.1","article-title":"Evaluation of the Repeatability of the LacryDiag Ocular Surface Analyzer for Assessment of the Meibomian Glands and Tear Film","volume":"10","author":"Ward","year":"2021","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: A flexible trimmer for Illumina sequence data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.1923","article-title":"Fast gapped-read alignment with Bowtie 2","volume":"9","author":"Langmead","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1038\/nmeth.2066","article-title":"Metagenomic microbial community profiling using unique clade-specific marker genes","volume":"9","author":"Segata","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"The Human Microbiome Project Consortium (2012). A framework for human microbiome research. Nature, 486, 215\u2013221.","DOI":"10.1038\/nature11209"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Abubucker, S., Segata, N., Goll, J., Schubert, A.M., Izard, J., Cantarel, B.L., Rodriguez-Mueller, B., Zucker, J., Thiagarajan, M., and Henrissat, B. (2012). Metabolic reconstruction for metagenomic data and its application to the human microbiome. PLoS Comput. Biol., 8.","DOI":"10.1371\/journal.pcbi.1002358"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1038\/nbt.1511","article-title":"Maxquant Enables High Peptide Identification Rates, Individualized P.P.B.-Range Mass Accuracies and Proteome-Wide Protein Quantification","volume":"26","author":"Cox","year":"2008","journal-title":"Nat. Biotechnol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v022.i04","article-title":"The ade4 Package: Implementing the Duality Diagram for Ecologists","volume":"22","author":"Dray","year":"2007","journal-title":"J. Stat. Softw."},{"key":"ref_47","first-page":"32","article-title":"A new method for non-parametric multivariate analysis of variance","volume":"26","author":"Anderson","year":"2001","journal-title":"Austral Ecol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"R79","DOI":"10.1186\/gb-2012-13-9-r79","article-title":"Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment","volume":"13","author":"Morgan","year":"2012","journal-title":"Genome Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/18\/14091\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:50:49Z","timestamp":1760129449000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/18\/14091"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,14]]},"references-count":48,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["ijms241814091"],"URL":"https:\/\/doi.org\/10.3390\/ijms241814091","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,14]]}}}