{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T11:20:58Z","timestamp":1789644058366,"version":"4.0.0"},"reference-count":42,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2013,9,17]],"date-time":"2013-09-17T00:00:00Z","timestamp":1379376000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"},{"start":{"date-parts":[[2013,9,17]],"date-time":"2013-09-17T00:00:00Z","timestamp":1379376000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Susceptibility to chronic inflammatory diseases is determined by immunogenetic and environmental risk factors. Resident microbial communities often differ between healthy and diseased states, but whether these differences are of primary aetiological importance or secondary to the altered inflammatory environment remains largely unknown. Here we provide evidence for host gene\u2013microbiota interactions contributing to disease risk in a mouse model of epidermolysis bullosa acquisita, an autoantibody-induced inflammatory skin disease. Using an advanced intercross, we identify genetic loci contributing to skin microbiota variability, susceptibility to skin blistering and their overlap. Furthermore, by treating bacterial species abundances as covariates with disease we reveal a novel disease locus. The majority of the identified covariate taxa are characterized by reduced abundance being associated with increased disease risk, providing evidence of a primary role in protection from disease. Further characterization of these putative probiotic species or species assemblages offers promising potential for preventative and therapeutic treatment development.<\/jats:p>","DOI":"10.1038\/ncomms3462","type":"journal-article","created":{"date-parts":[[2013,9,17]],"date-time":"2013-09-17T10:03:52Z","timestamp":1379412232000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":92,"title":["Genome-wide mapping of gene\u2013microbiota interactions in susceptibility to autoimmune skin blistering"],"prefix":"10.1038","volume":"4","author":[{"given":"Girish","family":"Srinivas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"M\u00f6ller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"K\u00fcnzel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Detlef","family":"Zillikens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John F.","family":"Baines","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saleh M.","family":"Ibrahim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2013,9,17]]},"reference":[{"key":"BFncomms3462_CR1","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1016\/j.meegid.2011.03.022","volume":"11","author":"M Rosenthal","year":"2011","unstructured":"Rosenthal, M., Goldberg, D., Aiello, A., Larson, E. & Foxman, B. Skin microbiota: microbial community structure and its potential association with health and disease. Infect. Genet. Evol. 11, 839\u2013848 (2011).","journal-title":"Infect. Genet. Evol."},{"key":"BFncomms3462_CR2","doi-asserted-by":"publisher","first-page":"1694","DOI":"10.1126\/science.1177486","volume":"326","author":"EK Costello","year":"2009","unstructured":"Costello, E. K. et al. Bacterial community variation in human body habitats across space and time. Science 326, 1694\u20131697 (2009).","journal-title":"Science"},{"key":"BFncomms3462_CR3","doi-asserted-by":"publisher","first-page":"18933","DOI":"10.1073\/pnas.1007028107","volume":"107","author":"AK Benson","year":"2010","unstructured":"Benson, A. K. et al. Individuality in gut microbiota composition is a complex polygenic trait shaped by multiple environmental and host genetic factors. Proc. Natl Acad. Sci. USA 107, 18933\u201318938 (2010).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms3462_CR4","doi-asserted-by":"publisher","first-page":"e39191","DOI":"10.1371\/journal.pone.0039191","volume":"7","author":"AM McKnite","year":"2012","unstructured":"McKnite, A. M. et al. Murine gut microbiota is defined by host genetics and modulates variation of metabolic traits. PLoS One 7, e39191 (2012).","journal-title":"PLoS One"},{"key":"BFncomms3462_CR5","doi-asserted-by":"publisher","first-page":"R43","DOI":"10.1093\/hmg\/ddh094","volume":"13 Spec No 1","author":"AM Bowcock","year":"2004","unstructured":"Bowcock, A. M. & Cookson, W. O. C. M. The genetics of psoriasis, psoriatic arthritis and atopic dermatitis. Hum. Mol. Genet. 13 Spec No 1, R43\u2013R55 (2004).","journal-title":"Hum. Mol. Genet."},{"key":"BFncomms3462_CR6","doi-asserted-by":"publisher","first-page":"91","DOI":"10.3109\/08916934.2011.606450","volume":"45","author":"M Chen","year":"2012","unstructured":"Chen, M., Kim, G. H., Prakash, L. & Woodley, D. T. Epidermolysis bullosa acquisita: autoimmunity to anchoring fibril collagen. Autoimmunity 45, 91\u2013101 (2012).","journal-title":"Autoimmunity"},{"key":"BFncomms3462_CR7","doi-asserted-by":"publisher","first-page":"1409","DOI":"10.1038\/jid.2011.466","volume":"132","author":"RJ Ludwig","year":"2012","unstructured":"Ludwig, R. J. et al. Identification of quantitative trait Loci in experimental epidermolysis bullosa acquisita. J. Invest. Dermatol. 132, 1409\u20131415 (2012).","journal-title":"J. Invest. Dermatol."},{"key":"BFncomms3462_CR8","doi-asserted-by":"publisher","first-page":"2393","DOI":"10.1111\/j.1582-4934.2009.00959.x","volume":"14","author":"G Hundorfean","year":"2010","unstructured":"Hundorfean, G., Neurath, M. F. & Sitaru, C. Autoimmunity against type VII collagen in inflammatory bowel disease. J. Cell Mol. Med. 14, 2393\u20132403 (2010).","journal-title":"J. Cell Mol. Med."},{"key":"BFncomms3462_CR9","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1038\/nrg1607","volume":"6","author":"S Schreiber","year":"2005","unstructured":"Schreiber, S., Rosenstiel, P., Albrecht, M., Hampe, J. & Krawczak, M. Genetics of Crohn disease, an archetypal inflammatory barrier disease. Nat. Rev. Genet. 6, 376\u2013388 (2005).","journal-title":"Nat. Rev. Genet."},{"key":"BFncomms3462_CR10","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1101\/gr.075549.107","volume":"18","author":"EA Grice","year":"2008","unstructured":"Grice, E. A. et al. A diversity profile of the human skin microbiota. Genome Res. 18, 1043\u20131050 (2008).","journal-title":"Genome Res."},{"key":"BFncomms3462_CR11","doi-asserted-by":"publisher","first-page":"2927","DOI":"10.1073\/pnas.0607077104","volume":"104","author":"Z Gao","year":"2007","unstructured":"Gao, Z., Tseng, C., Pei, Z. & Blaser, M. J. Molecular analysis of human forearm superficial skin bacterial biota. Proc. Natl Acad. Sci. USA 104, 2927\u20132932 (2007).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms3462_CR12","doi-asserted-by":"publisher","first-page":"17994","DOI":"10.1073\/pnas.0807920105","volume":"105","author":"N Fierer","year":"2008","unstructured":"Fierer, N., Hamady, M., Lauber, C. L. & Knight, R. The influence of sex, handedness, and washing on the diversity of hand surface bacteria. Proc. Natl Acad. Sci. USA 105, 17994\u201317999 (2008).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms3462_CR13","first-page":"121","volume":"2","author":"DP Faith","year":"2006","unstructured":"Faith, D. P. & Baker, A. M. Phylogenetic diversity (PD) and biodiversity conservation: some bioinformatics challenges. Evol. Bioinform. 2, 121\u2013128 (2006).","journal-title":"Evol. Bioinform."},{"key":"BFncomms3462_CR14","doi-asserted-by":"publisher","first-page":"8228","DOI":"10.1128\/AEM.71.12.8228-8235.2005","volume":"71","author":"C Lozupone","year":"2005","unstructured":"Lozupone, C. & Knight, R. UniFrac: a new phylogenetic method for comparing microbial communities. Appl. Environ. Microbiol. 71, 8228\u20138235 (2005).","journal-title":"Appl. Environ. Microbiol."},{"key":"BFncomms3462_CR15","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1038\/ismej.2009.97","volume":"4","author":"M Hamady","year":"2010","unstructured":"Hamady, M., Lozupone, C. & Knight, R. Fast UniFrac: facilitating high-throughput phylogenetic analyses of microbial communities including analysis of pyrosequencing and PhyloChip data. ISME J. 4, 17\u201327 (2010).","journal-title":"ISME J."},{"key":"BFncomms3462_CR16","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1093\/genetics\/151.1.373","volume":"151","author":"J Dupuis","year":"1999","unstructured":"Dupuis, J. & Siegmund, D. Statistical methods for mapping quantitative trait loci from a dense set of markers. Genetics 151, 373\u2013386 (1999).","journal-title":"Genetics"},{"key":"BFncomms3462_CR17","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","volume":"Ser. B 57","author":"Y Benjamini","year":"1995","unstructured":"Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: A practical and powerful approach to multiple testing. J. R Statis. Soc. Ser. B 57, 289\u2013289 (1995).","journal-title":"J. R Statis. Soc."},{"key":"BFncomms3462_CR18","doi-asserted-by":"publisher","first-page":"2076","DOI":"10.1126\/science.1081902","volume":"299","author":"C Picard","year":"2003","unstructured":"Picard, C. et al. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 299, 2076\u20132079 (2003).","journal-title":"Science"},{"key":"BFncomms3462_CR19","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1016\/j.cell.2006.02.015","volume":"124","author":"S Akira","year":"2006","unstructured":"Akira, S., Uematsu, S. & Takeuchi, O. Pathogen recognition and innate immunity. Cell 124, 783\u2013801 (2006).","journal-title":"Cell"},{"key":"BFncomms3462_CR20","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/j.cell.2004.07.002","volume":"118","author":"S Rakoff-Nahoum","year":"2004","unstructured":"Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. & Medzhitov, R. Recognition of commensal microflora by Toll-like receptors is required for intestinal homeostasis. Cell 118, 229\u2013241 (2004).","journal-title":"Cell"},{"key":"BFncomms3462_CR21","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1038\/sj.jid.5701102","volume":"128","author":"J Schauber","year":"2007","unstructured":"Schauber, J. et al. Histone acetylation in keratinocytes enables control of the expression of cathelicidin and CD14 by 1,25-dihydroxyvitamin D3. J. Invest. Dermatol. 128, 816\u2013824 (2007).","journal-title":"J. Invest. Dermatol."},{"key":"BFncomms3462_CR22","doi-asserted-by":"publisher","first-page":"5541","DOI":"10.1128\/IAI.71.10.5541-5548.2003","volume":"71","author":"SH Han","year":"2003","unstructured":"Han, S. H., Kim, J. H., Martin, M., Michalek, S. M. & Nahm, M. H. Pneumococcal lipoteichoic acid (LTA) is not as potent as staphylococcal LTA in stimulating Toll-like receptor 2. Infect. Immun. 71, 5541\u20135548 (2003).","journal-title":"Infect. Immun."},{"key":"BFncomms3462_CR23","doi-asserted-by":"publisher","first-page":"1673","DOI":"10.1084\/jem.182.6.1673","volume":"182","author":"T Kusunoki","year":"1995","unstructured":"Kusunoki, T., Hailman, E., Juan, T. S., Lichenstein, H. S. & Wright, S. D. Molecules from Staphylococcus aureus that bind CD14 and stimulate innate immune responses. J. Exp. Med. 182, 1673\u20131682 (1995).","journal-title":"J. Exp. Med."},{"key":"BFncomms3462_CR24","doi-asserted-by":"publisher","first-page":"15587","DOI":"10.1074\/jbc.M212829200","volume":"278","author":"NWJ Schr\u00f6der","year":"2003","unstructured":"Schr\u00f6der, N. W. J. et al. Lipoteichoic acid (LTA) of Streptococcus pneumoniae and Staphylococcus aureus activates immune cells via Toll-like receptor (TLR)-2, lipopolysaccharide-binding protein (LBP), and CD14, whereas TLR-4 and MD-2 are not involved. J. Biol. Chem. 278, 15587\u201315594 (2003).","journal-title":"J. Biol. Chem."},{"key":"BFncomms3462_CR25","doi-asserted-by":"publisher","first-page":"1243","DOI":"10.1093\/rheumatology\/kem096","volume":"46","author":"JR Garc\u00eda-Lozano","year":"2007","unstructured":"Garc\u00eda-Lozano, J. R. et al. Caspase 7 influences susceptibility to rheumatoid arthritis. Rheumatology 46, 1243\u20131247 (2007).","journal-title":"Rheumatology"},{"key":"BFncomms3462_CR26","first-page":"1912","volume":"35","author":"VH Teixeira","year":"2008","unstructured":"Teixeira, V. H. et al. Genetic and expression analysis of CASP7 gene in a European Caucasian population with rheumatoid arthritis. J. Rheumatol. 35, 1912\u20131918 (2008).","journal-title":"J. Rheumatol."},{"key":"BFncomms3462_CR27","doi-asserted-by":"publisher","first-page":"e1000361","DOI":"10.1371\/journal.ppat.1000361","volume":"5","author":"A Akhter","year":"2009","unstructured":"Akhter, A. et al. Caspase-7 activation by the Nlrc4\/Ipaf inflammasome restricts Legionella pneumophila infection. PLoS Pathog. 5, e1000361 (2009).","journal-title":"PLoS Pathog."},{"key":"BFncomms3462_CR28","doi-asserted-by":"publisher","first-page":"850","DOI":"10.1101\/gr.131029.111","volume":"22","author":"HH Kong","year":"2012","unstructured":"Kong, H. H. et al. Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis. Genome Res. 22, 850\u2013859 (2012).","journal-title":"Genome Res."},{"key":"BFncomms3462_CR29","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1111\/bjd.12322","volume":"169","author":"L Fry","year":"2013","unstructured":"Fry, L., Baker, B. S., Powles, A. V., Fahlen, A. & Engstrand, L. Is chronic plaque psoriasis triggered by microbiota in the skin? Br. J. Dermatol. 169, 47\u201352 (2013).","journal-title":"Br. J. Dermatol."},{"key":"BFncomms3462_CR30","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1111\/j.1087-0024.2004.00833.x","volume":"9","author":"V Aoki","year":"2004","unstructured":"Aoki, V. et al. Environmental risk factors in endemic pemphigus foliaceus (fogo selvagem). J. Investig. Dermatol. Symp. Proc. 9, 34\u201340 (2004).","journal-title":"J. Investig. Dermatol. Symp. Proc."},{"key":"BFncomms3462_CR31","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1136\/jmg.2011.089730","volume":"48","author":"F Asghari","year":"2011","unstructured":"Asghari, F. et al. Identification of quantitative trait loci for murine autoimmune pancreatitis. J. Med. Genet. 48, 557\u2013562 (2011).","journal-title":"J. Med. Genet."},{"key":"BFncomms3462_CR32","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/0022-2836(81)90087-5","volume":"147","author":"TF Smith","year":"1981","unstructured":"Smith, T. F. & Waterman, M. S. Identification of common molecular subsequences. J. Mol. Biol. 147, 195\u2013197 (1981).","journal-title":"J. Mol. Biol."},{"key":"BFncomms3462_CR33","doi-asserted-by":"publisher","first-page":"5261","DOI":"10.1128\/AEM.00062-07","volume":"73","author":"Q Wang","year":"2007","unstructured":"Wang, Q., Garrity, G. M., Tiedje, J. M. & Cole, J. R. Naive Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy. Appl. Environ. Microbiol. 73, 5261\u20135267 (2007).","journal-title":"Appl. Environ. Microbiol."},{"key":"BFncomms3462_CR34","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1038\/nmeth.f.303","volume":"7","author":"JG Caporaso","year":"2010","unstructured":"Caporaso, J. G. et al. QIIME allows analysis of high-throughput community sequencing data. Nat. Methods 7, 335\u2013336 (2010).","journal-title":"Nat. Methods"},{"key":"BFncomms3462_CR35","doi-asserted-by":"publisher","first-page":"12649","DOI":"10.1073\/pnas.230304397","volume":"97","author":"R Mott","year":"2000","unstructured":"Mott, R., Talbot, C. J., Turri, M. G., Collins, A. C. & Flint, J. A method for fine mapping quantitative trait loci in outbred animal stocks. Proc. Natl Acad. Sci. USA 97, 12649\u201312654 (2000).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms3462_CR36","doi-asserted-by":"publisher","first-page":"2630","DOI":"10.1002\/art.30425","volume":"63","author":"AK Johnsen","year":"2011","unstructured":"Johnsen, A. K. et al. Genome-wide and species-wide dissection of the genetics of arthritis severity in heterogeneous stock mice. Arthritis. Rheum. 63, 2630\u20132640 (2011).","journal-title":"Arthritis. Rheum."},{"key":"BFncomms3462_CR37","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1038\/ng1840","volume":"38","author":"W Valdar","year":"2006","unstructured":"Valdar, W. et al. Genome-wide genetic association of complex traits in heterogeneous stock mice. Nat. Genet. 38, 879\u2013887 (2006).","journal-title":"Nat. Genet."},{"key":"BFncomms3462_CR38","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1186\/1471-2148-11-95","volume":"11","author":"AM Graham","year":"2011","unstructured":"Graham, A. M. et al. Support for the reproductive ground plan hypothesis of social evolution and major QTL for ovary traits of Africanized worker honey bees (Apis mellifera L.). BMC Evol. Biol. 11, 95 (2011).","journal-title":"BMC Evol. Biol."},{"key":"BFncomms3462_CR39","doi-asserted-by":"publisher","first-page":"1639","DOI":"10.1101\/gr.092759.109","volume":"19","author":"M Krzywinski","year":"2009","unstructured":"Krzywinski, M. et al. Circos: an information aesthetic for comparative genomics. Genome Res. 19, 1639\u20131645 (2009).","journal-title":"Genome Res."},{"key":"BFncomms3462_CR40","doi-asserted-by":"crossref","unstructured":"Tuomisto, H. A diversity of beta diversities: straightening up a concept gone awry. Part 1. Defining beta diversity as a function of alpha and gamma diversity. Ecography 2\u201322 (2010).","DOI":"10.1111\/j.1600-0587.2009.05880.x"},{"key":"BFncomms3462_CR41","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1111\/j.1654-1103.2003.tb02228.x","volume":"14","author":"P Dixon","year":"2003","unstructured":"Dixon, P. VEGAN, a package of R functions for community ecology. J. Veget. Sci. 14, 927\u2013930 (2003).","journal-title":"J. Veget. Sci."},{"key":"BFncomms3462_CR42","doi-asserted-by":"crossref","unstructured":"Bray, J. & Curtis, J. An ordination of the upland forest communities of southern Wisconsin. Ecol. Monogr. 325\u2013349 (1957).","DOI":"10.2307\/1942268"}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/ncomms3462.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms3462","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms3462.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T22:39:23Z","timestamp":1715985563000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/ncomms3462"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,9,17]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2013,12,20]]}},"alternative-id":["BFncomms3462"],"URL":"https:\/\/doi.org\/10.1038\/ncomms3462","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,9,17]]},"assertion":[{"value":"15 May 2013","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 August 2013","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 September 2013","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"2462"}}