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The HS microbiome is polymicrobial with an abundance of commensal gram\u2010positive facultative (GPs) <jats:italic>Staphylococcus<\/jats:italic> species and gram\u2010negative anaerobic (GNA) bacteria like <jats:italic>Prevotella<\/jats:italic>, <jats:italic>Fusobacterium<\/jats:italic> and <jats:italic>Porphyromonas<\/jats:italic> with increasing predominance of GNAs with disease severity. We sought to define the keratinocyte response to bacteria commonly isolated from HS lesions to probe pathogenic relationships between HS and the microbiome. Type strains of <jats:italic>Prevotella nigrescens<\/jats:italic>, <jats:italic>Prevotella melaninogenica<\/jats:italic>, <jats:italic>Prevotella intermedia<\/jats:italic>, <jats:italic>Prevotella asaccharolytica<\/jats:italic>, <jats:italic>Fusobacterium nucleatum<\/jats:italic>, as well as <jats:italic>Staphylococcus aureus<\/jats:italic> and the normal skin commensal <jats:italic>Staphylococcus epidermidis<\/jats:italic> were heat\u2010killed and co\u2010incubated with normal human keratinocytes. RNA was collected and analysed using RNAseq and RT\u2010qPCR. The supernatant was collected from cell culture for protein quantification. Transcriptomic profiles between HS clinical samples and stimulated keratinocytes were compared. Co\u2010staining of patient HS frozen sections was used to localize bacteria in lesions. A mouse intradermal injection model was used to investigate early immune recruitment. TLR4 and JAK inhibitors were used to investigate mechanistic avenues of bacterial response inhibition. GNAs, especially <jats:italic>F.\u2009nucleatum<\/jats:italic>, stimulated vastly higher <jats:italic>CXCL8<\/jats:italic>, <jats:italic>IL17C<\/jats:italic>, <jats:italic>CCL20<\/jats:italic>, <jats:italic>IL6<\/jats:italic>, <jats:italic>TNF<\/jats:italic> and <jats:italic>IL36\u03b3<\/jats:italic> transcription in normal skin keratinocytes than the GPs <jats:italic>S. epidermidis<\/jats:italic> and <jats:italic>S. aureus<\/jats:italic>. Using RNAseq, we found that <jats:italic>F.\u2009nucleatum<\/jats:italic> (and <jats:italic>Prevotella<\/jats:italic>) strongly induced the IL\u201017 pathway in keratinocytes and overlapped with transcriptome profiles of HS patient clinical samples. Bacteria were juxtaposed to activated keratinocytes in\u00a0vivo, and <jats:italic>F.\u2009nucleatum<\/jats:italic> strongly recruited murine neutrophil and macrophage migration. Both the TLR4 and pan\u2010JAK inhibitors reduced cytokine production. Detailed transcriptomic profiling of healthy skin keratinocytes exposed to GNAs prevalent in HS revealed a potent, extensive inflammatory response vastly stronger than GPs. GNAs stimulated HS\u2010relevant genes, including many genes in the IL\u201017 response pathway, and were significantly associated with HS tissue transcriptomes. The close association of activated keratinocytes with bacteria in HS lesions and innate infiltration in murine skin cemented GNA pathogenic potential. These novel mechanistic insights could drive future targeted therapies.<\/jats:p>","DOI":"10.1111\/exd.15087","type":"journal-article","created":{"date-parts":[[2024,4,30]],"date-time":"2024-04-30T06:39:59Z","timestamp":1714459199000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Gram\u2010negative anaerobes elicit a robust keratinocytes immune response with potential insights into <scp>HS<\/scp> pathogenesis"],"prefix":"10.1111","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1916-1579","authenticated-orcid":false,"given":"Samuel C.","family":"Williams","sequence":"first","affiliation":[{"name":"Laboratory of Investigative Dermatology The Rockefeller University  New York New York USA"},{"name":"The Rockefeller University\u2010Memorial Sloan Kettering\u2010Weill Cornell Medicine Tri\u2010Institutional MD\u2010PhD Program  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Garcet","sequence":"additional","affiliation":[{"name":"Laboratory of Investigative Dermatology The Rockefeller University  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Hur","sequence":"additional","affiliation":[{"name":"Laboratory of Investigative Dermatology The Rockefeller University  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunsuke","family":"Miura","sequence":"additional","affiliation":[{"name":"Laboratory of Investigative Dermatology The Rockefeller University  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juana","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Laboratory of Investigative Dermatology The Rockefeller University  New York New York 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory of Investigative Dermatology The Rockefeller University  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Frew","sequence":"additional","affiliation":[{"name":"Laboratory of Investigative Dermatology The Rockefeller University  New York New York USA"},{"name":"Department of Dermatology, Liverpool Hospital University of New South Wales  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent A.","family":"Fischetti","sequence":"additional","affiliation":[{"name":"Laboratory of Bacterial Pathogenesis and Immunology The Rockefeller University  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uri","family":"Sela","sequence":"additional","affiliation":[{"name":"Laboratory of Bacterial Pathogenesis and 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