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Only two antibiotics are currently recommended for treating <jats:italic>C. difficile<\/jats:italic> infection (CDI), which may contribute to unsatisfactory treatment outcomes and an increased likelihood of recurrence. In this study, we aim to evaluate the difference in gene expression between symptomatic and asymptomatic mice after infection with <jats:italic>C. difficile<\/jats:italic> using spatial transcriptomics analysis. We also aim to evaluate the spatial aspect of altered genes between different layers of intestinal mucosa (superficial vs. deep) and identify the key pathways. Formalin-fixed paraffin-embedded (FFPE) intestinal sections were utilized for analysis using NanoString<jats:sup>TM<\/jats:sup>\u00a0platform to evaluate differential gene expressions in the caecum and colon. The IL-17 pathway, including <jats:italic>Lcn2<\/jats:italic>, <jats:italic>Cxcl2<\/jats:italic>, and <jats:italic>S100a8<\/jats:italic> genes, was significantly upregulated in symptomatic mice. The IL-17 signaling pathway activated downstream signaling through NF-\u03baB and MAPK pathways. Gene expression was significantly altered between the intestinal superficial and deep mucosal layers, highlighting layer-specific differences in gene expression patterns in the intestines of symptomatic and asymptomatic mice. Gene expression patterns in the enteric mucosa explain several clinical signs and lesions in CDI mice.<\/jats:p>","DOI":"10.1038\/s41598-025-19106-3","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T11:26:12Z","timestamp":1759922772000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Proinflammatory pathways contribute to the pathogenesis of Clostridioides difficile infection in a murine model using Spatial transcriptomics"],"prefix":"10.1038","volume":"15","author":[{"given":"Niloufar","family":"Ghahari","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjeev","family":"Narayanan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"AbdelKhalek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepti","family":"Pillai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,8]]},"reference":[{"key":"19106_CR1","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1016\/j.gtc.2021.02.010","volume":"50","author":"CLR Abad","year":"2021","unstructured":"Abad, C. 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