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The molecular regulatory mechanisms governing host responses to MAP infection remain unclear. This study elucidated the roles of microRNAs (miRNAs) in the ileum (IL), ileal lymph node (ILLN), and liver of cows during subclinical MAP infection. Tissues (IL, ILLN, and liver) were collected from four JD-positive (JDP), five MAP-tolerant (MAPT), and five healthy control (HC) cows. MiRNA transcriptomes were analyzed using miRNA-sequencing, differential miRNA expression, correlation, and functional analyses. A total of 441, 405, and 201 miRNAs were identified in IL, ILLN, and liver, respectively, including 12 miRNAs highly expressed across all three tissues. ILLN exhibited more differentially expressed (DE) miRNAs, including 20 (JDP vs. HC), 21 (MAPT vs. HC), and 15 (JDP vs. MAPT) than the IL: 17 (JDP vs. HC), 8 (MAPT vs. HC), and 6 (JDP vs. MAPT). MiRNAs DE in both IL and ILLN (bta-miR-146b, bta-miR-375, bta-miR-21-5p, bta-miR-146a, bta-miR-125a, bta-miR-100, bta-miR-147, bta-miR-99a-5p, bta-miR-320 from JDP vs. HC, and bta-miR-146a, bta-let-7b from MAPT vs. HC comparisons) have roles in the immune process suggesting their potential impacts on the host response to MAP infection. The target genes of IL DE miRNAs were overrepresented in more gene ontology terms (68) while those of the ILLN were overrepresented in more pathways (20) demonstrating tissue specificity. In addition, the majority of DE miRNAs and overrepresented functional terms were unique to comparison groups and phenotypes while few were shared by two or more comparison groups and phenotype or infection status. Most of the functional terms such as cytokine receptor activity, regulation of leukocyte mediated immunity, T cell receptor signaling pathway, positive regulation of interleukin-4 production among others, have immune related functions revealing important roles of DE miRNAs in the host immune response to MAP infection. In summary, these findings underscore the pivotal regulatory roles of the identified miRNAs in shaping the host response of cows to JD. Moreover, the results indicated that mostly different sets of miRNAs, biological process and pathways were driving the JDP and MAPT phenotypes, as well as emphasize the tissue-specific nature of the miRNA response to JD, shedding light on the nuanced intricacies of host-pathogen interactions in response to MAP infection.\n                  <\/jats:p>","DOI":"10.1038\/s41598-025-23969-x","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T11:00:43Z","timestamp":1764759643000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["MicroRNA-mediated regulatory mechanisms in cow\u2019s ileum and ileum lymph node in response to Mycobacterium avium subspecies paratuberculosis infection"],"prefix":"10.1038","volume":"15","author":[{"given":"Mengqi","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Bissonnette","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pier-Luc","family":"Dudemaine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eveline M.","family":"Ibeagha-Awemu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,3]]},"reference":[{"key":"23969_CR1","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.cimid.2008.08.006","volume":"33","author":"S Kumar","year":"2010","unstructured":"Kumar, S. et al. 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