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The gastrointestinal microbiota and its metabolites can modulate the host\u2019s physiology and immune system. Recent research demonstrated the role of commensal bacteria and short-chain fatty acids (SCFAs) in developing resistance to Salmonella infection and colonization. However, the complex interactions among chicken, Salmonella, host\u2013microbiome, and microbial metabolites remain unelucidated. Therefore, this study aimed to explore these complex interactions by identifying the driver and hub genes highly correlated with factors that confer resistance to Salmonella. Differential gene expression (DEGs) and dynamic developmental genes (DDGs) analyses and weighted gene co-expression network analysis (WGCNA) were performed using transcriptome data from the cecum of Salmonella Enteritidis-infected chicken at 7 and 21 days after infection. Furthermore, we identified the driver and hub genes associated with important traits such as the heterophil\/lymphocyte (H\/L) ratio, body weight post-infection, bacterial load, propionate and valerate cecal contents, and Firmicutes, Bacteroidetes, and Proteobacteria cecal relative abundance. Among the multiple genes detected in this study, EXFABP, S100A9\/12, CEMIP, FKBP5, MAVS, FAM168B, HESX1, EMC6, and others were found as potential candidate gene and transcript (co-) factors for resistance to Salmonella infection. In addition, we found that the PPAR and oxidative phosphorylation (OXPHOS) metabolic pathways were also involved in the host\u2019s immune response\/defense against Salmonella colonization at the earlier and later stage post-infection, respectively. This study provides a valuable resource of transcriptome profiles from chicken cecum at the earlier and later stage post-infection and mechanistic understanding of the complex interactions among chicken, Salmonella, host\u2013microbiome, and associated metabolites.<\/jats:p>","DOI":"10.3390\/ijms24054824","type":"journal-article","created":{"date-parts":[[2023,3,2]],"date-time":"2023-03-02T03:29:00Z","timestamp":1677727740000},"page":"4824","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Gene Co-Expression Network Analysis Reveals the Hub Genes and Key Pathways Associated with Resistance to Salmonella Enteritidis Colonization in Chicken"],"prefix":"10.3390","volume":"24","author":[{"given":"Qiao","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2533-3720","authenticated-orcid":false,"given":"Mamadou","family":"Thiam","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Astrid Lissette","family":"Barreto S\u00e1nchez","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zixuan","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qinghe","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Wen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guiping","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1080\/03079457.2012.718071","article-title":"The long view: Salmonella--the last forty years","volume":"41","author":"Barrow","year":"2012","journal-title":"Avian Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"261","DOI":"10.3389\/fgene.2012.00261","article-title":"Toward integrative genomics study of genetic resistance to Salmonella and Campylobacter intestinal colonization in fowl","volume":"3","author":"Calenge","year":"2012","journal-title":"Front. 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