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In this study, we measured five blood biochemical indicators, including total cholesterol (CHOL), low-density lipoprotein cholesterol (LDL-CH), triglycerides (TG), high-density lipoprotein cholesterol (HDL-CH), and blood glucose (BG), as well as 19 growth traits of 206 male chickens. By integrating host whole-genome information and 16S rRNA sequencing of the duodenum, jejunum, ileum, cecum, and feces microbiota, we assessed the contributions of host genetics and gut microbiota to blood biochemical indicators and their interrelationships. Our results demonstrated significant negative phenotypic and genetic correlations (<jats:italic>r<\/jats:italic>\u2009=\u2009\u2009\u2212\u20090.20\u2009~\u2009\u2009\u2212\u20090.67) between CHOL and LDL-CH with growth traits such as body weight, abdominal fat content, muscle content, and shin circumference. The results of heritability and microbiability indicated that blood biochemical indicators were jointly regulated by host genetics and gut microbiota. Notably, the heritability of HDL-CH was estimated to be 0.24, while the jejunal microbiability for BG and TG reached 0.45 and 0.23. Furthermore, by conducting genome-wide association study (GWAS) with the single-nucleotide polymorphism (SNPs), insertion\/deletion (indels), and structural variation (SV), we identified RAP2C, member of the RAS oncogene family (<jats:italic>RAP2C)<\/jats:italic>, dedicator of cytokinesis 11 (<jats:italic>DOCK11<\/jats:italic>), neurotensin (<jats:italic>NTS<\/jats:italic>) and BOP1 ribosomal biogenesis factor (<jats:italic>BOP1<\/jats:italic>) as regulators of HDL-CH, and glycerophosphodiester phosphodiesterase domain containing 5 (<jats:italic>GDPD5<\/jats:italic>), dihydrodiol dehydrogenase (<jats:italic>DHDH<\/jats:italic>), and potassium voltage-gated channel interacting protein 1 (<jats:italic>KCNIP1<\/jats:italic>) as candidate genes of BG. Moreover, our findings suggest that cecal <jats:italic>RF39<\/jats:italic> and <jats:italic>Clostridia_UCG_014<\/jats:italic> may be linked to the regulation of CHOL, and jejunal <jats:italic>Streptococcaceae<\/jats:italic> may be involved in the regulation of TG. Additionally, microbial GWAS results indicated that the presence of gut microbiota was under host genetic regulation. Our findings provide valuable insights into the complex interaction between host genetics and microbiota in shaping the blood biochemical profile of chickens.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Key points<\/jats:title>\n                <jats:p><jats:italic>\u2022 Multiple candidate genes were identified for the regulation of CHOL, HDL-CH, and BG.<\/jats:italic><\/jats:p>\n                <jats:p><jats:italic>\u2022 RF39, Clostridia_UCG_014, and Streptococcaceae were implicated in CHOL and TG modulation.<\/jats:italic><\/jats:p>\n                <jats:p><jats:italic>\u2022 The composition of gut microbiota is influenced by host genetics.<\/jats:italic><\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00253-023-12814-8","type":"journal-article","created":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T11:01:44Z","timestamp":1696417304000},"page":"7601-7620","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Host genetics and gut microbiota jointly regulate blood biochemical indicators in chickens"],"prefix":"10.1007","volume":"107","author":[{"given":"Xinwei","family":"Jiang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boxuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangren","family":"Lan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Conghao","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaming","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaochang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junying","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoliang","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9673-9533","authenticated-orcid":false,"given":"Congjiao","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,10,4]]},"reference":[{"key":"12814_CR1","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.cell.2020.05.021","volume":"182","author":"M Alonge","year":"2020","unstructured":"Alonge M, Wang X, Benoit M, Soyk S, Pereira L, Zhang L, Suresh H, Ramakrishnan S, Maumus F, Ciren D, Levy Y, Harel TH, Shalev-Schlosser G, Amsellem Z, Razifard H, Caicedo AL, Tieman DM, Klee H, Kirsche M, Aganezov S, Ranallo-Benavidez TR, Lemmon ZH, Kim J, Robitaille G, Kramer M, Goodwin S, McCombie WR, Hutton S, Van Eck J, Gillis J, Eshed Y, Sedlazeck FJ, van der Knaap E, Schatz MC, Lippman ZB (2020) Major impacts of widespread structural variation on gene expression and crop improvement in tomato. 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