{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T15:17:30Z","timestamp":1783351050413,"version":"3.54.6"},"reference-count":49,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T00:00:00Z","timestamp":1718582400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation","doi-asserted-by":"publisher","award":["32272899"],"award-info":[{"award-number":["32272899"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The aryl hydrocarbon receptor (AhR) is a transcription factor that regulates the immune system through complicated transcriptional programs. Genistein, an AhR ligand, exhibits anti-inflammatory properties. However, its role in modulating immune responses via the AhR signaling pathway remains unclear. In this study, 360 male Arbor Acre broilers (1-day-old) were fed a basal diet supplemented with 40 or 80 mg\/kg genistein and infected with or without Clostridium perfringens (Cp). Our results demonstrated that genistein ameliorated Cp-induced intestinal damage, as reflected by the reduced intestinal lesion scores and improved intestinal morphology and feed-to-gain ratio. Moreover, genistein increased intestinal sIgA, TGF-\u03b2, and IL-10, along with elevated serum IgG, IgA, and lysozyme levels. Genistein improved intestinal AhR and cytochrome P450 family 1 subfamily A member 1 (CYP1A1) protein levels and AhR+ cell numbers in Cp-challenged broilers. The increased number of AhR+CD163+ cells in the jejunum suggested a potential association between genistein-induced AhR activation and anti-inflammatory effects mediated through M2 macrophage polarization. In IL-4-treated RAW264.7 cells, genistein increased the levels of AhR, CYP1A1, CD163, and arginase (Arg)-1 proteins, as well as IL-10 mRNA levels. This increase was attenuated by the AhR antagonist CH223191. In summary, genistein activated the AhR signaling pathway in M2 macrophages, which enhanced the secretion of anti-inflammatory cytokines and attenuated intestinal damage in Cp-infected broilers Cp.<\/jats:p>","DOI":"10.3390\/ijms25126656","type":"journal-article","created":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T11:14:16Z","timestamp":1718622856000},"page":"6656","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Genistein Promotes M2 Macrophage Polarization via Aryl Hydrocarbon Receptor and Alleviates Intestinal Inflammation in Broilers with Necrotic Enteritis"],"prefix":"10.3390","volume":"25","author":[{"given":"Shuli","family":"Quan","sequence":"first","affiliation":[{"name":"College of Animal Science & Technology, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingxi","family":"Huang","sequence":"additional","affiliation":[{"name":"College of Animal Science & Technology, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guiqin","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Animal Science & Technology, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anrong","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Animal Science & Technology, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Animal Science & Technology, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenlong","family":"Wu","sequence":"additional","affiliation":[{"name":"College of Animal Science & Technology, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1038\/s41577-019-0125-8","article-title":"The aryl hydrocarbon receptor: An environmental sensor integrating immune responses in health and disease","volume":"19","author":"Rothhammer","year":"2019","journal-title":"Nat. Rev. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1146\/annurev.cellbio.12.1.55","article-title":"Ah receptor signaling pathways","volume":"12","author":"Schmidt","year":"1996","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1038\/s41586-019-0899-7","article-title":"Interleukin-22 protects intestinal stem cells against genotoxic stress","volume":"566","author":"Gronke","year":"2019","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.lfs.2016.05.001","article-title":"Aryl hydrocarbon receptor influences nitric oxide and arginine production and alters M1\/M2 macrophage polarization","volume":"155","author":"Gonzalez","year":"2016","journal-title":"Life Sci."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Cui, X., Ye, Z., Wang, D., Yang, Y., Jiao, C., Ma, J., Tang, N., and Zhang, H. (2022). Aryl hydrocarbon receptor activation ameliorates experimental colitis by modulating the tolerogenic dendritic and regulatory T cell formation. Cell Biosci., 12.","DOI":"10.1186\/s13578-022-00780-z"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/j.cell.2011.09.025","article-title":"Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation","volume":"147","author":"Li","year":"2011","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1126\/science.1214914","article-title":"Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles","volume":"334","author":"Kiss","year":"2011","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1038\/nature21080","article-title":"Feedback control of AHR signalling regulates intestinal immunity","volume":"542","author":"Schiering","year":"2017","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"112135","DOI":"10.1016\/j.celrep.2023.112135","article-title":"Dietary tryptophan deficiency promotes gut RORgammat(+) Treg cells at the expense of Gata3(+) Treg cells and alters commensal microbiota metabolism","volume":"42","author":"Rankin","year":"2023","journal-title":"Cell Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/j.immuni.2023.01.023","article-title":"Repression of the aryl-hydrocarbon receptor prevents oxidative stress and ferroptosis of intestinal intraepithelial lymphocytes","volume":"56","author":"Panda","year":"2023","journal-title":"Immunity"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1418s","DOI":"10.1093\/ajcn\/68.6.1418S","article-title":"Mechanisms of action of the soy isoflavone genistein: Emerging role for its effects via transforming growth factor beta signaling pathways","volume":"68","author":"Kim","year":"1998","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2163838","DOI":"10.1155\/2019\/2163838","article-title":"Dietary Genistein Could Modulate Hypothalamic Circadian Entrainment, Reduce Body Weight, and Improve Glucose and Lipid Metabolism in Female Mice","volume":"2019","author":"Zhou","year":"2019","journal-title":"Int. J. Endocrinol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Zhang, M., Kou, J., Wu, Y., Wang, M., Zhou, X., Yang, Y., and Wu, Z. (2020). Dietary genistein supplementation improves intestinal mucosal barrier function in Escherichia coli O78-challenged broilers. J. Nutr. Biochem., 77.","DOI":"10.1016\/j.jnutbio.2019.108267"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.intimp.2013.07.013","article-title":"Phytoestrogens mediated anti-inflammatory effect through suppression of IRF-1 and pSTAT1 expressions in lipopolysaccharide-activated microglia","volume":"17","author":"Jantaratnotai","year":"2013","journal-title":"Int. Immunopharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.jns.2008.12.007","article-title":"Inhibition of hemolysate-induced iNOS and COX-2 expression by genistein through suppression of NF-small ka, CyrillicB activation in primary astrocytes","volume":"278","author":"Lu","year":"2009","journal-title":"J. Neurol. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"40249","DOI":"10.1021\/acsami.1c09215","article-title":"Genistein-Derived ROS-Responsive Nanoparticles Relieve Colitis by Regulating Mucosal Homeostasis","volume":"13","author":"Fan","year":"2021","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e2100209","DOI":"10.1002\/mnfr.202100209","article-title":"Genistein Inhibits Colonic Goblet Cell Loss and Colorectal Inflammation Induced by Salmonella Typhimurium Infection","volume":"65","author":"He","year":"2021","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"820969","DOI":"10.3389\/fphar.2022.820969","article-title":"Genistein: A Review on its Anti-Inflammatory Properties","volume":"13","author":"Goh","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1017\/S1751731116000562","article-title":"In vivo immunomodulatory effects of plant flavonoids in lipopolysaccharide-challenged broilers","volume":"10","author":"Kamboh","year":"2016","journal-title":"Animal"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.aca.2008.09.054","article-title":"Food flavonoid aryl hydrocarbon receptor-mediated agonistic\/antagonistic\/synergic activities in human and rat reporter gene assays","volume":"637","author":"Bechoux","year":"2009","journal-title":"Anal. Chim. Acta"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.1021\/jf204625y","article-title":"Dietary Flavonoid Naringenin Induces Regulatory T Cells via an Aryl Hydrocarbon Receptor Mediated Pathway","volume":"60","author":"Wang","year":"2012","journal-title":"J. Agric. Food. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"331","DOI":"10.4149\/gpb_2015008","article-title":"Agonistic effect of selected isoflavones on arylhydrocarbon receptor in a novel AZ-AhR transgenic gene reporter human cell line","volume":"34","author":"Bialesova","year":"2015","journal-title":"Gen. Physiol. Biophys."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.mce.2016.08.025","article-title":"Estrogen receptor-\u03b1 and aryl hydrocarbon receptor involvement in the actions of botanical estrogens in target cells","volume":"437","author":"Gong","year":"2016","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.tim.2008.09.005","article-title":"Rethinking our understanding of the pathogenesis of necrotic enteritis in chickens","volume":"17","author":"Rood","year":"2009","journal-title":"Trends Microbiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1080\/03079457.2016.1150587","article-title":"Necrotic enteritis predisposing factors in broiler chickens","volume":"45","author":"Moore","year":"2016","journal-title":"Avian Pathol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6425","DOI":"10.1002\/jcp.26429","article-title":"Macrophage plasticity, polarization, and function in health and disease","volume":"233","author":"Mohammadian","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.immuni.2022.01.006","article-title":"Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity","volume":"55","author":"Hezaveh","year":"2022","journal-title":"Immunity"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.mib.2020.08.003","article-title":"Immunoglobulin A and the microbiome","volume":"56","author":"Yang","year":"2020","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1016\/j.tim.2021.01.012","article-title":"Crosstalk between sIgA-Coated Bacteria in Infant Gut and Early-Life Health","volume":"29","author":"Ding","year":"2021","journal-title":"Trends Microbiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.canlet.2015.07.009","article-title":"The paradoxical role of IL-10 in immunity and cancer","volume":"367","author":"Mannino","year":"2015","journal-title":"Cancer Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1126\/science.aai8132","article-title":"Macrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells","volume":"356","author":"Bosurgi","year":"2017","journal-title":"Science"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"520","DOI":"10.3389\/fimmu.2014.00520","article-title":"IgG subclasses and allotypes: From structure to effector functions","volume":"5","author":"Vidarsson","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Ragland, S.A., and Criss, A.K. (2017). From bacterial killing to immune modulation: Recent insights into the functions of lysozyme. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006512"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5161","DOI":"10.1038\/s41598-018-23530-z","article-title":"Dietary genistein supplementation for breeders and their offspring improves the growth performance and immune function of broilers","volume":"8","author":"Lv","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.jnutbio.2018.08.009","article-title":"Soy genistein administered in soluble chitosan microcapsules maintains antioxidant activity and limits intestinal inflammation","volume":"62","author":"Nunez","year":"2018","journal-title":"J. Nutr. Biochem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1016\/j.it.2018.10.010","article-title":"The Aryl Hydrocarbon Receptor: Connecting Immunity to the Microenvironment","volume":"39","author":"Shinde","year":"2018","journal-title":"Trends Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1007\/s12016-020-08789-3","article-title":"The Aryl Hydrocarbon Receptor (AHR) as a Potential Target for the Control of Intestinal Inflammation: Insights from an Immune and Bacteria Sensor Receptor","volume":"59","author":"Pernomian","year":"2020","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Trikha, P., and Lee, D.A. (2020). The role of AhR in transcriptional regulation of immune cell development and function. Biochim. Biophys. Acta-Rev. Cancer, 1873.","DOI":"10.1016\/j.bbcan.2019.188335"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1289\/ehp.6322","article-title":"Flavonoids as Aryl Hydrocarbon Receptor Agonists\/Antagonists: Effects of Structure and Cell Context","volume":"111","author":"Zhang","year":"2003","journal-title":"Environ. Health. Perspect."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e562","DOI":"10.3945\/cdn.117.000562","article-title":"Genistein Prevents BRCA1 CpG Methylation and Proliferation in Human Breast Cancer Cells with Activated Aromatic Hydrocarbon Receptor","volume":"1","author":"Romagnolo","year":"2017","journal-title":"Curr. Dev. Nutr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/nature14452","article-title":"Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation","volume":"523","author":"Gagliani","year":"2015","journal-title":"Nature"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.jhep.2020.06.044","article-title":"Altered aryl-hydrocarbon-receptor signalling affects regulatory and effector cell immunity in autoimmune hepatitis","volume":"74","author":"Vuerich","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Dang, G., Wen, X., Zhong, R., Wu, W., Tang, S., Li, C., Yi, B., Chen, L., Zhang, H., and Schroyen, M. (2023). Pectin modulates intestinal immunity in a pig model via regulating the gut microbiota-derived tryptophan metabolite-AhR-IL22 pathway. J. Anim. Sci. Biotechnol., 14.","DOI":"10.1186\/s40104-023-00838-z"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.stem.2013.09.006","article-title":"Mesenchymal stromal cells: Sensors and switchers of inflammation","volume":"13","author":"Bernardo","year":"2013","journal-title":"Cell Stem Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.3389\/fimmu.2018.01713","article-title":"Aryl Hydrocarbon Receptor Regulates Apoptosis and Inflammation in a Murine Model of Experimental Autoimmune Uveitis","volume":"9","author":"Huang","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Abron, J.D., Singh, N.P., Price, R.L., Nagarkatti, M., Nagarkatti, P.S., and Singh, U.P. (2018). Genistein induces macrophage polarization and systemic cytokine to ameliorate experimental colitis. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0199631"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.immuni.2014.06.008","article-title":"Macrophage activation and polarization: Nomenclature and experimental guidelines","volume":"41","author":"Murray","year":"2014","journal-title":"Immunity"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4347","DOI":"10.2147\/JIR.S329091","article-title":"The Flavonoid Kurarinone Regulates Macrophage Functions via Aryl Hydrocarbon Receptor and Alleviates Intestinal Inflammation in Irritable Bowel Syndrome","volume":"14","author":"Xu","year":"2021","journal-title":"J. Inflamm. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1093\/ps\/84.12.1875","article-title":"Dietary glycine concentration affects intestinal Clostridium perfringens and lactobacilli populations in broiler chickens","volume":"84","author":"Dahiya","year":"2005","journal-title":"Poult. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/12\/6656\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:00:07Z","timestamp":1760108407000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/12\/6656"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,17]]},"references-count":49,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["ijms25126656"],"URL":"https:\/\/doi.org\/10.3390\/ijms25126656","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,17]]}}}