{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T04:19:04Z","timestamp":1791865144967,"version":"4.3.4"},"reference-count":43,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T00:00:00Z","timestamp":1669939200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["32072745"],"award-info":[{"award-number":["32072745"]}]},{"name":"National Natural Science Foundation of China","award":["U20A2054"],"award-info":[{"award-number":["U20A2054"]}]},{"name":"National Natural Science Foundation of China","award":["32102571"],"award-info":[{"award-number":["32102571"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Vitamin A (VA) and its metabolite, retinoic acid (RA), play important roles in modulating intestinal mucosal immunity, yet little is known about their regulatory effects on enteric nervous system function. The study aims to explore the protective effects of dietary VA on diarrhea in a piglet model involving enteric glia and immune cell modulation. Twenty-eight weaned piglets were fed either the basal or VA (basal diet supplemented with 18,000 IU\/kg VA) diet and with or without irinotecan (CPT-11) injection. CPT-11 induced increased diarrhea incidence, immune infiltration, and reactive enteric gliosis. A diet supplemented with 18,000 IU\/kg VA ameliorated the adverse effects of CPT-11 on the gut barrier. VA reduced diarrhea incidence and attenuated enteric glial gliosis, immune cell infiltrations, and inflammatory responses of CPT-induced piglets. An in vitro experiment with 1 nmol\/L RA showed direct protective effects on monocultures of enteric glial cells (EGCs) or macrophages in LPS-simulated inflammatory conditions. Furthermore, 1 ng\/mL glial-derived neurotropic factors (GDNF) could inhibit M1-macrophage polarization and pro-inflammatory cytokines production. In summary, VA exerted protective effects on the intestinal barrier by modulating enteric glia and immune cells, perhaps enhancing epithelial recovery under CPT-11 challenge. Our study demonstrated that RA signaling might promote the roles of enteric glia in intestinal immunity and tissue repair, which provided a reference for the VA supplementation of patient diets.<\/jats:p>","DOI":"10.3390\/nu14235120","type":"journal-article","created":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T03:00:36Z","timestamp":1669950036000},"page":"5120","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Vitamin A Ameliorated Irinotecan-Induced Diarrhea in a Piglet Model Involving Enteric Glia Modulation and Immune Cells Infiltration"],"prefix":"10.3390","volume":"14","author":[{"given":"Meng","family":"Li","sequence":"first","affiliation":[{"name":"College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China"},{"name":"Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China"},{"name":"Hainan Institute, Zhejiang University, Sanya 572000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonggang","family":"Huang","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huimin","family":"Jin","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daixiu","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Medicine, Jishou University, Jishou 416000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Huang","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0138-1530","authenticated-orcid":false,"given":"Bie","family":"Tan","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China"},{"name":"Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulong","family":"Yin","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China"},{"name":"Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1016\/S0140-6736(98)02309-5","article-title":"Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer","volume":"352","author":"Cunningham","year":"1998","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1177\/1758834009355164","article-title":"Chemotherapy-induced diarrhea: Pathophysiology, frequency and guideline-based management","volume":"2","author":"Stein","year":"2010","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"414","DOI":"10.3389\/fphar.2016.00414","article-title":"Chemotherapy-induced constipation and diarrhea: Pathophysiology, current and emerging treatments","volume":"7","author":"McQuade","year":"2016","journal-title":"Front. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1093\/jnci\/86.6.446","article-title":"Irinotecan (CPT-11) high-dose escalation using intensive high-dose loperamide to control diarrhea","volume":"86","author":"Abigerges","year":"1994","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/nri2707","article-title":"Toll-like receptor signalling in the intestinal epithelium: How bacterial recognition shapes intestinal function","volume":"10","author":"Abreu","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1038\/ni.3489","article-title":"Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis","volume":"17","author":"Klose","year":"2016","journal-title":"Nat. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1038\/s41590-020-0741-2","article-title":"The mesenchymal context in inflammation, immunity and cancer","volume":"21","author":"Koliaraki","year":"2020","journal-title":"Nat. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1038\/s41586-021-04006-z","article-title":"Regulation of intestinal immunity and tissue repair by enteric glia","volume":"599","author":"Progatzky","year":"2021","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Cheadle, G.A., Costantini, T.W., Lopez, N., Bansal, V., Eliceiri, B.P., and Coimbra, R. (2013). Enteric glia cells attenuate cytomix-induced intestinal epithelial barrier breakdown. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0069042"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1002\/glia.10169","article-title":"Role of enteric glial cells in inflammatory bowel disease","volume":"41","author":"Cabarrocas","year":"2003","journal-title":"Glia"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"d5758","DOI":"10.1126\/scitranslmed.abd5758","article-title":"Importance of the pig as a human biomedical model","volume":"13","author":"Lunney","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1002\/eji.201344398","article-title":"Seeing through the dark: New insights into the immune regulatory functions of vitamin A","volume":"45","author":"Brown","year":"2015","journal-title":"Eur. J. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1038\/nri2378","article-title":"Vitamin effects on the immune system: Vitamins A and D take centre stage","volume":"8","author":"Mora","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1002\/neu.20242","article-title":"Overview of retinoid metabolism and function","volume":"66","author":"Blomhoff","year":"2006","journal-title":"J. Neurobiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1301\/nr.2007.aug.385-388","article-title":"Identification of a membrane receptor for retinol-binding protein functioning in the cellular uptake of retinol","volume":"65","author":"Wolf","year":"2007","journal-title":"Nutr. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"10911","DOI":"10.1073\/pnas.1812069116","article-title":"Epithelial retinoic acid receptor \u03b2 regulates serum amyloid A expression and vitamin A-dependent intestinal immunity","volume":"116","author":"Gattu","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3067126","DOI":"10.1155\/2018\/3067126","article-title":"Impact of Retinoic Acid on Immune Cells and Inflammatory Diseases","volume":"2018","author":"Oliveira","year":"2018","journal-title":"Mediators Inflamm."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"S40","DOI":"10.1301\/00296640260130722","article-title":"Micronutrient malnutrition, infection, and immunity: An overview","volume":"60","author":"Bhaskaram","year":"2002","journal-title":"Nutr. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"d5094","DOI":"10.1136\/bmj.d5094","article-title":"Vitamin A supplements for preventing mortality, illness, and blindness in children aged under 5: Systematic review and meta-analysis","volume":"343","author":"Imdad","year":"2011","journal-title":"BMJ"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1080\/10409238.2019.1611734","article-title":"Vitamin A and vitamin D regulate the microbial complexity, barrier function, and the mucosal immune responses to ensure intestinal homeostasis","volume":"54","author":"Cantorna","year":"2019","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1876","DOI":"10.1093\/jnci\/87.24.1876","article-title":"Irinotecan (CPT-11) and characteristic mucosal changes in the mouse ileum and cecum","volume":"87","author":"Ikuno","year":"1995","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1046\/j.1440-1746.2003.03136.x","article-title":"Irinotecan causes severe small intestinal damage, as well as colonic damage, in the rat with implanted breast cancer","volume":"18","author":"Gibson","year":"2003","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"skaa020","DOI":"10.1093\/jas\/skaa020","article-title":"Dietary vitamin A affects growth performance, intestinal development, and functions in weaned piglets by affecting intestinal stem cells","volume":"98","author":"Wang","year":"2020","journal-title":"J. Anim. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1016\/j.toxicon.2007.07.010","article-title":"Role of retinol in protecting epithelial cell damage induced by Clostridium difficile toxin A","volume":"50","author":"Maciel","year":"2007","journal-title":"Toxicon"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1124\/pr.58.4.4","article-title":"International Union of Pharmacology. LX. Retinoic acid receptors","volume":"58","author":"Germain","year":"2006","journal-title":"Pharmacol. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/j.immuni.2004.08.011","article-title":"Retinoic acid imprints gut-homing specificity on T cells","volume":"21","author":"Iwata","year":"2004","journal-title":"Immunity"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.tiv.2013.11.007","article-title":"The antioxidants, vitamin A and E but not vitamin C and melatonin enhance the proapoptotic effects of irinotecan in cancer cells in vitro","volume":"2","author":"Kontek","year":"2014","journal-title":"Toxicol. Vitr."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5519","DOI":"10.4049\/jimmunol.0903942","article-title":"Retinoic acid determines the precise tissue tropism of inflammatory Th17 cells in the intestine","volume":"184","author":"Wang","year":"2010","journal-title":"J. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1038\/mi.2017.91","article-title":"Intestinal epithelial cell-specific RARalpha depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system","volume":"11","author":"Jijon","year":"2018","journal-title":"Mucosal Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e3206","DOI":"10.7554\/eLife.03206","article-title":"Serum amyloid A is a retinol binding protein that transports retinol during bacterial infection","volume":"3","author":"Derebe","year":"2014","journal-title":"eLife"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.cell.2015.08.061","article-title":"An IL-23R\/IL-22 Circuit Regulates Epithelial Serum Amyloid A to Promote Local Effector Th17 Responses","volume":"163","author":"Sano","year":"2015","journal-title":"Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1007\/s00280-007-0534-4","article-title":"Role of cytokines (TNF-alpha, IL-1beta and KC) in the pathogenesis of CPT-11-induced intestinal mucositis in mice: Effect of pentoxifylline and thalidomide","volume":"61","author":"Melo","year":"2008","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.taap.2015.09.025","article-title":"CPT-11 activates NLRP3 inflammasome through JNK and NF-kappaB signalings","volume":"289","author":"Li","year":"2015","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.immuni.2008.03.004","article-title":"The biological functions of T helper 17 cell effector cytokines in inflammation","volume":"28","author":"Ouyang","year":"2008","journal-title":"Immunity"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1016\/S0016-5085(03)00404-9","article-title":"Glial-derived neurotrophic factor regulates apoptosis in colonic epithelial cells","volume":"124","author":"Steinkamp","year":"2003","journal-title":"Gastroenterology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"11273","DOI":"10.3748\/wjg.v20.i32.11273","article-title":"Enteric glial cells and their role in the intestinal epithelial barrier","volume":"20","author":"Yu","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.jcmgh.2018.05.009","article-title":"Communication between Enteric Neurons, Glia, and Nociceptors Underlies the Effects of Tachykinins on Neuroinflammation","volume":"6","author":"Delvalle","year":"2018","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"ref_38","first-page":"590","article-title":"The Neuromodulation of the Intestinal Immune System and Its Relevance in Inflammatory Bowel Disease","volume":"6","author":"Verheijden","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1038\/nature18644","article-title":"Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence","volume":"535","author":"Ibiza","year":"2016","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.intimp.2014.01.008","article-title":"Glial-derived neurotrophic factor reduces inflammation and improves delayed colonic transit in rat models of dextran sulfate sodium-induced colitis","volume":"19","author":"Liu","year":"2014","journal-title":"Int. Immunopharmacol."},{"key":"ref_41","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_42","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1038\/nri2448","article-title":"Exploring the full spectrum of macrophage activation","volume":"8","author":"Mosser","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_43","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."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/23\/5120\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:32:31Z","timestamp":1760146351000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/23\/5120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,2]]},"references-count":43,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["nu14235120"],"URL":"https:\/\/doi.org\/10.3390\/nu14235120","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,2]]}}}