{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T19:16:56Z","timestamp":1791227816698,"version":"4.1.0"},"reference-count":34,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,24]],"date-time":"2022-01-24T00:00:00Z","timestamp":1642982400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Inflammatory responses have been shown to induce hyperglycemia, yet the underlying mechanism is still largely unclear. GLP-1 is an important intestinal hormone for regulating glucose homeostasis; however, few studies have investigated the influence of digestive tract Salmonella infection on enteroendocrine L cell secretions. In this study, we established a model of Salmonella-infected piglets by oral gavage in order to analyze the effects of Salmonella infection on enteroendocrine L cell function. Furthermore, in vitro lipopolysaccharide (LPS) was administered to STC-1 cells to clarify its direct effect on GLP-1 secretion. The results showed that significantly increased blood glucose in the group of Salmonella-infected piglets was observed, and Salmonella infection decreased blood GLP-1 content. Then, ileal epithelium damage was observed by histological detection, and this was further verified by TUNEL staining. We identified activation of TLR signaling demonstrating up-regulated expressions of TLR4 and nuclear factor-kappa B (NF-\u039aB). Furthermore, it was shown that Salmonella induced pyroptosis of enteroendocrine L cells and enhanced the secretion of IL-1\u03b2 through augmenting gene and protein expressions of NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing a carboxyl-terminal CARD (ASC), Caspase 1, and gasdermin D (GSDMD). Meanwhile, in vitro LPS treatment induced the pyroptosis of STC-1 cells and reduced the secretion of GLP-1. Altogether, the results demonstrated that Salmonella infection can reduce secretion of GLP-1 by inducing pyroptosis of intestinal L cells, which may eventually result in hyperglycemia. The results provided evidence for the cause of hyperglycemia induced by inflammation and shed new light on glucose homeostasis regulation.<\/jats:p>","DOI":"10.3390\/ijms23031272","type":"journal-article","created":{"date-parts":[[2022,1,25]],"date-time":"2022-01-25T20:38:58Z","timestamp":1643143138000},"page":"1272","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Salmonella Infection Causes Hyperglycemia for Decreased GLP-1 Content by Enteroendocrine L Cells Pyroptosis in Pigs"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3961-7310","authenticated-orcid":false,"given":"Yibo","family":"Zong","sequence":"first","affiliation":[{"name":"MOE Joint Key Laboratory of Animal Physiology and Biochemistry Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjing","family":"Chen","sequence":"additional","affiliation":[{"name":"MOE Joint Key Laboratory of Animal Physiology and Biochemistry Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongsen","family":"Zhao","sequence":"additional","affiliation":[{"name":"MOE Joint Key Laboratory of Animal Physiology and Biochemistry Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyi","family":"Suo","sequence":"additional","affiliation":[{"name":"MOE Joint Key Laboratory of Animal Physiology and Biochemistry Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojing","family":"Yang","sequence":"additional","affiliation":[{"name":"MOE Joint Key Laboratory of Animal Physiology and Biochemistry Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"68","DOI":"10.3109\/10715762.2015.1108412","article-title":"Protective effect of trans-delta-viniferin against high glucose-induced oxidative stress in human umbilical vein endothelial cells through the SIRT1 pathway","volume":"50","author":"Zhao","year":"2016","journal-title":"Free Radic. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"243","DOI":"10.2337\/db12-0293","article-title":"C-peptide prevents hyperglycemia-induced endothelial apoptosis through inhibition of reactive oxygen species-mediated transglutaminase 2 activation","volume":"62","author":"Bhatt","year":"2013","journal-title":"Diabetes"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.cytogfr.2018.06.003","article-title":"Inflammation-induced metabolic derangements or adaptation: An immunometabolic perspective","volume":"43","author":"Engelbrecht","year":"2018","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1007\/978-3-319-42118-6_11","article-title":"Ketogenic Diet and Cancer-a Perspective","volume":"207","author":"Smyl","year":"2016","journal-title":"Recent Results Cancer Res."},{"key":"ref_5","first-page":"10","article-title":"The effects of acute and chronic stress on diabetes control","volume":"5","author":"Marcovecchio","year":"2012","journal-title":"Sci. Signal"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.toxlet.2013.04.005","article-title":"The Fusarium toxin deoxynivalenol (DON) modulates the LPS induced acute phase reaction in pigs","volume":"220","author":"Danicke","year":"2013","journal-title":"Toxicol. Lett."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1055\/s-0029-1212086","article-title":"Mechanisms of TNF-alpha-induced insulin resistance","volume":"107","author":"Hotamisligil","year":"1999","journal-title":"Exp. Clin. Endocrinol. Diabetes"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Gugliandolo, E., Licata, P., Peritore, A.F., Siracusa, R., D\u2019Amico, R., Cordaro, M., Fusco, R., Impellizzeri, D., Di Paola, R., and Cuzzocrea, S. (2021). Effect of Cannabidiol (CBD) on Canine Inflammatory Response: An Ex Vivo Study on LPS Stimulated Whole Blood. Vet. Sci., 8.","DOI":"10.3390\/vetsci8090185"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.metabol.2013.09.010","article-title":"Anti-diabetic actions of glucagon-like peptide-1 on pancreatic beta-cells","volume":"63","author":"Lee","year":"2014","journal-title":"Metabolism"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.metabol.2019.07.003","article-title":"TGR5 agonist ameliorates insulin resistance in the skeletal muscles and improves glucose homeostasis in diabetic mice","volume":"99","author":"Huang","year":"2019","journal-title":"Metabolism"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"105","DOI":"10.4161\/gmic.2.2.15610","article-title":"A comparative analysis of the effect of antibiotic treatment and enteric infection on intestinal homeostasis","volume":"2","author":"Antunes","year":"2011","journal-title":"Gut Microbes"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.tibs.2016.10.004","article-title":"Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death","volume":"42","author":"Shi","year":"2017","journal-title":"Trends Biochem. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1146\/annurev.immunol.021908.132715","article-title":"The inflammasomes: Guardians of the body","volume":"27","author":"Martinon","year":"2009","journal-title":"Annu. Rev. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/s41577-019-0165-0","article-title":"The NLRP3 inflammasome: Molecular activation and regulation to therapeutics","volume":"19","author":"Swanson","year":"2019","journal-title":"Nat. Rev. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e12829","DOI":"10.1111\/cpr.12829","article-title":"TNF-alpha\/HMGB1 inflammation signalling pathway regulates pyroptosis during liver failure and acute kidney injury","volume":"53","author":"Wang","year":"2020","journal-title":"Cell Prolif."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"137382","DOI":"10.1016\/j.scitotenv.2020.137382","article-title":"Perturbation of the lipid metabolism and intestinal inflammation in growing pigs with low birth weight is associated with the alterations of gut microbiota","volume":"719","author":"Huang","year":"2020","journal-title":"Sci. Total Environ."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Fattinger, S.A., Bock, D., Di Martino, M.L., Deuring, S., Samperio, V.P., Ek, V., Furter, M., Kreibich, S., Bosia, F., and Muller-Hauser, A.A. (2020). Salmonella Typhimurium discreet-invasion of the murine gut absorptive epithelium. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008503"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1152\/japplphysiol.00536.2015","article-title":"Intestinal epithelial barrier function and tight junction proteins with heat and exercise","volume":"120","author":"Dokladny","year":"2016","journal-title":"J. Appl. Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/s00424-015-1722-4","article-title":"Oxygen sensing in intestinal mucosal inflammation","volume":"468","author":"Fluck","year":"2016","journal-title":"Pflugers Arch."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.3389\/fimmu.2018.01166","article-title":"Persistent Salmonella enterica serovar Typhimurium Infection Increases the Susceptibility of Mice to Develop Intestinal Inflammation","volume":"9","author":"Schultz","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Suwandi, A., Galeev, A., Riedel, R., Sharma, S., Seeger, K., Sterzenbach, T., Garcia, P.L., Boyle, E.C., Gal-Mor, O., and Hensel, M. (2019). Std fimbriae-fucose interaction increases Salmonella-induced intestinal inflammation and prolongs colonization. PLoS Pathog., 15.","DOI":"10.1371\/journal.ppat.1007915"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7788","DOI":"10.1038\/s41598-018-26083-3","article-title":"Early Salmonella Typhimurium infection in pigs disrupts Microbiome composition and functionality principally at the ileum mucosa","volume":"8","author":"Arguello","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/j.cmet.2018.03.001","article-title":"Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1","volume":"27","author":"Drucker","year":"2018","journal-title":"Cell Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.molmet.2019.09.010","article-title":"Glucagon-like peptide 1 (GLP-1)","volume":"30","author":"Muller","year":"2019","journal-title":"Mol. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2489","DOI":"10.1210\/jc.2014-4009","article-title":"beta-Cell Sensitivity to GLP-1 in Healthy Humans Is Variable and Proportional to Insulin Sensitivity","volume":"100","author":"Aulinger","year":"2015","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"108670","DOI":"10.1016\/j.biopha.2019.108670","article-title":"Genistein enhances the secretion of glucagon-like peptide-1 (GLP-1) via downregulation of inflammatory responses","volume":"112","author":"Rehman","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1016\/j.cell.2018.02.055","article-title":"IRF8 Regulates Transcription of Naips for NLRC4 Inflammasome Activation","volume":"173","author":"Karki","year":"2018","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1002\/JLB.MA0318-112RR","article-title":"The Salmonella pathogenicity island-2 subverts human NLRP3 and NLRC4 inflammasome responses","volume":"105","author":"Bierschenk","year":"2019","journal-title":"J. Leukoc. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1016\/j.cell.2014.04.007","article-title":"Mechanisms and functions of inflammasomes","volume":"157","author":"Lamkanfi","year":"2014","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2562","DOI":"10.1111\/j.1462-5822.2007.01036.x","article-title":"Pyroptosis and host cell death responses during Salmonella infection","volume":"9","author":"Fink","year":"2007","journal-title":"Cell. Microbiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"31309","DOI":"10.1073\/pnas.2013877117","article-title":"Retinol binding protein 4 primes the NLRP3 inflammasome by signaling through Toll-like receptors 2 and 4","volume":"117","author":"Yore","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1038\/cr.2015.139","article-title":"Gasdermin D is an executor of pyroptosis and required for interleukin-1beta secretion","volume":"25","author":"He","year":"2015","journal-title":"Cell Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.3892\/mmr.2013.1744","article-title":"Lipopolysaccharide-induced apoptosis in a murine intestinal endocrine cell line by modulation of Bcl-2, Bax and caspase-3","volume":"8","author":"Lei","year":"2013","journal-title":"Mol. Med. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.biochi.2019.04.001","article-title":"The apoptosis and GLP-1 hyposecretion induced by LPS via RIP\/ROS\/mTOR pathway in GLUTag cells","volume":"162","author":"Wang","year":"2019","journal-title":"Biochimie"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/3\/1272\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:06:25Z","timestamp":1760133985000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/3\/1272"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,24]]},"references-count":34,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["ijms23031272"],"URL":"https:\/\/doi.org\/10.3390\/ijms23031272","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,24]]}}}