{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T08:03:36Z","timestamp":1780301016258,"version":"3.54.0"},"posted":{"date-parts":[[2026,5,28]]},"group-title":"Immunology","reference-count":45,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NIH NIAID","award":["R01AI150647"],"award-info":[{"award-number":["R01AI150647"]}]},{"name":"NIH NIAID","award":["R56AI179656"],"award-info":[{"award-number":["R56AI179656"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Bidirectional communication between the nervous and immune systems has been demonstrated to limit or enhance immune cell function across organ systems and conditions. Although these neuroimmune circuits can become activated as an anti-inflammatory reflex, vagus nerve stimulation\n                  <jats:bold>(VNS)<\/jats:bold>\n                  reduces inflammation in models of endotoxemia, rheumatoid arthritis, and intestinal inflammation. In the spleen during endotoxemia, VNS activates a \u201ccholinergic anti-inflammatory pathway\u201d (CAIP), whereby choline acetyltransferase (ChAT)-expressing T cells release acetylcholine to reduce macrophage activation. VNS can also drive CAIP-independent pathways to reduce inflammation in the spleen and intestinal tract, although the circuitry modulating colonic inflammation remains underexplored. Here, we demonstrate that left cervical VNS reduces acute LPS-induced inflammation, evidenced by reduced\n                  <jats:italic>Tnfa<\/jats:italic>\n                  expression in colon and spleen and decreased circulating TNF\u03b1. In the colon, these protective effects required efferent but not afferent VNS and were independent of ChAT+ T cells, IL10, \u03b2-adrenergic signaling, and colonic sympathetic innervation. Critically, the ability of VNS to modulate colonic inflammation depended on prior tissue-specific inflammation. Mice recovering from DSS colitis, despite near-complete histological recovery, were refractory to the protective effects of VNS in the colon. This lack of efficacy in the colon was not reflected in measures of inflammation in the spleen or serum, highlighting the need for target-organ-specific monitoring. This loss of efficacy after colonic inflammation was transient, with restoration occurring upon complete recovery. These findings demonstrate that VNS efficacy in colonic inflammation depends on circuitry distinct from canonical systemic anti-inflammatory pathways, and that tissue responsiveness is shaped by anatomical site and inflammatory history.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Key Points<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Electrical stimulation of the left cervical vagus nerve reduces LPS-induced inflammation in the mouse colon.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>This colonic anti-inflammatory effect requires vagal efferents but not afferent signaling.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Unlike canonical splenic anti-inflammatory pathways, the colonic response does not require ChAT+ T cells, IL-10, \u03b2-adrenergic signaling, or local sympathetic innervation.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Recent DSS colitis abolishes colonic responsiveness to VNS despite preserved splenic and systemic anti-inflammatory effects.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Recovery of VNS anti-inflammatory efficacy after colitis shows that neuroimmune responsiveness in the colon is dynamically shaped by inflammatory history.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.28.724702","type":"posted-content","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T07:10:14Z","timestamp":1780038614000},"source":"Crossref","is-referenced-by-count":0,"title":["Vagus nerve stimulation limits colonic inflammation through distinct neuroimmune circuitry shaped by inflammatory history"],"prefix":"10.64898","author":[{"given":"Kristina","family":"Sanchez","sequence":"first","affiliation":[{"name":"VM: Anatomy, Physiology & Cell Biology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jungjae","family":"Park","sequence":"additional","affiliation":[{"name":"VM: Anatomy, Physiology & Cell Biology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmy","family":"Tay","sequence":"additional","affiliation":[{"name":"VM: Anatomy, Physiology & Cell Biology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gatha","family":"Pore","sequence":"additional","affiliation":[{"name":"VM: Anatomy, Physiology & Cell Biology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail","family":"Wagner","sequence":"additional","affiliation":[{"name":"VM: Anatomy, Physiology & Cell Biology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Lee","sequence":"additional","affiliation":[{"name":"VM: Anatomy, Physiology & Cell Biology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Li","sequence":"additional","affiliation":[{"name":"VM: Anatomy, Physiology & Cell Biology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayra","family":"Mirza","sequence":"additional","affiliation":[{"name":"VM: Anatomy, Physiology & Cell Biology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Gareau","sequence":"additional","affiliation":[{"name":"VM: Anatomy, Physiology & Cell Biology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2204-8091","authenticated-orcid":false,"given":"Colin","family":"Reardon","sequence":"additional","affiliation":[{"name":"VM: Anatomy, Physiology & Cell Biology"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026060100301341000_2026.05.28.724702v1.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra2403213"},{"key":"2026060100301341000_2026.05.28.724702v1.2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2982.2012.01921.x"},{"key":"2026060100301341000_2026.05.28.724702v1.3","doi-asserted-by":"crossref","first-page":"2574","DOI":"10.1016\/j.bbadis.2017.03.005","article-title":"The intestinal microenvironment in sepsis","volume":"1863","year":"2017","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"2026060100301341000_2026.05.28.724702v1.4","doi-asserted-by":"crossref","first-page":"e20210862","DOI":"10.1084\/jem.20210862","article-title":"Intercrypt sentinel macrophages tune antibacterial NF-\u03baB responses in gut epithelial cells via TNF","volume":"218","year":"2021","journal-title":"Journal of Experimental Medicine"},{"key":"2026060100301341000_2026.05.28.724702v1.5","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00035.2017"},{"key":"2026060100301341000_2026.05.28.724702v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/35013070"},{"key":"2026060100301341000_2026.05.28.724702v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/nature01339"},{"key":"2026060100301341000_2026.05.28.724702v1.8","doi-asserted-by":"publisher","DOI":"10.1007\/BF03402177"},{"key":"2026060100301341000_2026.05.28.724702v1.9","doi-asserted-by":"publisher","DOI":"10.1126\/science.1209985"},{"key":"2026060100301341000_2026.05.28.724702v1.10","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/j.brs.2023.04.003","article-title":"Focused ultrasound neuromodulation of the spleen activates an anti-inflammatory response in humans","volume":"16","year":"2023","journal-title":"Brain Stimul"},{"key":"2026060100301341000_2026.05.28.724702v1.11","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20052362"},{"key":"2026060100301341000_2026.05.28.724702v1.12","doi-asserted-by":"publisher","DOI":"10.1113\/JP281189"},{"key":"2026060100301341000_2026.05.28.724702v1.13","doi-asserted-by":"crossref","first-page":"eadw7080","DOI":"10.1126\/sciadv.adw7080","article-title":"Inhibition of acute lung inflammation by a neuroimmune circuit induced by vagal nerve stimulation","volume":"11","year":"2025","journal-title":"Science Advances"},{"key":"2026060100301341000_2026.05.28.724702v1.14","doi-asserted-by":"publisher","DOI":"10.1038\/ni1229"},{"key":"2026060100301341000_2026.05.28.724702v1.15","doi-asserted-by":"crossref","first-page":"103058","DOI":"10.1016\/j.conb.2025.103058","article-title":"Gut-brain communication: Functional anatomy of vagal afferents","volume":"93","year":"2025","journal-title":"Current Opinion in Neurobiology"},{"key":"2026060100301341000_2026.05.28.724702v1.16","doi-asserted-by":"crossref","first-page":"e13911","DOI":"10.1111\/nmo.13911","article-title":"A 12-month pilot study outcomes of vagus nerve stimulation in Crohn\u2019s disease","volume":"32","year":"2020","journal-title":"Neurogastroenterol Motil"},{"key":"2026060100301341000_2026.05.28.724702v1.17","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1093\/ecco-jcc\/jjad151","article-title":"Neuroimmune Modulation Through Vagus Nerve Stimulation Reduces Inflammatory Activity in Crohn\u2019s Disease Patients: A Prospective Open-label Study","volume":"17","year":"2023","journal-title":"J Crohns Colitis"},{"key":"2026060100301341000_2026.05.28.724702v1.18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1007719"},{"key":"2026060100301341000_2026.05.28.724702v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2019.08.188"},{"key":"2026060100301341000_2026.05.28.724702v1.20","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1605635113"},{"key":"2026060100301341000_2026.05.28.724702v1.21","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07469-y"},{"key":"2026060100301341000_2026.05.28.724702v1.22","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2021758118"},{"key":"2026060100301341000_2026.05.28.724702v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2024.01.012"},{"key":"2026060100301341000_2026.05.28.724702v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.02.031"},{"key":"2026060100301341000_2026.05.28.724702v1.25","doi-asserted-by":"crossref","unstructured":"N. Stakenborg et al., Abdominal vagus nerve stimulation as a new therapeutic approach to prevent postoperative ileus. Neurogastroenterol Motil 29 (2017).","DOI":"10.1111\/nmo.13075"},{"key":"2026060100301341000_2026.05.28.724702v1.26","doi-asserted-by":"publisher","DOI":"10.1002\/cne.903010107"},{"key":"2026060100301341000_2026.05.28.724702v1.27","first-page":"52","article-title":"Vagus Nerve Stimulation in Refractory Epilepsy: Effects on Pro- and Anti-Inflammatory Cytokines in Peripheral Blood","volume":"18","year":"2010","journal-title":"Neuroimmunomodulation"},{"key":"2026060100301341000_2026.05.28.724702v1.28","doi-asserted-by":"publisher","DOI":"10.1172\/JCI83658"},{"key":"2026060100301341000_2026.05.28.724702v1.29","doi-asserted-by":"publisher","DOI":"10.1097\/MIB.0000000000000326"},{"key":"2026060100301341000_2026.05.28.724702v1.30","doi-asserted-by":"crossref","first-page":"e20251761","DOI":"10.1084\/jem.20251761","article-title":"Inflammation rewires the enteric nervous system through neurogenic monocyte recruitment","volume":"223","year":"2026","journal-title":"Journal of Experimental Medicine"},{"key":"2026060100301341000_2026.05.28.724702v1.31","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1111\/j.1365-2982.2004.00607.x","article-title":"Plasticity of the enteric nervous system during intestinal inflammation","volume":"17","year":"2005","journal-title":"Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society"},{"key":"2026060100301341000_2026.05.28.724702v1.32","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v25.i27.3572"},{"key":"2026060100301341000_2026.05.28.724702v1.33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0056867"},{"key":"2026060100301341000_2026.05.28.724702v1.34","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/S0022-3565(24)35257-7","article-title":"Specific type IV phosphodiesterase inhibitor rolipram mitigates experimental colitis in mice","volume":"292","year":"2000","journal-title":"J Pharmacol Exp Ther"},{"key":"2026060100301341000_2026.05.28.724702v1.35","doi-asserted-by":"crossref","first-page":"3840","DOI":"10.1038\/s41467-025-59248-6","article-title":"Neural representation of cytokines by vagal sensory neurons","volume":"16","year":"2025","journal-title":"Nature Communications"},{"key":"2026060100301341000_2026.05.28.724702v1.36","first-page":"237","article-title":"No consistent evidence for the anti-inflammatory effect of vagus nerve stimulation in humans: A systematic review and meta-analysis","volume":"116","year":"2023","journal-title":"Brain Behav Immun"},{"key":"2026060100301341000_2026.05.28.724702v1.37","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1038\/s41591-025-04114-7","article-title":"Vagus nerve-mediated neuroimmune modulation for rheumatoid arthritis: a pivotal randomized controlled trial","volume":"32","year":"2026","journal-title":"Nature Medicine"},{"key":"2026060100301341000_2026.05.28.724702v1.38","doi-asserted-by":"crossref","first-page":"e14876","DOI":"10.1111\/nmo.14876","article-title":"Characterization of idiopathic chronic diarrhea and associated intestinal inflammation and preliminary observations of effects of vagal nerve stimulation in a non-human primate","volume":"36","year":"2024","journal-title":"Neurogastroenterology & Motility"},{"key":"2026060100301341000_2026.05.28.724702v1.39","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2005.084285"},{"key":"2026060100301341000_2026.05.28.724702v1.40","doi-asserted-by":"publisher","DOI":"10.1177\/0192623313505929"},{"key":"2026060100301341000_2026.05.28.724702v1.41","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.69.7.4417-4423.2001"},{"key":"2026060100301341000_2026.05.28.724702v1.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.05.015"},{"key":"2026060100301341000_2026.05.28.724702v1.43","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkp1005"},{"key":"2026060100301341000_2026.05.28.724702v1.44","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2415287122"},{"key":"2026060100301341000_2026.05.28.724702v1.45","doi-asserted-by":"publisher","DOI":"10.64898\/2026.01.14.699546"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.05.28.724702","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T07:30:24Z","timestamp":1780299024000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.05.28.724702"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,28]]},"references-count":45,"URL":"https:\/\/doi.org\/10.64898\/2026.05.28.724702","relation":{},"subject":[],"published":{"date-parts":[[2026,5,28]]},"subtype":"preprint"}}