Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2022

Open Access 01-12-2022 | Chronic Inflammatory Bowel Disease | Research

Electrical stimulation of the splenic nerve bundle ameliorates dextran sulfate sodium-induced colitis in mice

Authors: David J. Brinkman, Thomas Simon, Anne S. ten Hove, Konstantina Zafeiropoulou, Olaf Welting, Patricia H. P. van Hamersveld, Rose A. Willemze, Andrew Y. F. Li Yim, Caroline Verseijden, Theodorus B. M. Hakvoort, Misha D. Luyer, Margriet J. Vervoordeldonk, Philippe Blancou, Wouter J. de Jonge

Published in: Journal of Neuroinflammation | Issue 1/2022

Login to get access

Abstract

Background

Vagus nerve stimulation has been suggested to affect immune responses, partly through a neuronal circuit requiring sympathetic innervation of the splenic nerve bundle and norepinephrine (NE) release. Molecular and cellular mechanisms of action remain elusive. Here, we investigated the therapeutic value of this neuromodulation in inflammatory bowel disease (IBD) by applying electrical splenic nerve bundle stimulation (SpNS) in mice with dextran sulfate sodium (DSS)-induced colitis.

Methods

Cuff electrodes were implanted around the splenic nerve bundle in mice, whereupon mice received SpNS or sham stimulation. Stimulation was applied 6 times daily for 12 days during DSS-induced colitis. Colonic and splenic tissues were collected for transcriptional analyses by qPCR and RNA-sequencing (RNA-seq). In addition, murine and human splenocytes were stimulated with lipopolysaccharide (LPS) in the absence or presence of NE. Single-cell RNA-seq data from publicly available data sets were analyzed for expression of β-adrenergic receptors (β-ARs).

Results

Colitic mice undergoing SpNS displayed reduced colon weight/length ratios and showed improved Disease Activity Index scores with reduced Tumor Necrosis Factor α mRNA expression in the colon compared with sham stimulated mice. Analyses of splenocytes from SpNS mice using RNA-seq demonstrated specific immune metabolism transcriptome profile changes in myeloid cells. Splenocytes showed expression of β-ARs in myeloid and T cells. Cytokine production was reduced by NE in mouse and human LPS-stimulated splenocytes.

Conclusions

Together, our results demonstrate that SpNS reduces clinical features of colonic inflammation in mice with DSS-induced colitis possibly by inhibiting splenic myeloid cell activation. Our data further support exploration of the clinical use of SpNS for patients with IBD.
Appendix
Available only for authorised users
Literature
1.
Koopman FA, Chavan SS, Miljko S, Grazio S, Sokolovic S, Schuurman PR, Mehta AD, Levine YA, Faltys M, Zitnik R, et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci U S A. 2016;113:8284–9.PubMedPubMedCentralCrossRef
2.
Bonaz B, Sinniger V, Hoffmann D, Clarencon D, Mathieu N, Dantzer C, Vercueil L, Picq C, Trocme C, Faure P, et al. Chronic vagus nerve stimulation in Crohn’s disease: a 6-month follow-up pilot study. Neurogastroenterol Motil. 2016;28:948–53.PubMedCrossRef
3.
Genovese MC, Gaylis NB, Sikes D, Kivitz A, Horowitz DL, Peterfy C, Glass EV, Levine YA, Chernoff D. Safety and efficacy of neurostimulation with a miniaturised vagus nerve stimulation device in patients with multidrug-refractory rheumatoid arthritis: a two-stage multicentre, randomised pilot study. Lancet Rheumatol. 2020:e527–538.
4.
Meregnani J, Clarencon D, Vivier M, Peinnequin A, Mouret C, Sinniger V, Picq C, Job A, Canini F, Jacquier-Sarlin M, Bonaz B. Anti-inflammatory effect of vagus nerve stimulation in a rat model of inflammatory bowel disease. Auton Neurosci. 2011;160:82–9.PubMedCrossRef
5.
Sun P, Zhou K, Wang S, Li P, Chen S, Lin G, Zhao Y, Wang T. Involvement of MAPK/NF-kappaB signaling in the activation of the cholinergic anti-inflammatory pathway in experimental colitis by chronic vagus nerve stimulation. PLoS ONE. 2013;8: e69424.PubMedPubMedCentralCrossRef
6.
Jin H, Guo J, Liu J, Lyu B, Foreman RD, Yin J, Shi Z, Chen JDZ. Anti-inflammatory effects and mechanisms of vagal nerve stimulation combined with electroacupuncture in a rodent model of TNBS-induced colitis. Am J Physiol Gastrointest Liver Physiol. 2017;313:G192–202.PubMedCrossRef
7.
Payne SC, Furness JB, Burns O, Sedo A, Hyakumura T, Shepherd RK, Fallon JB. Anti-inflammatory effects of abdominal vagus nerve stimulation on experimental intestinal inflammation. Front Neurosci. 2019;13:418.PubMedPubMedCentralCrossRef
8.
Rosas-Ballina M, Olofsson PS, Ochani M, Valdes-Ferrer SI, Levine YA, Reardon C, Tusche MW, Pavlov VA, Andersson U, Chavan S, et al. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science. 2011;334:98–101.PubMedPubMedCentralCrossRef
9.
Guyot M, Simon T, Panzolini C, Ceppo F, Daoudlarian D, Murris E, Macia E, Abelanet S, Sridhar A, Vervoordeldonk MJ, et al. Apical splenic nerve electrical stimulation discloses an anti-inflammatory pathway relying on adrenergic and nicotinic receptors in myeloid cells. Brain Behav Immun. 2019;80:238–46.PubMedCrossRef
10.
Huston JM, Ochani M, Rosas-Ballina M, Liao H, Ochani K, Pavlov VA, Gallowitsch-Puerta M, Ashok M, Czura CJ, Foxwell B, et al. Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. J Exp Med. 2006;203:1623–8.PubMedPubMedCentralCrossRef
11.
Rosas-Ballina M, Ochani M, Parrish WR, Ochani K, Harris YT, Huston JM, Chavan S, Tracey KJ. Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia. Proc Natl Acad Sci U S A. 2008;105:11008–13.PubMedPubMedCentralCrossRef
12.
Munyaka P, Rabbi MF, Pavlov VA, Tracey KJ, Khafipour E, Ghia JE. Central muscarinic cholinergic activation alters interaction between splenic dendritic cell and CD4+CD25- T cells in experimental colitis. PLoS ONE. 2014;9: e109272.PubMedPubMedCentralCrossRef
13.
Ji H, Rabbi MF, Labis B, Pavlov VA, Tracey KJ, Ghia JE. Central cholinergic activation of a vagus nerve-to-spleen circuit alleviates experimental colitis. Mucosal Immunol. 2014;7:335–47.PubMedCrossRef
14.
Grandi A, Zini I, Flammini L, Cantoni AM, Vivo V, Ballabeni V, Barocelli E, Bertoni S. alpha7 nicotinic agonist AR-R17779 protects mice against 2,4,6-trinitrobenzene sulfonic acid-induced colitis in a spleen-dependent way. Front Pharmacol. 2017;8:809.PubMedPubMedCentralCrossRef
15.
Brinkman DJ, Ten Hove AS, Vervoordeldonk MJ, Luyer MD, de Jonge WJ. Neuroimmune Interactions in the Gut and Their Significance for Intestinal Immunity. Cells. 2019; 8.
16.
Vida G, Pena G, Deitch EA, Ulloa L. alpha7-cholinergic receptor mediates vagal induction of splenic norepinephrine. J Immunol. 2011;186:4340–6.PubMedCrossRef
17.
Nunes NS, Chandran P, Sundby M, Visioli F, da Costa GF, Burks SR, Paz AH, Frank JA. Therapeutic ultrasound attenuates DSS-induced colitis through the cholinergic anti-inflammatory pathway. EBioMedicine. 2019;45:495–510.PubMedPubMedCentralCrossRef
18.
Melgar S, Karlsson A, Michaelsson E. Acute colitis induced by dextran sulfate sodium progresses to chronicity in C57BL/6 but not in BALB/c mice: correlation between symptoms and inflammation. Am J Physiol Gastrointest Liver Physiol. 2005;288:G1328-1338.PubMedCrossRef
19.
Becker C, Fantini MC, Wirtz S, Nikolaev A, Kiesslich R, Lehr HA, Galle PR, Neurath MF. In vivo imaging of colitis and colon cancer development in mice using high resolution chromoendoscopy. Gut. 2005;54:950–4.PubMedPubMedCentralCrossRef
20.
ten Hove T, Drillenburg P, Wijnholds J, Te Velde AA, van Deventer SJ. Differential susceptibility of multidrug resistance protein-1 deficient mice to DSS and TNBS-induced colitis. Dig Dis Sci. 2002;47:2056–63.PubMedCrossRef
21.
FastQC: a quality control tool for high throughput sequence data.
22.
Ewels P, Magnusson M, Lundin S, Kaller M. MultiQC: summarize analysis results for multiple tools and samples in a single report. Bioinformatics. 2016;32:3047–8.PubMedPubMedCentralCrossRef
23.
Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, Batut P, Chaisson M, Gingeras TR. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.PubMedCrossRef
24.
Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R, Genome Project Data Processing S. The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009;25:2078–9.PubMedPubMedCentralCrossRef
25.
26.
Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30:923–30.PubMedCrossRef
27.
Zerbino DR, Achuthan P, Akanni W, Amode MR, Barrell D, Bhai J, Billis K, Cummins C, Gall A, Giron CG, et al. Ensembl 2018. Nucleic Acids Res. 2018;46:D754–61.PubMedCrossRef
28.
29.
30.
31.
32.
Ruijter JM, Ramakers C, Hoogaars WM, Karlen Y, Bakker O, van den Hoff MJ, Moorman AF. Amplification efficiency: linking baseline and bias in the analysis of quantitative PCR data. Nucleic Acids Res. 2009;37: e45.PubMedPubMedCentralCrossRef
33.
Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002;3:RESEARCH0034.PubMedPubMedCentralCrossRef
34.
Tabula Muris C, Overall c, Logistical c, Organ c, processing, Library p, sequencing, Computational data a, Cell type a, Writing g, et al. Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature. 2018;562:367–72.CrossRef
35.
Team R. RStudio: Integrated Development for R. RStudio, PBC; 2020.
36.
Stuart T, Butler A, Hoffman P, Hafemeister C, Papalexi E, Mauck WM 3rd, Hao Y, Stoeckius M, Smibert P, Satija R. Comprehensive integration of single-cell data. Cell. 2019;177(1888–1902): e1821.
37.
Ghia JE, Blennerhassett P, Kumar-Ondiveeran H, Verdu EF, Collins SM. The vagus nerve: a tonic inhibitory influence associated with inflammatory bowel disease in a murine model. Gastroenterology. 2006;131:1122–30.PubMedCrossRef
38.
Willemze RA, Welting O, van Hamersveld P, Verseijden C, Nijhuis LE, Hilbers FW, Meijer SL, Heesters BA, Folgering JHA, Darwinkel H, et al. Loss of intestinal sympathetic innervation elicits an innate immune driven colitis. Mol Med. 2019;25:1.PubMedPubMedCentralCrossRef
39.
Van den Bossche J, Baardman J, Otto NA, van der Velden S, Neele AE, van den Berg SM, Luque-Martin R, Chen HJ, Boshuizen MC, Ahmed M, et al. Mitochondrial dysfunction prevents repolarization of inflammatory macrophages. Cell Rep. 2016;17:684–96.PubMedCrossRef
40.
Vos AC, Wildenberg ME, Arijs I, Duijvestein M, Verhaar AP, de Hertogh G, Vermeire S, Rutgeerts P, van den Brink GR, Hommes DW. Regulatory macrophages induced by infliximab are involved in healing in vivo and in vitro. Inflamm Bowel Dis. 2012;18:401–8.PubMedCrossRef
41.
Kees MG, Pongratz G, Kees F, Scholmerich J, Straub RH. Via beta-adrenoceptors, stimulation of extrasplenic sympathetic nerve fibers inhibits lipopolysaccharide-induced TNF secretion in perfused rat spleen. J Neuroimmunol. 2003;145:77–85.PubMedCrossRef
42.
Cotero V, Fan Y, Tsaava T, Kressel AM, Hancu I, Fitzgerald P, Wallace K, Kaanumalle S, Graf J, Rigby W, et al. Noninvasive sub-organ ultrasound stimulation for targeted neuromodulation. Nat Commun. 2019;10:952.PubMedPubMedCentralCrossRef
43.
Zachs DP, Offutt SJ, Graham RS, Kim Y, Mueller J, Auger JL, Schuldt NJ, Kaiser CRW, Heiller AP, Dutta R, et al. Noninvasive ultrasound stimulation of the spleen to treat inflammatory arthritis. Nat Commun. 2019;10:951.PubMedPubMedCentralCrossRef
44.
Chassaing B, Aitken JD, Malleshappa M, Vijay-Kumar M. Dextran sulfate sodium (DSS)-induced colitis in mice. Curr Protoc Immunol. 2014; 104.
45.
Eichele DD, Kharbanda KK. Dextran sodium sulfate colitis murine model: an indispensable tool for advancing our understanding of inflammatory bowel diseases pathogenesis. World J Gastroenterol. 2017;23:6016–29.PubMedPubMedCentralCrossRef
46.
Heusermann U, Stutte HJ. Electron microscopic studies of the innervation of the human spleen. Cell Tissue Res. 1977;184:225–36.PubMedCrossRef
47.
Cleypool CGJ, Lotgeringk Bruinenberg D, Roeling T, Irwin E, Bleys R. Splenic artery loops: potential splenic plexus stimulation sites for neuroimmunomodulatory based anti-inflammatory therapy? Clin Anat. 2020;34:371.PubMedPubMedCentralCrossRef
48.
Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405:458–62.PubMedCrossRef
49.
de Jonge WJ, van der Zanden EP, The FO, Bijlsma MF, van Westerloo DJ, Bennink RJ, Berthoud HR, Uematsu S, Akira S, van den Wijngaard RM, Boeckxstaens GE. Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nat Immunol. 2005;6:844–51.PubMedCrossRef
50.
Levine YA, Koopman FA, Faltys M, Caravaca A, Bendele A, Zitnik R, Vervoordeldonk MJ, Tak PP. Neurostimulation of the cholinergic anti-inflammatory pathway ameliorates disease in rat collagen-induced arthritis. PLoS ONE. 2014;9: e104530.PubMedPubMedCentralCrossRef
51.
Inoue T, Abe C, Sung SS, Moscalu S, Jankowski J, Huang L, Ye H, Rosin DL, Guyenet PG, Okusa MD. Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through alpha7nAChR+ splenocytes. J Clin Invest. 2016;126:1939–52.PubMedPubMedCentralCrossRef
52.
Ten Hove AS, Brinkman DJ, Li Yim AYF, Verseijden C, Hakvoort TBM, Admiraal I, Welting O, van Hamersveld PHP, Sinniger V, Bonaz B, et al. The role of nicotinic receptors in SARS-CoV-2 receptor ACE2 expression in intestinal epithelia. Bioelectron Med. 2020;6:20.PubMedPubMedCentralCrossRef
53.
Meroni E, Stakenborg N, Gomez-Pinilla PJ, De Hertogh G, Goverse G, Matteoli G, Verheijden S, Boeckxstaens GE. Functional characterization of oxazolone-induced colitis and survival improvement by vagus nerve stimulation. PLoS ONE. 2018;13: e0197487.PubMedPubMedCentralCrossRef
54.
Willemze RA, Welting O, van Hamersveld HP, Meijer SL, Folgering JHA, Darwinkel H, Witherington J, Sridhar A, Vervoordeldonk MJ, Seppen J, de Jonge WJ. Neuronal control of experimental colitis occurs via sympathetic intestinal innervation. Neurogastroenterol Motil. 2018;30:e13163.CrossRef
55.
Guo J, Jin H, Shi Z, Yin J, Pasricha T, Chen JDZ. Sacral nerve stimulation improves colonic inflammation mediated by autonomic-inflammatory cytokine mechanism in rats. Neurogastroenterol Motil. 2019;31: e13676.PubMed
56.
Tu L, Gharibani P, Zhang N, Yin J, Chen JD. Anti-inflammatory effects of sacral nerve stimulation: a novel spinal afferent and vagal efferent pathway. Am J Physiol Gastrointest Liver Physiol. 2020;318:G624–34.PubMedCrossRef
Metadata
Title
Electrical stimulation of the splenic nerve bundle ameliorates dextran sulfate sodium-induced colitis in mice
Authors
David J. Brinkman
Thomas Simon
Anne S. ten Hove
Konstantina Zafeiropoulou
Olaf Welting
Patricia H. P. van Hamersveld
Rose A. Willemze
Andrew Y. F. Li Yim
Caroline Verseijden
Theodorus B. M. Hakvoort
Misha D. Luyer
Margriet J. Vervoordeldonk
Philippe Blancou
Wouter J. de Jonge
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2022
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-022-02504-z

Other articles of this Issue 1/2022

Journal of Neuroinflammation 1/2022 Go to the issue

Research

MORPHIOUS: an unsupervised machine learning workflow to detect the activation of microglia and astrocytes

Research

A novel aquaporin-4-associated optic neuritis rat model with severe pathological and functional manifestations

Research

Adamantinomatous craniopharyngioma cyst fluid can trigger inflammatory activation of microglia to damage the hypothalamic neurons by inducing the production of β-amyloid

Research

Immune response and pathogen invasion at the choroid plexus in the onset of cerebral toxoplasmosis

Research

Connexin 43 gap junction-mediated astrocytic network reconstruction attenuates isoflurane-induced cognitive dysfunction in mice

Research

Single-cell transcriptomics of the ventral posterolateral nucleus-enriched thalamic regions from HSV-1-infected mice reveal a novel microglia/microglia-like transcriptional response