Impaired parasympathetic function increases susceptibility to inflammatory bowel disease in a mouse model of depression
Open accessAbstract
Clinical and experimental evidence indicates that intestinal inflammatory conditions can be exacerbated by behavioral conditions such as depression. The recent demonstration of a tonic counterinflammatory influence mediated by the vagus nerve in experimental colitis provides a potential link between behavior and gut inflammation. Here we show that experimental conditions that induced depressive-like behaviors in mice increased susceptibility to intestinal inflammation by interfering with the tonic vagal inhibition of proinflammatory macrophages and that tricyclic antidepressants restored vagal function and reduced intestinal inflammation. These results show that reserpine-induced monoamine depletion and maternal separation, 2 models for depression, produced a vulnerability to colitis by a mechanism involving parasympathetic transmission and the presence of gut macrophages. The tricyclic antidepressant desmethylimipramine protected against this vulnerability by a vagal-dependent mechanism. Together these results illustrate the critical role of the vagus in both the vulnerability to inflammation induced by depressive-like conditions and the protection afforded by tricyclic antidepressants and rationalize a clinical evaluation of both parasympathomimetics and tricyclic antidepressants in treatment of inflammatory bowel disease.
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Vagus nerve dysfunction could exacerbate this neuroinflammatory pathway.
“Critically, vagus nerve dysfunction could exacerbate this neuroinflammatory pathway [43], [52].”
From The hidden genetic and microbial networks connecting neuropsychiatric and digestive disorders (2025) · cites this paper as [52]
The Introduction describes impaired vagal function as a proposed cause of increased susceptibility to gut inflammation, and the Discussion reports that vagotomy substantially worsened colitis in mice. This supports a vagus-mediated inflammatory mechanism, but the paper does not establish that dysfunction exacerbates a neuroinflammatory pathway specifically. (LLM, conf=0.83)
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“…2005; Martinez-Olivares et al., 2006; Sreemantula et al., 2004; Verheij and Cools, 2007), and as a result, reserpine administration in rats can induce depressive behavior (Ghia et al., 2008) and a marked hypothermia (Bill et al., 1989) which are accompanied by impaired parasympathetic function.”
BackgroundVagal Modulation of the Inflammatory Response in Sepsis
Wang, D.-W., Yin, Y.-M., & Yao, Y.-M. (2016) · International Reviews of Immunology · doi:10.3109/08830185.2015.1127369 · Cited by 48 · see citing works
“Tricyclic antidepressants reduced intestinal inflammation via a vagal-dependent mechanism [61].”
BackgroundBehavioral despair associated with a mouse model of Crohn's disease: Role of nitric oxide pathway
Heydarpour, P., Rahimian, R., Fakhfouri, G., Khoshkish, S., Fakhraei, N., Salehi-Sadaghiani, M., Wang, H., Abbasi, A., Dehpour, A. R., & Ghia, J. (2015) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2015.08.004 · Cited by 49 · see citing works
“We have previously shown that vagal nerve integrity is an important protective factor in experimental colitis (Ghia et al. , 2007, 2008).”
Self-citationLomax, L. B., Chisholm, S. P., Lukewich, M. K., & Lomax, A. E. (2009) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.2009.05242.x · Cited by 44 · see citing works
Giovangiulio, M. D., Bosmans, G., Meroni, E., Stakenborg, N., Florens, M., Farro, G., Gomez-Pinilla, P. J., Matteoli, G., & Boeckxstaens, G. (2016) · Molecular Medicine · doi:10.2119/molmed.2016.00062 · Cited by 46 · see citing works
Krabs, R. U., Enk, R., Teich, N., & Koelsch, S. (2015) · PLoS ONE · doi:10.1371/journal.pone.0126224 · Cited by 46 · see citing works
“Specifically, parasympathetic activity is taken to protect against intestinal inflammation [88,89], whereas sympathetic activity appears to worsen intestinal inflammation [90].”
BackgroundXiong, Y., Shi, L., Wang, L., Zhou, Z.-J., Wang, C., Lin, Y., Luo, D., Qiu, J.-J., & Chen, D.-P. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.05.030 · Cited by 45
Wang, D.-W., Zhou, R.-B., & Yao, Y.-M. (2009) · Chinese journal of traumatology = Zhonghua chuang shang za zhi · doi:10.3760/cma.j.issn.1008-1275.2009.06.007 · Cited by 44
Xiong, Y., Wang, J.-Y., Chu, H., Chen, D.-P., & Guo, H.-S. (2016) · Frontiers in Pharmacology · doi:10.3389/fphar.2016.00134 · Cited by 43 · see citing works
“According to the morphological criteria described previously, routine hematoxylin and eosin (HE)-stained colon section was measured to represent the degree of inflammation (Cooper et al., 1993; Ghia et al., 2008; Schwanke et al., 2013).”
MethodThe vagus nerve as a modulator of intestinal inflammation
van der Zanden, E. P., Boeckxstaens, G., & de Jonge, W. (2009) · Neurogastroenterology and Motility · doi:10.1111/j.1365-2982.2008.01252.x · Cited by 42 · see citing works
“Nevertheless, vagus nerve activity can regulate disease in animal models 10 , possibly clarified by the role of the spleen in exerting the anti-inflammatory effect of vagus nerve signaling or by changes in autonomic (para)sympathetic balance 96,97 .”
Salicylates Ameliorate Intestinal Inflammation by Activating Macrophage AMPK.
Banskota, S., Wang, H.-Q., Kwon, Y. H., Gautam, J., Gurung, P., Haq, S., Hassan, F. M. N., Bowdish, D., Kim, J.-A., Carling, D., et al. (2020) · Inflammatory Bowel Diseases · doi:10.1093/ibd/izaa305 · Cited by 41 · see citing works
Nowakowski, J., Chrobak, A. A., & Dudek, D. (2016) · Psychiatria Polska · doi:10.12740/pp/62382 · Cited by 50 · see citing works
“Impaired parasympathetic signaling aggravates symptoms of colitis and makes mice more vulnerable to it [41].”
BackgroundIBS-like symptoms in patients with ulcerative colitis
Gracie, D. J., & Ford, A. C. (2015) · Clinical and Experimental Gastroenterology · doi:10.2147/ceg.s58153 · Cited by 38 · see citing works
“Studies have demonstrated that in murine models of quiescent colitis, the induction of depression can reactivate inflammation of the colonic mucosa,(63) which can be attenuated by the administration of antidepressant drugs, and that this is mediated via interference with the inhibition of proinflammatory macrophage ac…”
The Gut's Little Brain in Control of Intestinal Immunity.
Jonge, D., & Wouter, J. (2013) · ISRN Gastroenterology · doi:10.1155/2013/630159 · Cited by 36 · see citing works
“Acetylcholine Nicotinic acetylcholine receptors Muscarinic acetylcholine receptors Multiple Vagotomy ameliorates colitis [68] Variable outcomes of nicotinic agonists on the course of colitis [51] Vagal nerve stimulation ameliorates intestinal inflammation: Postoperative ileus, [69] septic ileus Intestinal barrier brea…”
BackgroundPotential of Electrical Neuromodulation for Inflammatory Bowel Disease
Cheng, J., Shen, H., Chowdhury, R., Abdi, T., Selaru, F. M., & Chen, J. D. Z. (2019) · Inflammatory Bowel Diseases · doi:10.1093/ibd/izz289 · Cited by 41 · see citing works
Jarczyk, J., Yard, B., & Hoeger, S. (2019) · Kidney & Blood Pressure Research · doi:10.1159/000500920 · Cited by 36 · see citing works
The Versatile Role of the Vagus Nerve in the Gastrointestinal Tract
Stakenborg, N., Giovangiulio, M. D., Boeckxstaens, G., & Matteoli, G. (2013) · EMJ Gastroenterology · doi:10.33590/emjgastroenterol/10314603 · Cited by 36 · see citing works
Interleukin-17A Increases Neurite Outgrowth from Adult Postganglionic Sympathetic Neurons
Chisholm, S. P., Cervi, A. L., Nagpal, S., & Lomax, A. E. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.5343-11.2012 · Cited by 37 · see citing works
Ghia, J., Park, A. J., Blennerhassett, P., Khan, W., & Collins, S. (2011) · Inflammatory Bowel Diseases · doi:10.1002/ibd.21531 · Cited by 35 · see citing works
“2%) or reserpine solution (1 lg/day for 14 days) and were placed as previously described.(21) The same day vagotomy and pyloroplasty (VXP) was performed, ventral and dorsal truncal branches of the subdiaphragmatic vagus were cut (1 cm above gastroesophageal junction).”
MethodResultSelf-citationMikocka-Walus, A. A., Gordon, A. L., Stewart, B. J., & Andrews, J. M. (2012) · Journal of Psychosomatic Research · doi:10.1016/j.jpsychores.2011.06.006 · Cited by 34 · see citing works
“[1] have shown that inducing depression inmice increased their susceptibility to spontaneous intestinal inflammation by interfering with tonic vagal inhibition of pro-inflammatory macrophages.”
BackgroundEffect of 2 Psychotherapies on Depression and Disease Activity in Pediatric Crohnʼs Disease
Szigethy, E., Youk, A. O., Gonzalez-Heydrich, J., Bujoreanu, S. I., Weisz, J., Fairclough, D., Ducharme, P., Jones, N., Lotrich, F., Keljo, D., et al. (2015) · Inflammatory Bowel Diseases · doi:10.1097/mib.0000000000000358 · Cited by 34 · see citing works
Thomann, A., Mak, J. W. Y., Zhang, J., Wüstenberg, T., Ebert, M. P., Sung, J. J. �., Bernstein, C. N., Reindl, W., & Ng, S. C. (2020) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.15787 · Cited by 44 · see citing works
Cholinergic receptor activation on epithelia protects against cytokine‐induced barrier dysfunction
Dhawan, S., Hiemstra, I., Verseijden, C., Hilbers, F., Velde, A. T., Willemsen, L., Stap, J., den Haan, J. D., & de Jonge, W. (2015) · Acta Physiologica · doi:10.1111/apha.12469 · Cited by 34
“Third, muscarinic receptors are involved in colitis pathogenesis (Hirota & McKay 2006a, Hirota & Mckay 2006b), where the role of nicotinic receptors in mediating colitis disease course (Ghia et al. 2008) likely involves central activation of muscarinic receptors (Martelli et al.”
BackgroundGpr174 Knockout Alleviates DSS-Induced Colitis via Regulating the Immune Function of Dendritic Cells
Wei, W., Mu, S., Han, Y., Chen, Y., Kuang, Z.-S., Wu, X.-Y., Luo, Y., Tong, C.-Y., Zhang, Y., Yang, Y.-L., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.841254 · Cited by 33 · see citing works
“The health condition was monitored daily, and the disease activity index (DAI), including weight loss, stool consistency, and stool bleeding, was scored as described (14).”
BackgroundZhou, Z.-J., Wang, L., Feng, P., Yin, L., Wang, C., Zhi, S., Dong, J., Wang, J.-Y., Lin, Y., Chen, D.-P., et al. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01468 · Cited by 33
Marcon, R., Claudino, R., Dutra, R. C., Bento, A., Schmidt, E., Bouzon, Z., Sordi, R., Morais, R., Pesquero, J. B., & Calixto, J. Β. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2012.02136.x · Cited by 30 · see citing works
“All animals were examined once a day and the disease activity index (DAI) was assessed as previously described (Ghia et al., 2008).”
MethodTaché, Y., & Bernstein, C. N. (2009) · Gastroenterology · doi:10.1053/j.gastro.2009.04.032 · Cited by 32 · see citing works
Psychiatric Comorbidities of Inflammatory Bowel Disease: It Is a Matter of Microglia’s Gut Feeling
Fakhfouri, G., Mijailović, N. R., & Rahimian, R. (2024) · Cells · doi:10.3390/cells13020177 · Cited by 30 · see citing works
“In a pioneer study, Ghia et al. reported that impaired vagal nerve (VN) function increases susceptibility to IBD in a murine model of depression [24].”
BackgroundCholinergic Receptors Modulate Immune Complex–Induced Inflammation In Vitro and In Vivo
Vukelic, M., Qing, X., Redecha, P., Koo, G., & Salmon, J. (2013) · Journal of Immunology · doi:10.4049/jimmunol.1203467 · Cited by 31 · see citing works
Mikocka-Walus, A., Gordon, A. L., Stewart, B. J., & Andrews, J. (2012) · BMC Gastroenterology · doi:10.1186/1471-230x-12-93 · Cited by 31 · see citing works
“Moreover, in animal models antidepressant therapy has now been documented to ameliorate visible GI inflammation [22,23].”
BackgroundMaunder, R. G., Nolan, R. P., Hunter, J., Lancee, W. J., Steinhart, A., & Greenberg, G. R. (2012) · Inflammatory Bowel Diseases · doi:10.1002/ibd.21794 · Cited by 31 · see citing works
“Nonetheless, a common psychophysiological relationship may have particular importance in an inflammatory disease, because of the evidence that parasympathetic function downregulates inflammation.(13,18,47) Preliminary observations from our group indicate that fluctuations in HRV markers of parasympathetic function ove…”
Result
- Authors
- Ghia, J.-E., Blennerhassett, P., & Collins, S. M.
- Affiliations
- McMaster University (CA)
- Corresponding author
- Collins, Stephen M.
- Venue
- Journal of Clinical Investigation
- Published
- 2008-05-01
- Volume
- 118
- Issue
- 6
- Pages
- 2209-18
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2350428
- OpenAlex
- W2169338224
- Cited by
- 233
- References
- 0
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 13 · 2023: 14 · 2022: 16 · 2021: 10 · 2020: 13 · 2019: 9 · 2018: 12 · 2017: 10 · 2016: 23 · 2015: 16 · 2014: 15 · 2013: 19 · 2012: 10
- FWCI
- 9.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Institut de France
- McMaster University
- Crohn's and Colitis Foundation
- Crohn's and Colitis Foundation of Canada
- Canadian Association of Gastroenterology
- Topics
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- depression, inflammatory bowel disease, vagus nerve, parasympathetic nervous system, colitis, tricyclic antidepressants, desmethylimipramine, reserpine, maternal separation, monoamine depletion, gut-brain axis, neuroimmune regulation
- MeSH terms
- Animals, Antidepressive Agents, Brain, Colitis, Depressive Disorder, Disease Models, Animal, Female, Macrophages, Male, Mice, Inbred C57BL, Parasympathetic Nervous System, Reserpine, Serotonin, Inflammatory Bowel Diseases, Serotonin Agents, Genetic Predisposition to Disease, Mice
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