Neuroimmune Interactions in the Gut and Their Significance for Intestinal Immunity

Brinkman, David J.; Hove, Anne S. ten; Vervoordeldonk, Margriet J.; Luyer, Misha; Jonge, Wouter J. de

doi:10.3390/cells8070670

Cited by 66 publications

(66 citation statements)

References 155 publications

(188 reference statements)

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“…Today, VNS in CD patients is studied by another team 38 and in patients with rheumatoid arthritis 54 . Research on immune regulatory function by neural interfacing seems to provide a powerful tool to enhance remission in IBD patients, 77 and VNS research is currently conducted in order to perform and adapt the device to other diseases 78 . Of course, this pilot study requires confirmation in a larger randomized double‐blinded control study and, overall, a long‐lasting follow‐up of the patients to confirm these promising results 79 …”

Section: Discussionmentioning

confidence: 99%

A 12‐month pilot study outcomes of vagus nerve stimulation in Crohn's disease

Sinniger

Pellissier

Fauvelle

et al. 2020

Neurogastroenterology Motil

115

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Background The vagus nerve has anti‐inflammatory properties. We aimed to investigate vagus nerve stimulation (VNS) as a new therapeutic strategy targeting an intrinsic anti‐inflammatory pathway in a pilot study in Crohn's disease patients. The main objectives addressed the questions of long‐term safety, tolerability, and anti‐inflammatory effects of this therapy. This study is the continuation of previous reported findings at 6 months. Methods Nine patients with moderate active disease underwent VNS. An electrode wrapped around the left cervical vagus nerve was continuously stimulated over 1 year. Clinical, biological, endoscopic parameters, cytokines (plasma, gut), and mucosal metabolites were followed‐up. Key Results After 1 year of VNS, five patients were in clinical remission and six in endoscopic remission. C‐reactive protein (CRP) and fecal calprotectin decreased in six and five patients, respectively. Seven patients restored their vagal tone and decreased their digestive pain score. The patients' cytokinergic profile evolved toward a more “healthy profile”: Interleukins 6, 23, 12, tumor necrosis factor α, and transforming growth factorβ1 were the most impacted cytokines. Correlations were observed between CRP and tumor necrosis factor α, and some gut mucosa metabolites as taurine, lactate, alanine, and beta‐hydroxybutyrate. VNS was well tolerated. Conclusion & Inferences Vagus nerve stimulation appears as an innovative and well‐tolerated treatment in moderate Crohn's disease. After 12 months, VNS has restored a homeostatic vagal tone and reduced the inflammatory state of the patients. VNS has probably a global modulatory effect on the immune system along with gut metabolic regulations. This pilot study needs replication in a larger randomized double‐blinded control study.

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Section: Discussionmentioning

confidence: 99%

A 12‐month pilot study outcomes of vagus nerve stimulation in Crohn's disease

Sinniger

Pellissier

Fauvelle

et al. 2020

Neurogastroenterology Motil

115

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“…Nerve density measurements and denervation studies have been commonly used to elucidate the role of sympathetic and sensory nerves during IBD. Global sympathectomy can ameliorate and exacerbate colitis, depending on the model used (see summary in 31 ). Presently, we found a decrease in sympathetic nerve density (Figure 3), which is consistent with modestly decreased TH axons in gut submucosal arteries in 2,4,6-Trinitrobenzenesulfonic acid (TNBS) colitis 32 but in contrast to unchanged TH nerves in human submucosal arteries 33 and increased TH nerves in human MAs 34 with IBD.…”

Section: Discussionmentioning

confidence: 99%

Altered substance P signaling underlies perivascular sensory nerve dysfunction in inflammatory bowel disease

Norton

Grunz-Borgmann

Hart

et al. 2020

Preprint

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Objective: Inflammatory Bowel Disease (IBD) is associated with cardiovascular disease risk and impaired intestinal blood flow, but the functional role of perivascular nerves that control vasomotor function of mesenteric arteries (MAs) perfusing the intestine is unknown in IBD. Because perivascular sensory nerves and their transmitters calcitonin gene-related peptide (CGRP) and substance P (SP) are important mediators of both vasodilation and inflammatory responses, our objective was to identify IBD-related deficits in perivascular sensory nerve function and vascular neurotransmitter signaling.Approach and Results: In MAs from an IL-10 -/mouse model, we found that IBD significantly impairs EFS-mediated sensory vasodilation and sensory inhibition of sympathetic vasoconstriction, despite decreased sympathetic nerve density and vasoconstriction. The MA content and EFS-mediated release of both CGRP and SP are slightly decreased with IBD, but IBD has different effects on each transmitter. CGRP nerve density, receptor expression, hyperpolarization and vasodilation are preserved with IBD. In contrast, SP nerve density and receptor expression are increased, and SP hyperpolarization and vasodilation are impaired with IBD. A critical finding is that blocking neurokinin 1 (SP) receptors restored EFS-mediated sensory vasodilation and enhanced CGRP-mediated vasodilation in MAs from IBD but not Control mice.Conclusions: An aberrant role for the perivascular sensory neurotransmitter SP and its downstream signaling in MAs underlies vascular dysfunction with IBD. With IBD, SP signaling impedes CGRP-mediated sensory vasodilation, contributing to impaired blood flow. Substance P and NK1 receptors may represent an important target for treating vascular dysfunction in IBD.

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“…Together these studies provide a rationale for targeting neural circuits to regulate immune responses with potential therapeutic implications in the domain of TNF-mediated diseases, such as rheumatoid arthritis and inflammatory bowel disease (Crohn's disease and ulcerative colitis) as demonstrated successfully in pilot studies using VNS (Bonaz et al 2016;Koopman et al 2016). The sympathetic pathway, through the splanchnic nerves interacting with the spleen, has also shown anti-inflammatory effects and could be a target of bioelectronic medicine (Brinkman et al 2019).…”

Section: Impactmentioning

confidence: 96%

Parameters matter: modulating cytokines using nerve stimulation

Bonaz

2020

Bioelectron Med

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The vagus nerve-based inflammatory reflex regulates inflammation and cytokine release. Recent successful clinical trials using implantable bioelectronic devices to modulate the inflammatory reflex in patients with rheumatoid arthritis and inflammatory bowel disease have demonstrated the efficacy of targeting neural circuits as an efficient alternative to drug treatments. However, the optimal vagus nerve stimulation parameters to achieve efficacious symptomatic relief for inflammation are still unknown. In this issue of Bioelectronic Medicine, Tsaava et al. tested whether altering these electrical stimulation parameters would change circulating cytokine levels in healthy mice. They found that specific combinations of parameters produced significant increases in serum TNF while other parameters selectively lowered serum TNF levels, as compared to sham stimulated mice. These results have considerable implications for determining the optimal stimulation parameters to better treat common conditions and diseases that involve immune regulation.

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Neuroimmune Interactions in the Gut and Their Significance for Intestinal Immunity

Cited by 66 publications

References 155 publications

A 12‐month pilot study outcomes of vagus nerve stimulation in Crohn's disease

A 12‐month pilot study outcomes of vagus nerve stimulation in Crohn's disease

Altered substance P signaling underlies perivascular sensory nerve dysfunction in inflammatory bowel disease

Parameters matter: modulating cytokines using nerve stimulation

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