War Stories: James - Impact of Vitamin D

By Eugene L. Heyden, RN

I’m sure you’ve heard of Kelly by now. Others have told her story, and you can find my version here, on my website. And just so you don’t get the impression that Kelly is the only one who’s Crohn’s went into remission via vagal nerve stimulation (VNS), let me introduce you to James.

Case Report: James

James was 48 at the time a vagal nerve stimulator was implanted to see if he could suffer less in his battle against Crohn’s. The specifics of his disease were not thoroughly reported, but we will assume it was all ugly and he wanted no part of it. What was reported, however, was that James had Crohn’s for 28 years and somewhere along the way he had an ileocecal resection, yet his Crohn’s persisted. Additionally reported, for that past 7 years his disease was managed by the immunosuppressant drug Imurel (azathioprine).

In April 2012 a vagal nerve stimulator was implanted and set to deliver low frequency impulses to the left cervical vagus nerve.

“The device was switched on at 0.5 mA the day of the surgery and increased by 0.25 mA each week until 1 mA. Stimulation parameters were: 30 s ON e 5 min OFF, 500 ms, 10 Hz. VNS [vagal nerve stimulation] was continuously performed over 12 months.” (Clarençon et al., 2014)

And the result? James “presented a significant clinical improvement, with a progressive decrease of the CDAI score and an endoscopic remission at month 12.” And apparently his remission was durable. At month 12 his vagal nerve stimulation trial ended, at month 16 his immunosuppressant was discontinued, and at week 27 we find James still maintaining his remission.

James’s story can be found in Clarençon et al., 2014 (in References). Oh, by the way, James is not his real name (or is it?).

So, what’s going on here?

“The vagus nerve not only is essential in the detection of inflammation but also provides an important route through which the central nervous system can respond.” (Van Westerloo et al., 2005)

“Clinical evidence indicates that when vagus nerve activity is deficient, inflammation is excessive.” (Huston and Tracey, 2011)

“By lowering the inflammation in IBD patients, induction or maintenance of remission may be achieved.” (Sharifi et al., 2016)

The Cholinergic Anti-inflammatory Pathway is a network of nerves, associating receptors, and chemicals which act in concert to modulate inflammation. It starts with the brain, and “provides a way for the brain to regulate the cytokine response in a localized, controlled, and organ-specific manner.” (Tracey, 2005) And the nerve at the center of it all is the vagus nerve.

Briefly, the vagus nerve extends downward from the brain in a wandering fashion and establishes communication with the digestive system and a variety of key organs and tissues to influence their function. Operationally, its many terminal endings emit a neurotransmitter called acetylcholine. Once released, acetylcholine binds a special receptor located on the surface of the target cell, called the α7 nicotinic acetylcholine receptor (α7nAChR), and the magic happens. In fact, “The anti-inflammatory properties of the vagus nerve depend on activation of α7nAChR.” (Seyedabadi et al., 2018) When acetylcholine is sent forth as a signal, according to the scheme of things, a response follows. Importantly, because this receptor also resides on the surface of immune cells, such as the macrophage, the response evoked by vagal nerve stimulation is a reduction in the production of pro-inflammatory molecules, such as TNF-α and IL-6. Thus, an axis of sorts exists whereby, “when vagus nerve activity is deficient, inflammation is excessive.” (Huston and Tracey, 2011)

Due to the existence of this anti-inflammatory pathway, and due to the ability to increase vagal nerve signaling by electrical stimulation, James was able to leverage The Cholinergic Anti-inflammatory Pathway to reduce inflammation and achieve remission from Crohn’s. By taking advantage of this pathway, James likely experienced most if not all the established benefits of vagal nerve stimulation, including

A reduction in pro-inflammatory cytokine production without affecting the production of anti-inflammatory cytokines (Pavlov and Tracey, 2006; Giebelen et al., 2009)
A reduction in mucosal inflammation (Ji et al., 2014)
A reduction in intestinal permeability (Van Der Zanden et al., 2009)
The protection of involved tissues by inhibiting a local, excessive inflammatory response (Tracey, 2010)
An enhanced ability of the macrophage to devour the pathogen (De Winter and De Man, 2010)
The inhibition of proinflammatory, M1 macrophages (Bonaz et al., 2018)

I have a feeling that James is a big fan of vagal nerve stimulation.

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References:

Bonaz B, Bazin T, Pellissier S. The vagus nerve at the interface of the microbiota-gut-brain axis. Frontiers in neuroscience. 2018 Feb 7;12:49. https://www.frontiersin.org/articles/10.3389/fnins.2018.00049/full

Clarençon D, Pellissier S, Sinniger V, Kibleur A, Hoffman D, Vercueil L, David O, Bonaz B. Long term effects of low frequency (10 hz) vagus nerve stimulation on EEG and heart rate variability in Crohn’s disease: a case report. Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation. 2014 Nov 1;7(6):914-6. https://www.brainstimjrnl.com/article/S1935-861X(14)00270-8/abstract

De Winter BY, De Man JG. Interplay between inflammation, immune system and neuronal pathways: effect on gastrointestinal motility. World journal of gastroenterology: WJG. 2010 Nov 28;16(44):5523. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992670/

Giebelen IA, Leendertse M, Florquin S, van der Poll T. Stimulation of acetylcholine receptors impairs host defence during pneumococcal pneumonia. European Respiratory Journal. 2009 Feb 1;33(2):375-81. https://erj.ersjournals.com/content/33/2/375.short

Huston JM, Tracey KJ. The pulse of inflammation: heart rate variability, the cholinergic anti‐inflammatory pathway and implications for therapy. Journal of internal medicine. 2011 Jan;269(1):45-53. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2796.2010.02321.x

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 immunology. 2014 Mar;7(2):335. https://www.nature.com/articles/mi201352

Pavlov VA, Tracey KJ. Controlling inflammation: the cholinergic anti-inflammatory pathway. Biochemical Society transactions. 2006 Dec;34(Pt 6):1037. https://portlandpress.com/biochemsoctrans/article-abstract/34/6/1037/65963

Seyedabadi M, Rahimian R, Ghia JE. The role of alpha7 nicotinic acetylcholine receptors in inflammatory bowel disease: involvement of different cellular pathways. Expert opinion on therapeutic targets. 2018 Feb 1;22(2):161-76 https://www.tandfonline.com/doi/abs/10.1080/14728222.2018.1420166

Sharifi A, Hosseinzadeh-Attar MJ, Vahedi H, Nedjat S. A randomized controlled trial on the effect of vitamin D3 on inflammation and cathelicidin gene expression in ulcerative colitis patients. Saudi journal of gastroenterology: official journal of the Saudi Gastroenterology Association. 2016 Jul;22(4):316. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991203/

Tracey KJ. Fat meets the cholinergic antiinflammatory pathway. Journal of Experimental Medicine. 2005 Oct 17;202(8):1017-21. https://rupress.org/jem/article-abstract/202/8/1017/52927

Tracey KJ. Understanding immunity requires more than immunology. Nature immunology. 2010 Jul 1;11(7):561. https://www.nature.com/articles/ni0710-561

Van Der Zanden EP, Boeckxstaens GE, De Jonge WJ. The vagus nerve as a modulator of intestinal inflammation. Neurogastroenterology & Motility. 2009 Jan;21(1):6-17. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2982.2008.01252.x

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