The Gut, the Digestive System and Parkinson's Disease, Part 2

Introduction

In recent years, much has emerged and been written about in the scientific literature on possibly central roles of the gut, digestive system and enteric nervous system in the causality and prognosis of Parkinson’s Disease. Indeed, a while back, I wrote an article summarizing some of the most interesting and relevant scientific findings in this area,

THE GUT, THE DIGESTIVE SYSTEM AND PARKINSON'S DISEASE, PART 1.

Subsequently, I also proposed a simple and elegant, yet predictive, explanation for Idiopathic PD, namely that it occurs when we become stuck in a Dorsal Vagus Nerve mediated freeze/immobilization stress response,

THE DORSAL VAGUS NERVE AND PARKINSON'S DISEASE.

The Dorsal Vagus Nerve connects the sub-diaphragmatic organs of digestion to the brain, and also interfaces with the enteric nervous system embedded in the gut lining, and thus acts as a two-way information highway of the gut-brain axis. Thus this vagal perspective of PD also intrinsically involves the gut.

In this follow-up article, we continue the exploration of the role of the gut, the digestive system, and gut-brain communication via the Dorsal Vagus Nerve, in PD. We will consider more recent findings, and look at some other angles involving the gut which have practical importance.

THE GUT-BRAIN-AXIS AND DOPAMINE

A very important finding for PD arises from the scientific journal paper,

A Neural Circuit for Gut-Induced Reward,

which actually establishes a direct link of the Vagus Nerve endings in the gut with dopamine production in the Substantia Nigra part of the brain!

“Highlights

•Critical role for the vagal gut-to-brain axis in motivation and reward

• Optogenetic (light) stimulation of the vagal gut-to-brain axis produces reward behaviors

• Asymmetric brain pathways [from right side of gut only] of vagal origin mediate motivation and dopamine activity

• Gut-innervating vagal sensory neurons are major components of the reward circuitry”

Summary

"The gut is now recognized as a major regulator of motivational and emotional states."

The paper goes on to say:

"However, the relevant gut-brain neuronal circuitry remains unknown. We show that optical activation of gut-innervating vagal sensory neurons [create] the hallmark effects of stimulating brain reward neurons. Specifically, right, but not left, vagal sensory [nerve] activation sustained self-stimulation behavior, conditioned both flavor and place preferences, and induced dopamine release from Substantia Nigra."

This implies that sensory signals from the gut play a role in the production or lack thereof of dopamine in the brain. Indeed, the Substantia Nigra is precisely the area of the brain where dopamine production is impaired in PD, and hence a contributing factor to the degeneration of the dopamine producing brain cells here could be via a lack of appropriate reward signals arising in the gut.

Our findings establish the vagal gut-to-brain axis as an integral component of the neuronal reward pathway. They also suggest novel vagal stimulation approaches to affective disorders."

So this seems to help explain the "how" of the mechanism by which the Dorsal [subdiaphragmatic] Vagus branch actually activates freeze/immobilization in response to stress: by cutting off or inhibiting the reward signals from the gut to produce dopamine in the Subtantia Nigra, shutting down self-stimulating reward feedback, motivation and movement.

This would seem to indicate that not only does Parkinson's Disease “begin in the gut”, but also that onset of a symptom attack begins in the gut, through right sided Dorsal Vagus activation of its immobilzation function. This matches my own daily experience: when my gut goes quiet and I lose the sensation of my digestive tract, my symptoms are worse. Like most people with PD, my symptoms are also greatly increased when I am constipated or after a heavy meal. It may also explain why people with PD are so strongly affected by personal food intolerances. These may all result in alarm signals instead of reward signals being sent from the gut, inhibiting dopamine production more.

This link between the gut and dopamine in the brain also helps explains why those who have had their Dorsal Vagus surgically cut get a strong protection from PD, presumably because then the inhibitory communications and alarm signals between gut and Substantia Nigra are also severed, see Part 1. Severing the dorsal vagus can also prevent alpha-synuclein build up in the brain, as concluded in

Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson’s Disease,

where scientists abused mice to discover if the problem protein which is a signature of PD can get to the brain from the gut via the subdiaphragmatic (dorsal) vagus nerve bundle. They injected the mice with alpha-synuclein into their guts. In some of the mice they also severed the dorsal vagus beforehand. In the mice with intact nerve, they found alpha-synuclein in the brains of mice some time later, and these displayed typical mouse Parkinson's symptoms. On the other hand, the mice with severed dorsal vagus nerves did not show signs of alpha-synuclein in the brain and behaved like "normal" mice.

We can also tie this in with another paper experimenting on rodents, which showed that a malfunctioning dorsal vagus nerve results in dopamine deficiency in the brain,

Chronic impairment of the vagus nerve function leads to inhibition of dopamine but not serotonin neurons in rat brain structures,

“… suggests a close relationship between the [dorsal] vagus nerve impairment and the inhibition of dopamine system in the brain structures. This is the first report of such relationship which may suggest that mental changes (pro-depressive) could occur in the first stage of Parkinson's disease far ahead of motor impairment.”

Again, this points to unhealthy Dorsal Vagus Nerve activation causing a downregulation of dopamine in the brain via signals from the gut.

These signalling issues appear to be more concerned with the right branch of the Dorsal Vagus rather than the left. While stimulation of the right Dorsal Vagus has potential therapeutic value, as mentioned in the research, some care will need to be taken in people who experience freezing problems. The stimulation needs to enhance the dopamine reward system from the gut, but not stimulate the freeze response even more, worsening the issues. For example, an older article,

Selective vagal innervation of sinoatrial and atrioventricular nodes in canine heart,

suggests that some forms of stimulation of the Vagus Nerve in the right side (only) of the neck can cause bradycardia, a critical slowing down of heart and breathing rate, a state which will be so familiar for people with PD. Interestingly, this article also finds significant differences in the way the left and right vagus nerves interact with the heart:

“Left vagal projections … course primarily along and between the right pulmonary artery and left superior pulmonary vein. Right vagal projections … are somewhat more diffuse but concentrate around the right pulmonary vein complex and adjacent segments of the right pulmonary artery. We conclude there are parallel, yet functionally distinct, inputs from right and left vagi.”

Another study actually measured the cross-sectional area of the left and right vagus nerve bundles,

Atrophy of the Vagus Nerve in Parkinson's Disease Revealed by High-Resolution Ultrasonography,

which revealed that the Vagus Nerve is indeed significantly smaller in cross-section in people with Parkinson’s Disease than the general population. Interestingly, the right side vagus is found to be more significantly atrophied. Moreoever, the degree of atrophy correlated to symptom severity, and

“…the right vagus nerve [atrophy] but not of the left vagus nerve correlated with the parasympathetic [decrease] of heart rate variability [a measure of robustness to stress]… “

The study concludes that is the unmyelinated Vagus Nerve fibers which atrophy, corresponding to the subdiaphragmatic Dorsal Vagus. Thus this research also suggests that normal communication between the gut and the brain via the Dorsal Vagus Nerve is significantly disrupted and hence a major factor in PD.

So this does all point to the vagus nerve, especially the right branch of the Dorsal Vagus, having a principle role in the development of the disease.

Digestive issues and the gut-brain axis

I also came across more science on the role of the Dorsal Vagus Nerve in digestive and gut process, and in regulating pancreatic excretions in particular,

The dorsal motor nucleus of the vagus and regulation of pancreatic secretory function.

Again, given that digestive and gut issues abound in Parkinson’s Disease, this is another significant link between dorsal vagus dysregulation and the condition. Moreover, a direct link between dorsal vagus nerve issues and diabetes is also made, in regards to insulin production, and its affect on the gut-brain axis:

Glutamatergic drive facilitates synaptic inhibition of dorsal vagal motor neurons after experimentally induced diabetes in mice.

A more recent paper expands on this link:

A hindbrain inhibitory microcircuit mediates vagally-coordinated glucose regulation

The article is very technical and somewhat impenetrable, so I have attempted to extract the more digestible parts:

"Vagally-mediated parasympathetic output critically regulates visceral functions related to metabolic [balance]... insulin release requires an intact vagus nerve and [damage to the] vagus nerve potently suppresses effects of central insulin... Neurons in the DVC [Dorsal Vagus Complex] clearly influence blood glucose concentration, yet little is known about the circuitry underlying this effect."

"Neurons throughout the DVC are directly responsive to a wide range of nutrient and satiety signals, including leptin, insulin, lactate, and glucose. GABA release in the dorsal motor nucleus of the vagus (DMV) [part of the brain] is also significantly elevated after the induction of diabetes."

Dorsal vagus over-activation or dysregulation may therefore help explain the often proposed links between PD and diabetes too, such as those found in a recent article in Psychology Today,

Parkinson's, Alzheimer's, and the New Science of Hope,

which actually posits that excessive glucose in the brain may be causal of PD and Alzheimer’s.