The Gastroparesis Procedure: Brain Gut Connections--Top Down And Bottom Up.

Abstract -- Delayed gastric emptying (GE) is called gastroparesis (associated with Irritable Bowel Syndrome -constipation). The following procedure was developed to produce gastric emptying. Drinking coffee is a pre-requisite for the anti-gastro paretic effects of the procedure. The procedure, in a nutshell, is this: for one hour after taking coffee and rocking on one’s side, gastric emptying of coffee is induced (i.e. diuresis is produced). The above steps are necessary for the cervical traction device (TD) to function, in which one lays on one’s side while performing neck pulls. The following analysis of the inputs of the procedure uses known research about how the steps of the procedure work.

Coffee consumption led to an increase in caffeine and adiponectin (median: 6%), with 8 cups of coffee per day. There was a correlation of differences in caffeine concentrations with differences in adiponectin concentrations, (decaf coffee didn’t change adiponectin concentration).[i] The pyruvate dehydrogenase complex (PDC) activity maintains blood glucose and ATP levels, which largely depend on the phosphorylation status by pyruvate dehydrogenase kinase (PDK) isoenzymes. PDC is inactivated by PDK4 in metabolically active tissues including skeletal muscle. The mechanism by which expression of PDK4 is transcriptionally regulated (upregulation of PDK4) involves endogenous ligands that bind nuclear receptors, (adiponectin). Adiponectin, which has been recognized as an insulin sensitizer in skeletal muscle, stimulates fat oxidation via the activation of AMPK (adenosine mono phosphate kinase). Adiponectin decreased PDK4 expression, causing decreased blood glucose via the down-regulation of PDK4 in skeletal muscle, (dis-inhibiting PDC).[ii]

The brain uses glucose at astrocytes to produce pyruvate and powers a glutamate (Glut)/glutamine exchange transport across the blood-brain barrier and the remaining glucose is used as a fuel for the neurons, usually excited by Glut-the most abundant neurotransmitter in the body. The brain is exposed to the same relative change in glucose concentration as the rest of the body during acute episodes of hypo and hyperglycemia. In the brain, glucose concentrations have generally been found to be 20-30% of those measured in the plasma. Consequently, when plasma glucose concentrations are reduced to hypoglycemic levels, the concentration in the brain falls.[iii] There are interneurons that connect the thalamus to the cortex, (thalmo-cortical pathway). The thalamus may be involved in the coordination of the counter regulatory response to hypoglycemia. A positive correlation was observed between thalamic response and epinephrine response to hypoglycemia.[iv]

The epinephrine released effects the vagal sensory neurons via the plasma. The presence of beta-adrenergic receptors on vagal sensory neurons participates in the monitoring of plasma and tissue catecholamine concentrations. Furthermore, signaling transmitted by vagal afferents regulates the vagal efferent system activity at the level of the brain.[v] It is believed that diminished vagal sensory processing is a culprit in upper gastrointestinal dysmotility.[vi] The result of increased plasma epinephrine may be a gastro-excitatory signal that leads to upper GI motility. Activation of the DMV (dorsal motor nucleus of the vagus) causes both gastric contractions and cecal relaxations, which cause colonic motility, (passing of flatus—remember this for later), and gastric emptying.

Short chain fatty acids (specifically Butyrate-- with butyrate the preferred energy source for the colonocytes) initiate signals causing the release of factors that regulate nociceptive neuronal excitability. The signal transduction pathways responsible for the enhanced neuronal excitability in the dorsal root ganglion following sodium Butyrate enemas, caused a reduction in I(A) (current [amplitude]), to 48.9% of control and an increase in neuronal excitability.[vii] Nociceptive neurons are found primarily in the superficial laminae I-II and deep laminae V-VI of the spinal and medullary dorsal horns, and also in the thalamus and cortex. Direct activation of glial astrocytes can generate nociceptive neuronal hypersensitivity associated with mechanical and tactile allodynia (increased pain at touch). Findings suggest that astrocyte-released glutamate evokes NMDA receptor-mediated episodes of synchronous activity in groups of superficial laminae I-II neurons.[viii]

The spinothalamic tract (STT) arises primarily from cells in lamina I of the dorsal horn, from lamina V cells and responds only to noxious mechanical stimuli. STT cells of lamina V tend to respond to both innocuous and noxious stimuli. Using anterograde transport, it was found that there is a substantial projection of the dorsal STT to the posterior nuclei (Po). (Colon pain also projects to the Po—so neck pain, thalamic activation, and colon pain might be additive in producing an adrenaline release). There is increased activity in the primary somatosensory cortex (SI) a major projection target of Po that plays an important role in processing sensory-discriminative aspects of pain. STT axons passed through Po thalamus en route to VP, (I.E. the Po is caudal to the primary somatosensory nuclei,--in the ventral posterior thalamus). The Po thalamus plays a qualitatively different role in pain sensation from the VP).

Although the role of SI in nociceptive processing is controversial, several lines of evidence support the notion the SI is a key component of the cortical network that is responsible for pain perception. With regard for the specific role SI may play in pain processing, electrophysiological studies in animals and human functional neuroimaging studies have found that SI encodes stimulus intensity. To determine whether noxious movements of the mechanoreceptor-rich deep tissues of the neck modulate the sympathetic outflow to the adrenal glands, a computer driven small animal manipulator was used to impose ramp and hold rotational displacements of the 2nd vertebra while recording multi-unit activity from sympathetic nerves innervations of the adrenal gland. The data suggest that noxious stimuli may modulate sympathetic outflow.[ix]

The following is a theory to explain the increase in adrenal output as stated above. The projections of primary afferents from rostral cervical segments to the brainstem and the spinal cord of the rat were investigated by using anterograde transport techniques. Lateral collaterals projected mainly to the lateral spinal lamina V. Results from transganglionic staining indicated the lateral collaterals were contributed to by suboccipital proprioceptive fibers. Cervical traction causes the sympathetic plexus surrounding the vertebral arteries to be stretched and stimulated.[x] The deep pathway (vertebral nerve and its branches) with the superficial pathways (the sympathetic trunk and its branches) formed a sympathetic nervous “plexus” in the cervical region.[xi] The effect of a simulated manipulation position on blood flow in the vertebral arteries with color Doppler ultrasound imaging was used to image the vertebral arteries and to measure blood flow velocity with the neck in neutral and simulated manipulation positions. A measure of distal vascular resistance, the resistance index, was calculated. There was a significant reduction in the resistance index in the vertebral arteries ipsilateral to the rotation component of the simulated manipulation position.[xii]

Blood flow in the circle of Willis (CoW) was modeled using the 1-D equations of pressure and flow wave propagation in compliant vessels. The governing system of equations results from conservation of mass and momentum applied to a 1-D impermeable and deformable tubular control volume of incompressible and Newtonian fluid. The equation of momentum conservation together with the constitutive relation for a Newtonian fluid yield the famous Navier-Stokes equations, which are the principal conditions to be satisfied by a fluid as it flows. The fluid flow patterns in laminar flow are also called potential flow, because its linear velocity is the gradient of some function called the velocity potential. Potential flow is represented by the Laplace equation.[xiii]  The vascular system was analyzed as being analogous to an electrical transmission line where various influences on BP were described in quantitative terms via the Navier-Stokes equation, for the transmitted wave’s hemodynamic character. This was an exact analogy to an electrical transmission line where pressure is analogous to voltage, flow is analogous to current and the hydraulic parameters of resistance ®, inductance (L), and capacitance © are analogous to their electrical equivalents. The collateral ability of the complete CoW was studied in normal conditions and after occlusion of vertebral arteries (VAs). The communicating arteries become important in cases of occluded vessels, the posterior communicating arteries (PCoAs) being more critical if VAs are occluded. In patients with occluded VAs, the direction of flow measured at the PCoAs corresponds to an increase in the caliber of their lumen to compensate for any reduction in blood flows. Another three dimensional model of cerebrovascular flow stated that inflow is provided through two ICAs and two VAs. Outflow is provided through the anterior cerebral arteries, the middle cerebral arteries, and the posterior cerebral arteries, (PCAs). When flow in PCAs is high,
(caused by increased VA flow), the 1-D model predicts low collateral volume flow rates through the communicating arteries, (PCoAs), since they are the only possible pathway to a low pressure efferent vessel (PCA). In other words, blood flow takes the path of least resistance—from high to low pressure. This results in a decrease of blood flow through the internal carotid arteries (ICAs) and pressure (far upstream) at the point of the carotid bodies. According to Possuille’s equation, this would result in an decrease in blood pressure sensed at the carotid bodies. According to equation (3), with values of constants
provided by the text, the Area: pressure ratio is 2:1, ( for Area (cross-sectional area of VAs) relation with increased pressure sensed at carotid bodies).[xiv] Decreased stretch of the carotid bodies (equal to decreased resistance and pressure sensed at the carotids) causes a decreased MAP (mean arterial pressure)—BRR (baroreceptor reflex response) resulting in a release of epinephrine from the adrenals via the RVLM pathway.[xv] This activates the DMV (dorso motor nucleus of the vagus), causing stomach contractions and cecal relaxation. This causes Butyrate at the distal small intestine, causing ileal contractions causing an increased flow through the cecum.

Microbial metabolism of dietary carbohydrates results mainly in the formation of SCFAs and gases. The major bacterial fermentation products are acetate, propionate and butyrate, in which Butyric acid, which in health is absorbed completely by the proximal small intestine, is a major SCFA produced by bacterial fermentation of undigested carbohydrates and proteins.[xvi] The G protein-coupled receptors, GPR43, are activated by SCFAs that increased the frequency of peristaltic contraction in guinea-pig terminal ileum.[xvii] The ileocecocolonic junction is able to behave as a synchronized segment involving propagated contractions originating in the small intestine and provides a clearance mechanism for reflux of ileal contents into the colon. Cecal balloon distension caused a dilation and diminished CCJ (ceco-colonic junction) pressure.[xviii] Undigested amylose starch that is not fully hydrolyzed in the small intestine, passes into the large intestine (colon) where it is fermented by bacteria that produce SCFAs. Increased SCFA transfer to the colon causes increased pain transmission via the STT to SI, releasing epinephrine upon application of the traction device (in a positive feedback loop manner). This results in DMV activation and gastric emptying.

In patients with chronic constipation there is high prevalence of alterations of small bowel motility, with abnormally high rates of contraction.[xix] The enterochromaffin cell (EC cell), which also senses alterations in luminal or mucosal oxygen levels, is physiologically sensitive to fluctuations in oxygen levels. Reducing O2 elevated 5-HT secretion (2-3.2-fold). In diarrhea-dominated IBS, (accompanied by increased peristalsis and decreased transit time) there is increased postprandial plasma 5-HT. During fasting, the blood flow is low (5% of cardiac output), which then rises significantly to 30% after a meal, increasing PO2. Alterations in 5-HT release are critically relevant to the regulation of normal gut function; EEC cells mediate gut secretion, peristalsis, and motility by the secretion of 5-HT.[xx] Therefore, when gastric emptying is activated by SCFA at the colon, increased PO2 levels decrease 5-HT release and decrease ileal contractions associated with c-IBS.

Mechanosensitive channels on sensory neurons and P2X3 receptors are activated by mechanical distortion. Stretching of the ileum causes ATP-release and Ca(2+) signaling that was cell-shape dependent, i.e. they were further enhanced by stretching and the ileum acts as a mechanosensor. Subepithelial fibroblasts form a cellular network just under the epithelium of the gastrointestinal tract and have unique characteristics, such as cell-cell communication via released ATP and Ca(2+) signaling in the cellular network. Since Ca(2+) contributes to the activation of contractile proteins (actin) , these findings suggest a contribution from the actin cytoskeleton on ATP release in subepithelial fibroblasts. The released ATP activates Purine (P) 2Y receptors on the surrounding cells and propagates Ca (2+) waves through the network and also activates P2X on terminals of mucosal sensory neuron. The number of DRG neurons responding to ATP and the number of those staining for the P2X3 receptor, were increased after application of ATP.[xxi]

Activation of P2Y(4) (Purine) receptors, leads to inhibition of the contractile activity of 5-HT. ATP in the ileum, induces by activation of P2Y(4) receptors only muscular relaxation. [xxii] On the contrary to the functional entity corresponding to the CCJ, the ICS (ileocolonic sphincter) provides a clearance mechanism for reflux of colonic contents into the small intestine.[xxiii] The cecum has the highest concentration of SCFAs and the presence of SCFA in the distal ileum is an important actor in triggering this clearance mechanism, via GPR43. This would increase contractions of the ileum that would increase flow at the cecum, causing increased SCFA at the colon walls. This activates DRG projections to the SI (eventually) such that the cervical traction device function repeats.

[i] Kempf et al, “Effects of coffee consumption on subclinicalinflammation and other risk factors for type 2 diabetes: a clinical trial,” 2010, Am J Clin Nutr; 91(4): 950-7.

[ii] Jeong et al, “Transcriptional regulation of pyruvate dehydrogenase kinase,” 2012, Diabetes Metab J; 36; 328-335.

[iii] Seaquist ER, Oz G, “Sweet and low: Measuring brain glucose during hypoglycemia,” 2012, Diabetes; 61(8): 1918-1919.

[iv] Mangia et al, ”Hypoglycemia-induced increases in thalamic cerebral blood flow are blunted in subjects with type 1 diabetes and hypoglycemia unawareness,” 2012, J Cereb Blood Flow Metab, Epub 8/15/2012.

[v] Mravec B, “Role of catecholamine-induced activation of vagal afferent pathways in regulation of sympathoadrenal system activity: negative feedback loop of stress response,” 2011, Endocrine Regulations; 45: 37-41.

[vi] Holmes GM, “Upper gastrointestinal dysmotility after spinal cord injury: is diminished vagal sensory processing one culprit?,”2012, Front Physiol; 3:277.

[vii] Xu et al, “Butyrate-induced colonic hypersensitivity is mediated by mitogen-activated protein kinase activation in rat dorsal ganglia,” 2012, Gut [Epub ahead of print—7/24].

[viii] Chang CY, Sessie BJ, Dostrovsky JO, “Role of astrocytes in Pain,” Neurochem Res, 2012; 37: 2419-2431.

[ix] Bolton P, Budgell B, Kimpton A, “Influence of innocuous cervical vertebral movement on the efferent innervations of the adrenal gland in the rat.” Auton Neurosci, 2008; 124: 103-11.

[x] Pan et al., “Clinical response and autonomic modulation as seen in heart rate variability in mechanical intermittent cervical traction: a pilot study,” 2012, J Rehab Med; 44(3)):229-34.

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[xii] Bowler,N, Shamley D, Davies R, “The effect of a simulated manipulation position on internal carotid and vertebral artery blood flow in healthy individuals, Man Ther, 2011; 16(1): 87-93.

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[xvi] Scott et al, “The influence of diet on the gut microbiota,” Pharmacol Res, 2012; S1043-6618(12)00207-1.

[xvii] Dass et al, “The relationship between the effects of short-chain fatty acids on intestinal motility in vitro and GPR43 receptor activation,” Neurogastroenterol Motil, 2007; 19(1): 66-74.

[xviii] Shafik et al, “Study of the functional activity of the cecocolonic junction with identification of a “physiologic sphincter”, “cecocolonic inhibitory reflex” and “colocecal excitatory reflex,” Surg Radiol Anat, 2003; 25(1): 16-20.

[xix] Seidl et al, “Small bowel motility in functional chronic constipation,” Neurogastroenterol Motil, 2009; 21(2): 1278-e122.

[xx] Haugen et al, “Differential signal pathway activation and 5-HT function: the role of gut enterochromaffin cells as oxygen sensors,” Am J Physiol Gastrointest Liver Physiol, 2012;303: G1164-G1173.

[xxi] Furuya k, Sokabe M, Furuya S (2005) “ Characteristics of subepithelial fibroblasts as a mechano-sensor in the intestine: cell-shape-dependent ATP release and P2Y1 signaling.” J Cell Sci.; 118:3289-304.

[xxii] Zizzo et al, “Pharmacological characterization of uracil nucleotide-preferring P2Y receptors modulating intestinal motility: a study on mouse ileum,” Purinergic Signal, 2012; 8(2):275-85.

[xxiii] Malbert CH, “The ileocolonic sphincter,” Neurogastroenterol Motil, 2005; 17 Suppl 1: 41-9.
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