Experimental Cancer Cachexia Changes Neuron Numbers and Peptide Levels in the Intestine: Partial Protective Effects after Dietary Supplementation with L-Glutamine

Abstract

Gastrointestinal dysmotility frequently occurs in cancer cachexia and may result from damage to enteric innervation caused by oxidative stress, especially due to glutathione depletion. We assessed the effect of dietary supplementation with 20 g/kg l-glutamine (a glutathione precursor) on the intrinsic innervation of the enteric nervous system in healthy and Walker 256 tumor-bearing Wistar rats during the development of experimental cachexia (14 days), in comparison with non-supplemented rats, by using immunohistochemical methods and Western blotting. The total neural population and cholinergic subpopulation densities in the myenteric plexus, as well as the total population and VIPergic subpopulation in the submucosal plexus of the jejunum and ileum, were reduced in cachectic rats, resulting in adaptive morphometric alterations and an increase in vasoactive intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP) expression, suggesting a neuroplastic response. l-glutamine supplementation prevented decrease in myenteric neuronal density in the ileum, morphometric alterations in the neurons and nerve fibers (in both the plexuses of the jejunum and ileum), and the overexpression of VIP and CGRP. Cancer cachexia severely affected the intrinsic innervation of the jejunum and ileum to various degrees and this injury seems to be associated with adaptive neural plasticity. l-glutamine supplementation presented partial protective effects on the enteric innervation against cancer cachexia, possibly by attenuating oxidative stress.

Does the Rheumatoid Arthritis Affect the Enteric Nervous System?

“…The ganglionated plexuses of the ENS exhibit the expression of different neuropeptides such as the VIP and CGRP, which stimulate smooth muscle relaxation (22,23) . As described earlier, both varicosity areas for CGRP and VIP were reduced, which may indicate a decrease in the production and release of these neuropeptides, thereby affecting the normal functioning of the GI tract (24) . The VIP neuropeptide has anti-inflammatory, antioxidant and anti-apoptotic effects, mainly in inflammatory and autoimmune diseases since it is capable of regulating various nuclear transduction and transcription pathways.…”

“…Furthermore, CGRP has antioxidant and anti-inflammatory effects (22,33,34) . In this study, the reduction of VIP-IR varicosity areas may indicate the presence of inflammatory process in the ileum induced by the AR, which may lead to a decrease of production and release of this neuropetide (24,30) . Furthermore, NO induces the release of VIP in the myenteric plexus (35,36) , and both morphometric reductions may indicate correlations with decrease in the production of the neuronal NO and VIP.…”

“…However, the increased CGRP-IR varicosity areas suggest a compensatory mechanism against the other negative impacts above described, mostly due to antioxidant and anti-inflammatory properties of this neuropeptide. Varicosity hypertrophy indicates higher production and release of the CGRP which would ameliorate the intestinal function affected by the disease (24,37) .…”

“…Both ganglionated plexuses of the SNE express different neuropeptides such as calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP). VIPergic neuropeptide promotes smooth muscle relaxation and stimulates the secretion of fluids and electrolytes and CGRP is a vasodilator neuropeptide that enhances the intestinal blood flow through stimulation of smooth muscle relaxation (22,24) . Both CGRP and VIP are considered an antioxidant and anti-inflammatory neuropeptides (24) .…”

Effect of supplementation with a combination ofl‐arginine,l‐glutamine, and hydroxy methyl butyrate on cachexia: A systematic review

“…Gln can also decrease permeability of GI tract which is accompanied by reducing the risk of cachexia associated with diarrhea (Daniele et al, ; Noé, ). In addition, Gln plays a role in intrinsic gastrointestinal preservation, possibly by the redox status attenuation and maintenance of GI motility (Vicentini et al, ). Overall it is presumed that HMB supplementation decreases protein breakdown while Arg and Gln enhance protein synthesis (May, Barber, T D'Olimpio, Hourihane, & Abumrad, 2002).…”