Glutathione Metabolism in Crohn′s Disease

doi:10.1006/bmmb.1994.1062

Biochemical Medicine and Metabolic Biology

Volume 53, Issue 2, December 1994, Pages 87-91

Biochemical Medicine...

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Abstract

A statistically significant decrease of glutathione (GSH) and an increase of GSH disulfide (GSSG) both in healthy and ill ileum of patients with Crohn′s disease in comparison with the controls (without this pathology) is demonstrated. However, the lowering of these levels was more remarkable in ill ileum in which high levels of GSSG were detected, too. These alterations may be in part explained by the changes obtained in GSH-related enzyme levels. Finally, considering the results that others and we obtained by studies on GSH oral absorption in rat intestine, an oral therapy of GSH in Crohn′s disease is suggested.

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Cited by (55)

Brown marine algae Gongolaria baccata extract protects Caco-2 cells from oxidative stress induced by tert-butyl hydroperoxide
2021, Food and Chemical Toxicology
Citation Excerpt :
ROS have been implicated in the activation of various cellular signalling pathways and transcription factors, which can activate cell survival and/or cell death processes such as autophagy and apoptosis (Kaminskyy and Zhivotovsky, 2014; Kehrer and Klotz, 2015; Simon et al., 2000). ROS have been implicated in the pathogenesis of human chronic diseases such as Crohn's disease, ulcerative colitis, coronary heart disease, and certain cancers (Babbs, 1992; Halliwell, 1997; Iantomasi et al., 1994). ROS is a collective term used to describe both free radicals (hydroxyl radical, •OH; superoxide anion, O2•- peroxyl radical, ROO•), and non-radical compounds (hydrogen peroxide, H2O2; singlet oxygen, 1O2) (Aruoma, 1994; Diplock et al., 1998) that are produced in living cells as a result of normal cell metabolism.
Gongolaria baccata (S.G. Gmelin) is marine brown seaweed mainly found on the coasts of the Baltic Sea south to the Mediterranean Sea, Canary Islands, Mauritania and Western Sahara. Herein, we report the cell viability and protective effects attributed to molecular mechanisms underlying antioxidant response to survive oxidative stress injuries. Caco-2 cells were submitted to oxidative stress by treatment with tert-butylhydroperoxide (tert-BOOH). The extract prevented cell damage and enhanced activity of antioxidant defenses (NQO1 and GST activities and GSH levels) reduced by treatment with tert-BOOH. The increases of MDA levels, the amount of intracellular ROS and caspase 3/7 activity induced by tert-BOOH were prevented when cells were treated with the G. baccata extract. Moreover, G. baccata extract caused up-regulation of GSTM2, Nrf2, and AKT1 gene expressions, as well as G. baccata extract reduced significantly Bax, BNIP3, APAF1, ERK1, JNK1, MAPK1, P38, P53, NFκB1, TNFα, IL-6, IL-1β and HO-1 gene expressions related to apoptosis, proinflammation and oxidative stress induced by tert-BOOH. These results suggest that G.baccata extract protected the cells against oxidative damage and inflammation; protective effects that could be linked to their bioactive constituents. Hence, this brown seaweed G.baccata extract could be used for the development of functional foods and/or nutraceuticals.
Does active Crohn's disease have decreased intestinal antioxidant capacity?
2013, Journal of Crohn's and Colitis
Citation Excerpt :
The literature on the role of intestinal GPx enzyme as the main active cellular antioxidant mechanism in CD is still scarce. Previously, studies performed by Kruidenier et al.31 and Iantomasi et al.,32 addressed this issue describing a significant increase in GPx activity in inflamed intestinal CD mucosa compared to controls. Differences in methodologies used in these studies, however, do not allow accurate comparisons with the present study.
Oxidative stress is presumed to play an important role in Crohn's disease (CD) pathogenesis. Nevertheless, the evaluation of the intestinal antioxidant capacity through the analysis of glutathione peroxidase activity in CD remains to be determined.
20 CD outpatients and 16 volunteers going through colonic cancer screening were enrolled. Colonoscopy with biopsies was performed in all individuals. Samples from inflamed and non-inflamed mucosa were taken when there was CD endoscopic activity. Spectrophotometric assays were performed to measure tissue glutathione peroxidase (GPx) activity, and total (GSH_T) and oxidized (GSSG) glutathione in all samples. Demographics and clinical characteristics were collected from clinical charts.
Inflamed CD mucosa presented reduced GPx activity compared to non-inflamed CD mucosa (42.94 mU/mg protein vs 79.62 mU/mg protein, P < 0.05) and control mucosa (42.94 mU/mg protein vs 95.08 mU/mg protein, P < 0.001). GSH_T concentration was reduced in inflamed mucosa when compared to non-inflamed CD mucosa (0.78 μmol/g vs 1.98 μmol/g, P < 0.01) and the control group (0.78 μmol/g vs 2.11 μmol/g, P < 0.001). A significant correlation was detected between GPx activity and GSSG (r = − 0.599), disease duration (r = 0.546), and thiopurine treatment (r = − 0.480) in non-inflamed CD mucosa.
Our findings suggest that reduced GPx activity is present in inflamed CD mucosa. In addition, endoscopic activity, disease duration and thiopurine therapy could be associated with mucosal decreased antioxidant activity.
Intestinal redox biology and oxidative stress
2012, Seminars in Cell and Developmental Biology
Citation Excerpt :
Excessive inflammatory cell-induced ROS generation and tissue oxidative stress are central to the onset and development of chronic gut inflammation. Elevated tissue GSSG [125,126] and/or decreased GSH synthesis [127] have been correlated with the severity of mucosal inflammation or diminished mucosal GSH contents in IBD (intestinal bowel disease) patients [125]. It remains unclear whether intestinal oxidative stress is secondary to the inflammatory process or vice versa.
The intestinal epithelium sits at the interface between an organism and its luminal environment, and as such is prone to oxidative damage induced by luminal oxidants. Mucosal integrity is maintained by the luminal redox status of the glutathione/glutathione disulfide (GSH/GSSG) and cysteine/cystine (Cys/CySS) couples which also support luminal nutrient absorption, mucus fluidity, and a diverse microbiota. The epithelial layer is uniquely organized for rapid self-renewal that is achieved by the well-regulated processes of crypt stem cell proliferation and crypt-to-villus cell differentiation. The GSH/GSSG and Cys/CySS redox couples, known to modulate intestinal cell transition through proliferation, differentiation or apoptosis, could govern the regenerative potential of the mucosa. These two couples, together with that of the thioredoxin/thioredoxin disulfide (Trx/TrxSS) couple are the major intracellular redox systems, and it is proposed that they each function as distinctive redox control nodes or circuitry in the control of metabolic processes and networks of enzymatic reactions. Specificity of redox signaling is accomplished in part by subcellular compartmentation of the individual redox systems within the mitochondria, nucleus, endoplasmic reticulum, and cytosol wherein each defined redox environment is suited to the specific metabolic function within that compartment. Mucosal oxidative stress would result from the disruption of these unique redox control nodes, and the subsequent alteration in redox signaling can contribute to the development of degenerative pathologies of the intestine, such as inflammation and cancer.
Dietary sulfur amino acid supplementation reduces small bowel thiol/disulfide redox state and stimulates ileal mucosal growth after massive small bowel resection in rats
2009, Journal of Nutrition
Following massive small bowel resection in animal models, the remnant intestine undergoes a dynamic growth response termed intestinal adaptation. Cell growth and proliferation are intimately linked to cellular and extracellular thiol/disulfide redox states, as determined by glutathione (GSH) and GSH disulfide (GSSG) (the major cellular redox system in tissues), and cysteine (Cys) and its disulfide cystine (CySS) (the major redox system in plasma), respectively. The study was designed to determine whether dietary supplementation with sulfur amino acids (SAA) leads to a greater reduction in thiol/disulfide redox state in plasma and small bowel and colonic mucosa and alters gut mucosal growth in an established rat model of short bowel syndrome (SBS). Adult rats underwent 80% jejunal-ileal resection (RX) or small bowel transection (surgical control) and were pair-fed either isonitrogenous, isocaloric SAA-adequate (control) or SAA-supplemented diets (218% increase vs. control diet). Plasma and gut mucosal samples were obtained after 7 d and analyzed for Cys, CySS, GSH, and GSSG concentrations by HPLC. Redox status (E_h) of the Cys/CySS and GSH/GSSG couples were calculated using the Nernst equation. SAA supplementation led to a greater reduction in E_h GSH/GSSG in jejunal and ileal mucosa of resected rats compared with controls. Resected SAA-supplemented rats showed increased ileal adaptation (increased full-thickness wet weight, DNA, and protein content compared with RX control-fed rats; increased mucosal crypt depth and villus height compared with all other study groups). These data suggest that SAA supplementation has a trophic effect on ileal adaptation after massive small bowel resection in rats. This finding may have translational relevance as a therapeutic strategy in human SBS.
Butyrate modulates oxidative stress in the colonic mucosa of healthy humans
2009, Clinical Nutrition
Citation Excerpt :
In a rat model of colitis GSH administration improved the colonic histological score and reduced mucosal MDA concentrations.32 Reduced concentrations of GSH and increased concentrations of GSSG have been reported in patients with inflammatory bowel disease.33, 34 However, in several other stress situations, an increase in GSH has been reported.35
Butyrate, a short-chain fatty acid produced by colonic microbial fermentation of undigested carbohydrates, has been implicated in the maintenance of colonic health. This study evaluates whether butyrate plays a role in oxidative stress in the healthy colonic mucosa.
A randomized, double blind, cross-over study with 16 healthy volunteers was performed. Treatments consisted of daily rectal administration of a 60 ml enema containing 100 mM sodium butyrate or saline for 2 weeks. After each treatment, a blood sample was taken and mucosal biopsies were obtained from the sigmoid colon. In biopsies, the trolox equivalent antioxidant capacity, activity of glutathione-S-transferase, concentration of uric acid, glutathione (GSH), glutathione disulfide and malondialdehyde, and expression of genes involved in GSH and uric acid metabolism was determined. Secondary outcome parameters were CRP, calprotectin and intestinal fatty acid binding protein in plasma and histological inflammatory scores.
Butyrate treatment resulted in significantly higher GSH (p < 0.05) and lower uric acid (p < 0.01) concentrations compared to placebo. Changes in GSH and uric acid were accompanied by increased and decreased expression, respectively, of their rate limiting enzymes determined by RT–PCR. No significant differences were found in other parameters.
This study demonstrated that butyrate is able to beneficially affect oxidative stress in the healthy human colon.
Effect of exclusive enteral nutritional treatment on plasma antioxidant concentrations in childhood Crohn's disease
2007, Clinical Nutrition
Citation Excerpt :
Glutathione is a tripeptide made up of glutamate, cysteine and glycine and glutamine is an important source of the glutamate component.22 A decrease in glutathione concentration has been described in intestinal tissues of patients with CD.23 Glutamine infusion has been shown to increase both intestinal mucosal24 and plasma25 glutathione concentrations in experimental animals.
Oxidative stress and depletion of antioxidants may play a role in the pathogenesis of Crohn's disease (CD). The aim of this study was to determine the effect of exclusive enteral nutrition, which is increasingly being used as primary therapy for CD, on plasma antioxidant concentrations in children with active CD.
In a double-blind randomised controlled trial, 15 children with active CD (mean age, 11.3 years, range 6.8–15.7) attending a paediatric gastroenterology referral centre, were assigned to receive either a standard polymeric diet (Group S, n=8) or a glutamine-enriched polymeric diet (Group G, n=7) as primary therapy for active CD. Plasma concentrations of selenium, urates, vitamin A, vitamin E, vitamin C, glutathione, and also malondialdehyde (MDA) were measured at baseline and after 4 weeks of exclusive enteral nutritional treatment.
Mean (95% CI) selenium concentration of the cohort increased significantly from 0.82 μmol/l (0.72, 0.91) to 1.14 μmol/l (0.98, 1.3), P<0.001. There were, however, significant reductions in mean concentrations of vitamin C {11.8 mg/l (7.7, 15.8) to 6.5 mg/l (4.5, 8.7), P=0.01} and vitamin E {11.3 mg/l (10.3, 12.4) to 9.4 mg/l (8.7, 10.1), P=0.03}. The concentrations of vitamin A, urates, glutathione and MDA did not change significantly over the study period. Glutamine supplementation did not have any significant effect on plasma antioxidant concentrations.
Significant changes in circulating antioxidant concentrations occurred in children with active CD receiving exclusive enteral nutritional treatment. Glutamine supplementation was not beneficial in improving plasma antioxidant status.

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Glutathione Metabolism in Crohn′s Disease