Markers of Oxidative Stress in Inflammatory Bowel Diseases: Risk Factors and Implications for a Dietetic Approach

Inflammatory Bowel Diseases Clinical Trial

— OxIBDiet  

Official title:

Markers of Oxidative Stress in Inflammatory Bowel Disease in Children and Adults: Risk Factors and Implications for a Dietetic Approach

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04513015
• Other study ID #: OxIBDiet-2020
• Status: Recruiting
• Phase: N/A
• Start date: December 15, 2019
• Est. completion date: December 8, 2023

Study information

• Verified date: November 2023
• Source: Università Politecnica delle Marche
• Contact: Carlo Catassi, Professor
• Phone: 00390715962114
• Email: c.catassi[@]staff.univpm.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Inflammatory bowel disease (IBD), including Crohn's disease (CD), Ulcerative Colitis (UC) and IBD-unclassified (IBD-U) is a chronic inflammatory intestinal disorders that affect both children and adults. Patients with IBD can present with severe gastrointestinal symptoms, require frequent hospitalizations, expensive medical treatments and can develop invalidating complications requiring surgery. The incidence of IBD is increasing worldwide. The pathogenesis is multifactorial with immunological, environmental and genetic factors contributing to the disease. There is evidence that oxidative stress (OS) imbalance is involved in IBD onset and evolution, although the exact contribution to the pathogenes is unclear. An antioxidant dietetic approach is promising as an adjunctive treatment of IBD. The main aims of this project are to characterize the OS imbalance in IBD in relation to disease's features and to genetic factors and to evaluate the efficacy of an antioxidant dietetic treatment

Description:

IBD is a complex disorder that is thought to be the result of an aberrant immune response to commensal bacteria in a genetically susceptible host. The chronic inflammation along the gastrointestinal tract that characterizes IBD results from an imbalance of effector lymphocytes and pro-inflammatory cytokines. Some of the cytokines, as well as the triggered leukocytes and activated macrophages, can produce large amounts of reactive oxygen species (ROS) thus predisposing to oxidative stress disturbances. Many of the clinical and pathophysiological features of IBD, particularly tissue injury (mucosal erosions) and fibrosis have been associated to redox imbalance due to continuous ROS production and a net decrease of antioxidant molecules. Although uncontrolled oxidative stress is destructive in inflammatory conditions, the body's antioxidant defenses can counteract the effects caused by excess of ROS. Antioxidants are protective molecules/compounds toward pro-oxidant molecules. They can be endogenous or/and come from the diet. Endogenous compounds include intracellular enzymatic antioxidants such as superoxide dismutases (SODs), glutathione peroxidase (GPX), and catalase (CAT), intracellular nonenzymatic antioxidant such as glutathione (GSH) and extracellular antioxidants such as vitamins (Vit. A-C-E-B group). GSH is considered the major non-protein low molecular weight defender against oxidative (or redox) stress and the most important cellular thiol buffer. Moreover it acts as cofactor for the antioxidant enzymes GPxs and GST. GSH has been used as a biomarker for inflammation and several studies showed reduced levels of GSH in inflammatory conditions. Experimental colitis models showed decreased GSH levels that can be restored to a normal level by antioxidants supplementation. Also antioxidant enzymes as SODs, CAT and GPxs were found dysregulated in IBD condition. The differences in the regulation of expression of SOD, CAT and GPxs may not only reflect their importance in physiology, but may be also insufficient in removal of ROS under inflammatory conditions such as IBD. Recently an association between SOD1, CAT and GSHPX1 polymorphisms and the risk of inflammatory bowel disease in the Polish population has been described. Kosaka et al. found a correlation between age of onset and severity of IBD with polymorphisms in SOD2 manganese superoxide dismutase and NAD(P)H quinone oxidoreductase. In this respect, IBD disease can be regarded as multifactorial disease. There are several lines of evidence to suggest that diet is a key player in the onset, perpetuation and management of IBD. The most important evidence linking diet to IBD comes from exclusive enteral nutrition (EEN) that is the primary induction treatment of active paediatric Crohn Disease (CD). Epidemiological evidence associates certain dietary nutrients and components to the increased risk of IBD. There is emerging evidence that some diets, including the Specific Carbohydrate Diet (SCD) and the CD Exclusion Diet (CDED) could treat or prevent subsequent disease flare. Data previously presented induce to the hypothesis that an antioxidant dietetic approach, could have a role in the treatment of IBD. Dietary antioxidants may include ascorbic acid, vitamin E, glutathione, methionine, carotenoids, polyphenolic compounds, selenium and vitamin A. Clinical experience evaluating antioxidant dietetic approach in IBD patients is limited to few studies, mostly investigating the effects of single antioxidants in small number of patients. So far pediatric data regarding the oxidative status in children with IBD have rarely been reported. Collecting data in IBD children and comparing these with adults data, particularly in subjects at diagnosis, would give the unique opportunity to evaluate the role of oxidative stress in IBD pathogenesis. OxIBDiet working hypothesis is that oxidative stress imbalance is a key feature of IBD and the persistence of such imbalance is likely to contribute to the development of complications and more broadly to the evolution of the disease. A comparison between oxidative stress imbalance in children and adults with IBD and controls will address the question whether the stress imbalance is a consequence or a primary event in the inflammatory burden of IBD. Addressing these pathways and targeting the oxidative damage can have potential implications in IBD monitoring and treatment.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 40
• Est. completion date: December 8, 2023
• Est. primary completion date: December 8, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years to 80 Years

Eligibility

Inclusion Criteria:

• Diagnosis of IBD

Exclusion Criteria:

• permanent stoma
• cancer
• cardiovascular disease
• ischemic disease
• Alzheimer's disease
• type 2 diabetes

Related Conditions & MeSH terms

• Inflammatory Bowel Diseases
• Intestinal Diseases

Intervention

Dietary Supplement:
• Antioxidant diet
The "antioxidant diet" will include the principal antioxidant molecules/nutrients previously shown to be beneficial in IBD: Flavonoids, particularly resveratrol and curcumin; Olive oil; Glutathione, Vitamins A, C, E; Carotenoids; Selenium and Omega 3 Fatty Acids (PUFAs). The daily amount of these substances will be calculated following the published evidence, whether these amounts will not be achievable by a standard diet, a supplementary formulation will be proposed.
• Normal dietetic scheme
Isocaloric, normolipidic diet for age and sex

Locations

Country	Name	City	State
Italy	SOD Clinica di Gastroenterologia, Epatologia ed Endoscopia Digestiva, Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona	Ancona
Italy	SOD Clinica Pediatrica, Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona	Ancona

Sponsors (1)

Lead Sponsor	Collaborator
Università Politecnica delle Marche

Country where clinical trial is conducted

Italy, 

References & Publications (11)

Aghdassi E, Wendland BE, Steinhart AH, Wolman SL, Jeejeebhoy K, Allard JP. Antioxidant vitamin supplementation in Crohn's disease decreases oxidative stress. a randomized controlled trial. Am J Gastroenterol. 2003 Feb;98(2):348-53. doi: 10.1111/j.1572-024 — View Citation

Dryden GW, Lam A, Beatty K, Qazzaz HH, McClain CJ. A pilot study to evaluate the safety and efficacy of an oral dose of (-)-epigallocatechin-3-gallate-rich polyphenon E in patients with mild to moderate ulcerative colitis. Inflamm Bowel Dis. 2013 Aug;19(9 — View Citation

Gatti S, Galeazzi T, Franceschini E, Annibali R, Albano V, Verma AK, De Angelis M, Lionetti ME, Catassi C. Effects of the Exclusive Enteral Nutrition on the Microbiota Profile of Patients with Crohn's Disease: A Systematic Review. Nutrients. 2017 Aug 4;9(8):832. doi: 10.3390/nu9080832. — View Citation

Kolacek M, Muchova J, Dvorakova M, Paduchova Z, Zitnanova I, Cierna I, Orszaghova Z, Szekyova D, Jajcaiova-Zednickova N, Kovacs L, Durackova Z. Effect of natural polyphenols (Pycnogenol) on oxidative stress markers in children suffering from Crohn's disea — View Citation

Kolho KL, Ainamo A. Progress in the treatment and outcome of pediatric inflammatory bowel disease patients. Expert Rev Clin Immunol. 2016 Dec;12(12):1337-1345. doi: 10.1080/1744666X.2016.1201422. Epub 2016 Jun 29. — View Citation

Kosaka T, Yoshino J, Inui K, Wakabayashi T, Kobayashi T, Watanabe S, Hayashi S, Hirokawa Y, Shiraishi T, Yamamoto T, Tsuji M, Katoh T, Watanabe M. Involvement of NAD(P)H:quinone oxidoreductase 1 and superoxide dismutase polymorphisms in ulcerative colitis — View Citation

Mrowicka M, Mrowicki J, Mik M, Wojtczak R, Dziki L, Dziki A, Majsterek I. Association between SOD1, CAT, GSHPX1 polymorphisms and the risk of inflammatory bowel disease in the Polish population. Oncotarget. 2017 Nov 27;8(65):109332-109339. doi: 10.18632/o — View Citation

Pereira C, Gracio D, Teixeira JP, Magro F. Oxidative Stress and DNA Damage: Implications in Inflammatory Bowel Disease. Inflamm Bowel Dis. 2015 Oct;21(10):2403-17. doi: 10.1097/MIB.0000000000000506. — View Citation

Rastegarpanah M, Malekzadeh R, Vahedi H, Mohammadi M, Elahi E, Chaharmahali M, Safarnavadeh T, Abdollahi M. A randomized, double blinded, placebo-controlled clinical trial of silymarin in ulcerative colitis. Chin J Integr Med. 2015 Dec;21(12):902-6. doi: — View Citation

Sigall-Boneh R, Levine A, Lomer M, Wierdsma N, Allan P, Fiorino G, Gatti S, Jonkers D, Kierkus J, Katsanos KH, Melgar S, Yuksel ES, Whelan K, Wine E, Gerasimidis K. Research Gaps in Diet and Nutrition in Inflammatory Bowel Disease. A Topical Review by D-ECCO Working Group [Dietitians of ECCO]. J Crohns Colitis. 2017 Dec 4;11(12):1407-1419. doi: 10.1093/ecco-jcc/jjx109. — View Citation

Tian T, Wang Z, Zhang J. Pathomechanisms of Oxidative Stress in Inflammatory Bowel Disease and Potential Antioxidant Therapies. Oxid Med Cell Longev. 2017;2017:4535194. doi: 10.1155/2017/4535194. Epub 2017 Jun 28. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Blood levels of ROS and glutathione in patients with IBD after a specific antioxidant dietary treatment	Blood levels of ROS will be determined by cytofluorimetry, blood levels of glutathione by spectrofluorimetry at baseline and after 12 weeks of dietary treatment.	12 weeks
Other	Total antioxidant capacity (Trolox equivalent and ferrous equivalent) in patients with IBD after a specific antioxidant dietary treatment	Trolox equivalent will be assessed by antioxidant assay Kit, ferrous equivalent instead wille require a manual assessment at baseline and after 12 weeks of dietary treatment.	12 weeks
Other	Antioxidant enzymes pattern (GST, SOD, GPxs, GR enzyme levels, activity and transcripts) in patients with IBD after a specific antioxidant dietary treatment	Spectrophotometer will be used to assess enzyme levels and activity, cDNA kit to determine enzyme transcripts at baseline and after 12 weeks of dietary treatment	12 weeks
Other	Plasma hydroperoxides and thiobarbituric acid reactive species in patients with IBD after a specific antioxidant dietary treatment	Plasma hydroperoxides will be detected by LPO ELISA kit, thiobarbituric acid reactive species by TBARS assay kit at baseline and after 12 weeks of dietary treatment.	12 weeks
Other	Urine oxidized guanines (8-OHdG, 8-OHG e guanosine) levels in patients with IBD after a specific antioxidant dietary treatment	DNA/RNA oxydate damage kit will be used to study urine oxidized guanines levels at baseline and after 12 weeks of dietary treatment	12 weeks
Other	PUCAI in pediatric patients with RCU after a specific antioxidant dietary treatment	PUCAI score will be recorded at baseline and after 12 weeks of dietary treatment	12 weeks
Other	PCDAI in pediatric patients with CD after a specific antioxidant dietary treatment	PCDAI score will be recorded at baseline and after 12 weeks of dietary treatment	12 weeks
Other	Phisician Global Assessment (PGA) score in patients with IBD after a specific antioxidant dietary treatment	PGA score will be recorded at baseline and after 12 weeks of dietary treatment	12 weeks
Other	Calprotectin levels in patients with IBD after a specific antioxidant dietary treatment	Calprotectin levels will be analyzed in stool samples collected at baseline and after 12 weeks of dietary treatment	12 weeks
Other	Harvey-Bradshaw score in adult patients with CD after a specific antioxidant dietary treatment	Harvey-Bradshaw score will be recorded at baseline and after 12 weeks of dietary treatment	12 weeks
Other	Mayo score in adult patients with RCU after a specific antioxidant dietary treatment	Mayo score will be recorded at baseline and after 12 weeks of dietary treatment	12 weeks
Other	PedQoL score in pediatric patients with IBD after a specific antioxidant dietary treatment	PedQoL score will be recorded at baseline and after 12 weeks of dietary treatment	12 weeks
Other	QoL score in adult patients with IBD after a specific antioxidant dietary treatment	QoL score will be recorded at baseline and after 12 weeks of dietary treatment	12 weeks
Primary	Blood levels of ROS and glutathione in patients with IBD and controls	Blood levels of ROS will be determined by cytofluorimetry, blood levels of glutathione by spectrofluorimetry	Baseline
Primary	Total antioxidant capacity (Trolox equivalent and ferrous equivalent) in patients with IBD and controls	Trolox equivalent will be assessed by antioxidant assay Kit, ferrous equivalent instead wille require a manual assessment.	Baseline
Primary	Antioxidant enzymes pattern (GST, SOD, GPxs, GR enzyme levels, activity and transcripts) in patients with IBD and controls	Spectrophotometer will be used to assess enzyme levels and activity, cDNA kit to determine enzyme transcripts.	Baseline
Primary	Plasma hydroperoxides and thiobarbituric acid reactive species in patients with IBD and controls	Plasma hydroperoxides will be detected by LPO ELISA kit, thiobarbituric acid reactive species by TBARS assay kit.	Baseline
Primary	Urine oxidized guanines (8-OHdG, 8-OHG e guanosine) levels in patients with IBD and controls	DNA/RNA oxydate damage kit will be used to study urine oxidized guanines levels.	Baseline
Secondary	Polymorphisms of genes implicated in oxidative stress defense (SOD1, SOD2, SOD3; GPX1, GPX2, GPX3; GPX4; GPX5; GSTA1; GSTA2; GSTM1; GSTM2; GSTM3; GSTP1; GSTO1; NQ01 NQ02; NOX1; NOX3; NOX4 and NOX5 genes) in patients with IBD and controls	Genetic polymorphisms will be studied by next generation sequencing	Baseline