Clinical trial NCT04513015: Markers of Oxidative Stress in Inflammatory Bowel Diseases: Risk Factors and Implications for a Dietetic Approach
Official title: Markers of Oxidative Stress in Inflammatory Bowel Disease in Children and Adults: Risk Factors and Implications for a Dietetic Approach
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Inflammatory Bowel Diseases
Keywords: oxidative stress imbalance
antioxidant diet
Lead sponsor: Università Politecnica delle Marche
Sponsor class: OTHER
Collaborators: name: Ministry of Health, Italy
First posted: 2020-08-14
Enrollment: 155
Sex: ALL
Minimum age (years): 6
Maximum age (years): 80
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: IBD subjects (40 children and 40 adults, 50% with CD and 50% with UC) will be enrolled in different conditions: at diagnosis, in remission, at relapse. For each IBD subject an age and gender matched control subject will be enrolled (40 children and 40 adults).

In a subgroup of subjects (20 children and 20 adults, 50% with CD and 50% with UC) in clinical remission/mild disease a dietetic approach will be proposed. Patients on steroids and patients with strictures will not be enrolled for this part of the study. Patients will be randomized in 2 groups: Group Antioxidant diet will receive 8 weeks of antioxidant dietary treatment and group Normal diet will continue a normal dietetic scheme (corresponding to a isocaloric, normolipidic diet for age and sex).
Primary purpose: BASIC_SCIENCE

Brief 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

Detailed 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.

This study has been granted by the Italian Ministry of Health (grant RF 2018-12366976)

Eligibility criteria: Inclusion Criteria:

- Diagnosis of IBD

Exclusion Criteria:

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

Primary outcomes:
measure: Blood levels of ROS and glutathione in patients with IBD and controls
timeFrame: Baseline
measure: Total antioxidant capacity (Trolox equivalent and ferrous equivalent) in patients with IBD and controls
timeFrame: Baseline
measure: Antioxidant enzymes pattern (GST, SOD, GPxs, GR enzyme levels, activity and transcripts) in patients with IBD and controls
timeFrame: Baseline
measure: Plasma hydroperoxides and thiobarbituric acid reactive species in patients with IBD and controls
timeFrame: Baseline
measure: Urine oxidized guanines (8-OHdG, 8-OHG e guanosine) levels in patients with IBD and controls
timeFrame: Baseline
Secondary outcomes:
measure: 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
timeFrame: Baseline
Other outcomes:
measure: Blood levels of ROS and glutathione in patients with IBD after a specific antioxidant dietary treatment
timeFrame: 12 weeks
measure: Total antioxidant capacity (Trolox equivalent and ferrous equivalent) in patients with IBD after a specific antioxidant dietary treatment
timeFrame: 12 weeks
measure: Antioxidant enzymes pattern (GST, SOD, GPxs, GR enzyme levels, activity and transcripts) in patients with IBD after a specific antioxidant dietary treatment
timeFrame: 12 weeks
measure: Plasma hydroperoxides and thiobarbituric acid reactive species in patients with IBD after a specific antioxidant dietary treatment
timeFrame: 12 weeks
measure: Urine oxidized guanines (8-OHdG, 8-OHG e guanosine) levels in patients with IBD after a specific antioxidant dietary treatment
timeFrame: 12 weeks
measure: PUCAI in pediatric patients with RCU after a specific antioxidant dietary treatment
timeFrame: 12 weeks
measure: PCDAI in pediatric patients with CD after a specific antioxidant dietary treatment
timeFrame: 12 weeks
measure: Phisician Global Assessment (PGA) score in patients with IBD after a specific antioxidant dietary treatment
timeFrame: 12 weeks
measure: Calprotectin levels in patients with IBD after a specific antioxidant dietary treatment
timeFrame: 12 weeks
measure: Harvey-Bradshaw score in adult patients with CD after a specific antioxidant dietary treatment
timeFrame: 12 weeks
measure: Mayo score in adult patients with RCU after a specific antioxidant dietary treatment
timeFrame: 12 weeks
measure: PedQoL score in pediatric patients with IBD after a specific antioxidant dietary treatment
timeFrame: 12 weeks
measure: QoL score in adult patients with IBD after a specific antioxidant dietary treatment
timeFrame: 12 weeks
Locations:
city: Ancona
country: Italy
facility: SOD Clinica Pediatrica, Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona
city: Ancona
country: Italy
facility: SOD Clinica di Gastroenterologia, Epatologia ed Endoscopia Digestiva, Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona
Study officials:
affiliation: Università Politecnica delle Marche
name: Carlo Catassi, Professor
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.
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/oncotarget.22675. eCollection 2017 Dec 12.
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. DNA Cell Biol. 2009 Dec;28(12):625-31. doi: 10.1089/dna.2009.0877.
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):1904-12. doi: 10.1097/MIB.0b013e31828f5198.
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 disease--a pilot study. Free Radic Res. 2013 Aug;47(8):624-34. doi: 10.3109/10715762.2013.807508. Epub 2013 Jun 13.
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: 10.1007/s11655-012-1026-x. Epub 2012 Apr 11.
citation: 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.1572-0241.2003.07226.x.