The Effect of a Gluten Free Diet on the Permeability of the Blood Brain Barrier in Patients With Clinically Isolated Syndrome Measured by Dynamic Contrast Enhanced Magnetic Resonance Imaging
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 103
- 试验地点
- 4
- 主要终点
- Permeability of the blood brain barrier
研究概览
简要总结
Disruption of the blood brain barrier (BBB) is associated with inflammatory conditions of the central nervous system (CNS). This clinical trial aims to investigate whether following a gluten-free diet (GFD) for six months can contribute to normalizing BBB permeability in patients with newly diagnosed clinically isolated syndrome (CIS) and multiple sclerosis (MS). Furthermore, the study seeks to identify possible effects of a GFD on markers of systemic as well as CNS inflammation. Lastly, gut permeability is measured in order to examine whether there are any correlations between the permeability of the gut and the BBB as well as the inflammatory state in the intestine and CNS. From a patient's view, potential positive effects of a GFD will be manifested through an alleviation of symptoms, improved quality of life and reduced risk of CIS progressing to MS. Evaluating a possible role of gluten in MS pathogenesis can contribute to directing future research and optimizing treatment protocols.
详细描述
Background:
Disruption of the blood brain barrier (BBB) is believed to play a critical role in the pathogenesis of multiple sclerosis (MS). Cramer et al. (2014) found increased BBB permeability in MS patients compared to healthy controls (HC) with values being higher in cases with recent relapses (1). Furthermore, BBB permeability can contribute to predicting the conversion of optic neuritis (ON) to MS (2). In the same study, significant correlations were found between BBB permeability, leukocyte counts and levels of the chemokine CXCL10 in cerebrospinal fluid (CSF). Chemokines are believed to contribute to MS pathogenesis by attracting leukocyte populations to the CNS.
Sørensen et al. (1999) found elevated levels of the cytokines CXCL9, CXCL10 and CCL5 together with their receptors CXCR3 and CCR5 on leukocytes in CSF from MS patients during attacks (3). CXCR3 is expressed in human enterocytes, endothelial cells in the BBB and a variety of immune cells. Elevated expression of CXCR3 has also been measured on T cells from MS patients compared to HC, and in patients during relapses compared to remission (4). Exposure of intestinal epithelial cell lines to gliadin has been shown to activate the chemokine receptor CXCR3 and hereby leading to release of zonulin (5). Ex vivo experiments illustrated that zonulin, which has been identified as pre-haptoglobin 2, leads to a time- and dose dependent, reversible reduction of the transepithelial electrical resistance (TEER) of murine small intestinal mucosa (6). The effects of zonulin on gut permeability are assumed to be due to disruption of tight junctional integrity.
A pilot study (7) showed a higher proportion of individuals with increased intestinal permeability among patients with MS compared to sex-matched HC. A randomized clinical trial showed beneficial effects of a gluten-free diet (GFD) on annual relapse rate, lesional activity and expanded disability status scale (EDSS) in patients with relapsing-remitting MS (RRMS), when compared to a regular diet (8). Additionally, findings of significantly higher titers of IgA against gliadin, gluten and casein in MS patients compared to HC, could indicate a role of nutritional factors in MS (8).
The role of gluten in the pathogenesis of celiac disease (CD) is established. In CD dietary intake of gluten leads to the development of autoantibodies against the enzyme transglutaminase 2 (TG2). White matter autopsies have shown TG2 immunoreactivity in astrocytes from activated MS lesions (9). Furthermore, treatment with TG2 inhibitors led to attenuation of demyelination and clinical deficits in rats with chronic-relapsing experimental autoimmune encephalomyelitis (EAE) (10). A GFD has also been documented to protect against type 1 diabetes (T1D) in mice (11) and prolong the asymptomatic period after diagnosis of T1D in humans (12).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 59 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult men and women ≥18 and ≤59 years of age
- •Patients with newly diagnosed CIS or MS deemed physically and mentally able to participate in a study
排除标准
- •More conflicting disorders in the same patient
- •Pregnancy and lactating women and women planning pregnancy during the study period
- •People with severe claustrophobia
- •People with MR incompatible implants/ foreign objects, including implanted pacemakers, heart valve prostheses, prostheses in the middle ear, implanted devices (e.g. insulin pump), metal debris, e.g. metal splinters in the eyes, miscellaneous shunts and catheters, metal clips from operations
- •Surgeries within the last 6 weeks
- •Previous reactions to MR contrast agent, bronchial asthma or history of other allergies
- •Elevated serum creatinine
- •People already on a gluten restricted/ GFD
结局指标
主要结局
Permeability of the blood brain barrier
时间窗: Change from baseline at 6 months
Blood brain barrier permeability measured by contrast enhanced magnetic resonance imaging as well as concentration of pre-haptoglobin 2 in CSF
次要结局
- Intestinal permeability(Change from baseline at 6 months)
- Intestinal absorption capacity(Change from baseline at 6 months)
- Counts of T cell subpopulations in peripheral blood and CSF(Change from baseline at 6 months)
- Macrophage activation in peripheral blood and CSF(Change from baseline at 6 months)
- Neuroinflammation(Change from baseline at 6 months)
- Bacterial translocation(Change from baseline at 6 months)
- Osteopontin as a marker of disease activity in multiple sclerosis(Change from baseline at 6 months)
- Enterocyte damage(Change from baseline at 6 months)
- Gut microbiota profiling(Change from baseline at 6 months)
研究者
Jens Rikardt Andersen
Associate professor
University of Copenhagen