الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Bipolar disorder is a mental illness caused by a variety of factors. It is characterized by hidden early symptoms, long course of disease and poor prognosis in severe cases. Research on the etiology of BD has always been a hot issue in psychiatry. In recent years, important advances have been made in the biological role of gut microbiota in BD. Existing experiments provide evidence that one of the etiologies of BD is the disturbance of intestinal ecosystem, and the structural basis of the association between BD and the gut brain axis.
The relation between intestinal permeability and autoimmune diseases has been investigated in many studies, yet few studies have investigated the relation between intestinal permeability and BD using different biomarkers.
The principal pathways of the gut–brain axis include action through the vagus nerve, involving the endocrine system, the hypothalamic–pituitary–adrenal (HPA) axis, neurotransmitter pathways, metabolites, and immune system component.
Zonulaoccludens toxin (Zot) is an enterotoxin which is able to reversibly open intracellular tight junctions. Zot is able to interact with epithelial cells along the gastrointestinal tract with the highest binding in the jejunum and distal ileum. Given the complexity of the intracellular signaling activated by Zot leading to tight junction modulation, it was hypothesized that the toxin may mimic an endogenous protein which is able to regulate the epithelial tight junctions. Zonulin is a human analog to Zot. Ex vivo studies show endogenous human zonulin is able to increase permeability in both the jejunum and ileum.
This study aimed to verify the possible relation between intestinal permeability and BD using serum Zonulin as a biomarker for intestinal permeability, and to assess the relation between serum zonulin level and the severity of symptoms of bipolar disorder, the age of onset of the disorder, the frequency of relapses response to drug trials and other disease parameters.
This case-control observational study included 3 groups; 2 groups of patients and a control group. A total number of 200 bipolar I disorder patients who attended the outpatient clinic or have been admitted to the inpatient units were recruited after their agreement to participate in the study and divided into 2 groups, the first group including 100 patients in acute episode (manic or depressive), the second one included 100 patients with bipolar I disorder in full remission (Remission period was described as a minimum of one year). The third group included 100 age and sex matched healthy individuals.
We used the Structured Clinical Interview for DSM-IV Axis I Disorder (SCID-I) in its Arabic Version to confirm the diagnosis of bipolar disorder I and to exclude other psychiatric comorbidities. Young mania rating scale (YMRS) and Hamilton depression rating scale (HDRS) scores were recorded at the time of blood sample acquisition. A blood sample of 3-5 cm was collected after overnight fasting (8-12 hours) and analyzed by centrifugation in the laboratory of Ain Shams University hospitals, and then serum concentration of zonulin was measured using the Bioassay technology laboratory Zonulin ELISA kit. Measurements were made in duplicate, and the mean values were used for the analysis.
In the current study, the ratio of males to females was approximately 3:1. Although most studies report an almost equal gender ratio in the prevalence of bipolar disorder; this ratio may be explained by the fact that women and girls in the Middle East/North Africa (MENA) area face major barriers in accessing mental health services, programming, and information. Cultural stigma around mental health often prevents both access to services and effective treatment. There are additional social pressures that may affect women’s experience of mental illness in MENA area; in the context that husbands may use an accusation of mental illness against a wife, in order to gain support for taking a second wife or for obtaining a divorce. It is therefore not surprising that some studies have shown that, contrary to established literature, men outnumbered women in mental health care seeking in MENA area
In the current study, it was found that serum zonulin can be used as a diagnostic marker to differentiate patients with bipolar disorder (BD) from healthy controls (HC) at the cut-off value of 3.2 ng ml, serum zonulin had a sensitivity of 100%, and a specificity of 100%, with an area under the curve (AUC) of 1.
It was also found that serum Zonulin can be used for the discrimination between patients in remission from patients in acute episode at the cut-off value of 25.9 ng ml, zonulin had a sensitivity of 80% and specificity of 85%, respectively, with an AUC of 0.887.
In the current study, serum level of Zonulin was the highest among the patients in acute episode of bipolar compared to patients in full remission (P<0.001), and controls (P<0.001). This finding supports the hypothesis that there is evidence of increased intestinal permeability (denoted by high serum Zonulin levels) in patients of bipolar I disorder.
In the present study, there was a positive correlation between female gender and serum Zonulin level in the study population. The median serum Zonulin level was higher among females with a median range of 36.11 ng/ml (P=0.027).
The present study finding that serum zonulin was significantly higher in women with bipolar disorder during both euthymia and acute episode is intriguing. One possible implication of this finding is that increased permeability may pose a state of elevated susceptibility for depression or mania-inducing stimuli.
Regarding this hypothetical concept, zonulin’s possible effect on the blood-brain-barrier is of special interest. The identification of zonulin receptors in human brain tissue underpinned the hypothesis that zonulin may not only act as a regulator of intestinal permeability but could also influence passage through other epithelial barriers.
In line with this finding, in the current study there was also a positive correlation between peripartum onset of acute episodes and serum Zonulin levels (P=0.008). Patients with peripartum onset had higher serum Zonulin level in comparison with other specifiers with a median serum Zonulin level of 15.7 ng/ml.
In the present study, there was a negative correlation between history of suicidal attempts and serum zonulin levels. The median serum Zonulin level was lower among patients with history of suicidal attempts with a median range of 21.45 ng/ml (P=0.022)
The underlying mechanisms are currently unknown but it has been hypothesized that greater gut epithelial cell death or dysfunction might decrease the expression of zonulin, suggesting that low plasma zonulin levels may be indicative of greater gut permeability
In the current study, It was found that Serum Zonulin had a negative correlation with the age of onset of the disease (the younger the age at the onset of disease, the higher serum Zonulin levels; P=0.000).
These results may be interpreted by the fact that neuroinflammation is expected to occur during the early stages of disease in the younger age groups unlike the late stages of disease at which neurodegeneration is the main pathology rather than inflammation.
An interesting result of the current study was that the duration of illness didn’t correlate with serum Zonulin levels (p=0.591). This might also support the above mentioned fact that serum Zonulin levels and hence intestinal permeability correlate with neuroinflammation that is characteristically higher during the early stages of disease but not throughout the total duration of disease, in other words serum Zonulin and hence intestinal permeability deficits are part of the early stages of the disease which are characterized by inflammation and its role might decrease at the late stages of disease.
As regards the correlation of serum Zonulin level and the severity of the manic or depressive episodes, there was a positive correlation between the severity of depression (higher HDRS scores) and serum Zonulin level (P=0.044), however, there was no statiscal significance between severity of manic episodes indicated by (YMRS) scores and serum Zonulin level (P=0.516).
As regards the correlation between serum Zonulin levels and the different bipolar disorder specifiers; we found a positive correlation between melancholic features and serum zonulin level (P=0.022). Patients with melancholic features had a higher serum Zonulin level in comparison with patients who had other specifiers with a median serum Zonulin level of 59.9 ng/ml.
In the current study we found a negative correlation between serum Zonulin and family history of similar conditions; patients with no family history of similar condition had significantly higher serum Zonulin levels (P=0.01).These results suggest that host genetic background has limited contribution toward intestinal permeability.
The results of the current study showed that there was a negative correlation between receiving long acting antipsychotics injections (LAI) and serum Zonulin level (P=0.004), patients on (LAI) had lower serum Zonulin levels with a median of 21.45 ng/ml, and a positive correlation between receiving oxcarbazepine and serum Zonulin level (P=0.037), patients on oxcarbazepine had higher serum Zonulin levels with a median of 75.2 ng/ml. Correlations between serum zonluin and receiving other medications showed no statiscal significance.
Chronic low grade inflammation have been consistently reported in BD. However, inflammation may also affect the gut microbiota composition, and may lead to changes in gut permeability. In turn, increased gut permeability may lead to release of lipopolysaccharide, which can further induce pro-inflammatory cytokines (e.g. IL-6, IL-1) and norepinephrine levels
Animal models have been developed to study the effects of inflammation on behavior. These models have shown that many psychiatric drugs have anti-inflammatory characteristics, which might explain these results
In the present study, there was no significant correlation between serum zonulin and, marital status (P=0.796), residence (P=0.111), smoking (P=0.629), the type of index episode (P=0.822) nor history of BST sessions (P=0.509).
Additionally, the correlations between serum Zonulin level and the age of patients (P=0.380), BMI (p=0.493), duration of illness (p=0.591), duration of untreated illness (0.711), duration of treatment (P=0.438), compliance on treatment (P=0.079), number of episodes (P=0.985) and total number of hospitalizations (P=0.296) were insignificant.
The findings of this study support the role of intestinal permeability changes (assessed by high serum Zonulin levels) in the disease activity of bipolar disorder especially at the early stages of disease and in patients with younger age of onset of the disease. Serum Zonulin can be used as a marker of disease and can be postulated as a way to predict exacerbation into an acute episode, which can influence available therapeutic options.
A worth to mention point is that the changes in the intestinal barrier in BD are not disease specific. An altered intestinal barrier has also been found in other neuropsychiatric and systemic diseases as diverse as stroke, Parkinson’s disease, autism spectrum disorder and Crohn’s disease. The source of elevated Zonulin is unlikely to be exclusively from the gut, as cells other than enterocytes, such as macrophages, can produce Zonulin.
One of the limitations of this study is the cross sectional method to study patients compared to measuring serum Zonulin level in the same patient during periods of activity and non-activity; however the limited duration of this study was the reason.