The Relation of Intestinal Permeability Biomarkers and Cognitive Functions in Patients with Bipolar Disorder

The Relation of Intestinal Permeability Biomarkers and Cognitive Functions in Patients with Bipolar Disorder Introduction: Studies show that patients with bipolar disorder experience cognitive deficits both during the acute and remission phase of the disease. Gastrointestinal pathologies are long-term comorbidities of psychiatric disorders, and studies indicate that gut and brain physiologies are interconnected. The alterations in gut microbiota in adulthood may impair the intestinal barrier functions by causing an increase in intestinal permeability. An imbalance in the intestinal flora (dysbiosis) might also impair the permeability of the brain barrier. Recent studies demonstrated that probiotics provide positive improvements in cognitive functions by balancing the intestinal microbiota, which suggests that dysbiosis may be a factor in the cognitive damage in patients with dementia. Intestinal permeability can be determined by measuring Zonulin and intestinal fatty acid-binding protein (I-FABP) in blood plasma. Zonulin is known to induce tight junction disassembly between cells of the duodenum and small intestine, which results in increased permeability. Zonulin is an important modulator of intracellular tight junctions that balance permeability in both the gut and the blood-brain barrier. Another potential marker of gut integrity is I-FABP, also known asFABP2. This cytoplasmic protein is found in enterocytes of the small intestine and high levels of it indicates enterocyte damage. In our study, we aim to investigate the relationship between the intestinal permeability biomarkers, Zonulin and I-FABP levels, and cognitive functions of bipolar disorder patients, and compare them with healthy controls. Method: Forty patients diagnosed with bipolar disorder according to DSM-5 criteria and forty healthy controls, matched with patients in terms of gender and age, were recruited in the study. Socio-Demographic Data Form, Hamilton Depression Rating Scale, Young Mania Rating Scale, Stroop Test, Trail Making Test, Öktem Verbal Memory Process Test (VMPT), Wisconsin Card Sorting Test (WCST), Digit Span Tests were applied to the participants. In addition to Zonulin and Intestinal Fatty Acid Binding Protein (I-FABP), glucose, triglyceride, HDL-cholesterol, CRP levels of participants were measured to evaluate the metabolic status and to determine a possible systemic infection. Fasting blood samples were taken from the participants by a nurse working in the psychiatry clinic between 08.00- 10.00. These blood samples were evaluated in the biochemistry laboratory of Bezmialem Vakıf University Hospital. Results: In our study, Zonulin and I-FABP levels were significantly higher in the patient group than in control group (p< .001). In the patient group, the time to perform Stroop 1., 2., 3., 4., and 5. Card, and Stroop interference duration were found to be statistically significantly higher than the control group (p< .001). The patient group completed both the Trail Making A form and the Trail Making B form in a significantly longer time than the control group (p< .001).There was no significant difference between the number of mistakes made by the patient group and the number of mistakes made by the control group in both Trail Making A and Trail Making B forms (p= .98, p= .06, respectively). In Öktem Verbal Memory Processes Test, patients' immediate memory, learning scores, highest learning, spontaneous recall and total recall scores were significantly lower compared to the control group, while the recognition and misrecognition scores of patients were significantly higher in comparison to those of control group. In patient group, the total error, perseverative response, perseverative error, and perseverative error percentage were significantly higher, whereas the number of total correct answers and the number of completed categories were significantly lower than in the control group.Forward digit span and backward digit span test scores were found to be statistically significantly lower in the patient group compared to the control group. A positive correlation was found between the disease duration and Zonulin levels.It is noteworthy that there was a positive correlation between the number of manic episodes, and Zonulin and I-FABP levels. A positive correlation was found between the Zonulin levels of the patients and the Stroop Test 3. Card time, 4. Card time, 5. Card time scores and Stroop Interference Effect time (r= .59 p= .01, r= .49 p= .01, r= .58 p< .001, r= .46 p< .001, respectively).A positive correlation was found between the Zonulin levels of the patients and time to perform Trail Making Test B form (r= .78 p= .01).While an inverse correlation was found between the patients' Zonulin levels and their VMPT Learning Score, Highest Learning, Spontaneous Recall, and Total Recall scores, there was a positive correlation between patients' Zonulin levels and their Recognition score (r= -.305 p= .05, r= -.381 p= .01, r=- .416 p< .001, r= -.354 p= .02, r= .423 p< .001, respectively).For the patients, there was no statistically significant correlation between the Zonulin and I-FABP levels and the Wisconsin Card Sorting Test and digit span test parameters.For the control group, no significant correlation was found between the Stroop Test Scores and Zonulin and I-FABP levels.There was a positive correlation between the Zonulin levels of the control group and the time to perform Trail Making Test A form (r= .360 p= .02).While a positive correlation was observed between Zonulin levels and VMPT Learning scores of the control group, an inverse correlation was observed between their I-FABP levels and Immediate Memory scores (r= .314 p= .05, r= -.321 p= .04, respectively).It is noteworthy that there was a positive correlation between the Zonulin levels and the number of WCST Perseverative Errors of the control group(r= .347 p= .03).No statistically significant correlation was observed between the Zonulin and I-FABP levels of the control group and their Forward and Backward Digit Span Test scores. Conclusion: It is known that Zonulin induces disassembly of tight junctions between cells of the duodenum and small intestine, resulting in increased intestinal permeability. I-FABP is found in the enterocytes of the small intestine. The alterations of intestinal wall integrity will cause increased enterocyte damage, leading to increased plasma I-FABP level.According to the results of our study, intestinal permeability parameters, Zonulin and I-FABP levels,are increased in Bipolar Disorder patients compared to healthy controls.Additionally, in our study, it was found that the patient group performed cognitive tests with lower scores compared to the healthy controls.In order to test the hypothesis that intestinal dysbiosisaffects the blood brain barrier and may contribute to the cognitive impairment process, the correlations between cognitive tests and Zonulin and I-FABP levels were examined, and positive correlations were found between Zonulin levels and tests evaluating cognitive functions such as attention and memory. It has been revealed in our study that increasing Zonulin level has effect on cognitive impairment as well as causing an increase in intestinal permeability. Keywords: Bipolar disorder, intestinal permeability, cognitive functions