Elucidating the Significance of Zonulin in the Pathogenesis of Chronic Inflammatory Disorders: Emphasis on Intestinal Barrier Function and Tight Junction Regulation.

The intestinal barrier, a critical component of the body's defense system, plays a vital role in maintaining homeostasis by preventing the translocation of harmful substances from the gut lumen into the bloodstream. Disruptions in this barrier, often characterized by increased intestinal permeability, are increasingly recognized as contributors to the development and progression of various Chronic Inflammatory Disorders (CIDs). Zonulin, a key regulator of intestinal Tight Junctions (TJs), has emerged as a pivotal player in this process. Dysregulation of zonulin, leading to increased intestinal permeability, has been implicated in the pathogenesis of a wide range of CIDs, including Inflammatory Bowel Disease (IBD), celiac disease, and Multiple Sclerosis (MS). This review examines the intricate relationship between zonulin and intestinal permeability, emphasizing its role in regulating TJ integrity and its association with various CIDs. Recent research has demonstrated the therapeutic potential of targeting zonulin, specifically through the use of larazotide acetate, a zonulin antagonist. Preclinical and clinical studies have shown promising results in improving gut barrier integrity and reducing inflammation in patients with CIDs. These findings underscore the significance of zonulin as a potential biomarker for intestinal barrier function and a promising therapeutic target for managing CIDs. Further research is needed to elucidate the precise mechanisms of action of zonulin antagonists and evaluate their efficacy and safety in clinical trials. A deeper understanding of the complex interplay among zonulin, intestinal permeability, and CIDs is crucial, paving the way for novel therapeutic strategies and personalized approaches to patient care.

Prolonged Transient Global Amnesia: Part of the Clinical Spectrum or a Separate Disease Entity?

Background: Transient global amnesia (TGA) is the prototypical neurologic disease for acute-onset reversible amnesia. It is currently defined by resolution of symptoms within 24-hours. In this case report we describe an atypical case of prolonged TGA, emphasizing our current lack of knowledge surrounding this disease entity and its pathophysiology. Results: A 66-year old female presented acutely with profound anterograde amnesia and variable retrograde amnesia with no inciting event. A thorough workup to exclude alternative causes of amnesia (including computed tomography angiogram and electroencephalogram) was normal. Her magnetic resonance imaging was consistent with TGA, with punctate diffusion restriction changes bilaterally in the hippocampi. She was also mildly hypoxemic with no discernible cause. She was ultimately diagnosed with TGA although her diagnosis remains controversial as her symptoms persisted for 72-hours. Conclusion: Our patients clinical and imaging features (apart from her protracted time-course and hypoxemia) were in keeping with a diagnosis of TGA. The association of hypoxemia, COVID-19, obstructive sleep apnea, and the development of TGA remains to be elucidated. Although the underlying pathophysiology for TGA is unknown several mechanisms have been postulated including cortical spreading depression and reversible hypoxic-ischemic injury. The time course for symptom resolution, could be an important clue in discerning the pathophysiology of TGA on an individual basis. Importantly, a clinician should not be deterred by amnestic symptoms lasting >24-hours, if the patients clinical/radiologic presentation is consistent with TGA.

Simple parameters from complete blood count predict lymphopenia, adverse effects and efficacy in people with MS treated with dimethyl fumarate.

BACKGROUND: Dimethyl fumarate (DMF) is a first-line oral therapy for relapsing-remitting multiple sclerosis (RRMS). This retrospective study aims to determine the utility of routine complete blood counts (CBC) in predicting lymphopenia, adverse effects and efficacy in a real-world clinical setting. METHODS: The Calgary Multiple Sclerosis (MS) Clinic manages over 1800 people with MS on disease-modifying therapies (DMT). Data of patients with relapsing-remitting MS (pwMS) who initiated DMF between July 1, 2013 and December 31, 2014 were included. Patients were followed for one year. DMT use is carefully monitored and pwMS need a screening CBC and have regular CBCs done at follow-up. Demographic, clinical, MRI and relapse information are collected prospectively in a clinic database. We analyzed CBCs at baseline and month 3. RESULTS: We identified 139 pwMS in the study period who started DMF. Median follow-up time on-drug was 12 (0.16-12) months. In our study, 15.8% of pwMS developed lymphopenia grade 2 or higher. Baseline lymphocyte counts and older age were significant predictors of lymphopenia. Higher baseline eosinophil counts predicted flushing/gastrointestinal adverse effects, and higher baseline monocyte counts were predictive of breakthrough disease activity. Neutrophil and platelet to lymphocyte ratios, markers that have been associated with overall mortality in the general population, were increased at month 3. CONCLUSIONS: Routinely obtained CBCs during the screening and monitoring of people with MS starting DMF offer clinically useful information and generate interesting hypotheses. Age and baseline lymphocyte counts are reinforced as clinically useful predictors of lymphopenia. Our novel findings that baseline eosinophil and monocyte counts could offer insights into usual adverse effects and efficacy, respectively, should be further investigated as a potentially new set of biomarkers.

Longitudinally extensive transverse myelitis with positive aquaporin-4 IgG associated with dengue infection: a case report and systematic review of cases.

BACKGROUND: Neuromyelitis Optica Spectrum Disorder can be associated with parainfectious and post-infectious triggers. Dengue virus infection is one of the most common arbovirus infections in the world, and may present with neurological manifestations. OBJECTIVES: We present a case of DENV-associated with LETM and positive aquaporin-4 IgG, and a systematic review of published cases. METHODS: Medline (Ovid) and PubMed were search through June 2021, for case reports, series and observational studies that described patients with DENV-associated LETM and/or NMOSD. RESULTS: An adolescent girl who had recently immigrated from a Dengue-endemic region presented with a LETM with high positive AQP4-IgG titer and seropositive DENV IgM/IgG antibodies. She responded well to steroids and subsequently started maintenance rituximab for her NMOSD diagnosis. LITERATURE REVIEW: 22 publications describing 27 patients met inclusion criteria. In addition to this case, three published cases met current criteria for NMOSD with serological evidence of acute DENV infection. CONCLUSIONS: It is unknown whether there is a pathophysiological association between DENV infection and NMOSD. Regardless, if an immune-mediated event is suspected, particularly NMOSD, appropriate immunotherapy should be considered early. Decision regarding long term immunotherapy may depend on index of suspicion of true NMOSD, and this is where AQP4-IgG status and follow-up is helpful.

Multimodal peripheral fluid biomarker analysis in clinically isolated syndrome and early multiple sclerosis.

BACKGROUND: Increasing evidence suggests that various inflammatory, immunological and metabolic pathways are altered in the clinically isolated syndrome (CIS) of multiple sclerosis (MS). Moreover, recent diagnostic criteria have made possible the very early diagnosis of MS. We evaluated multiple fluid biomarkers in people with early MS and CIS. METHODS: We measured blood levels of cytokines, matrix metalloproteinases (MMPs), serum metabolomics and immune cell immunophenotyping in participants in the Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis. RESULTS: When compared with healthy controls, people with early MS/CIS had higher levels of eotaxin, MCP-3, IL-1 receptor antagonist, IL-1ß, IL-9 and IP-10, as well as MMPs 1, 8 and 9. In metabolomics analysis, the alanine, aspartate and glutamate metabolism and the synthesis and degradation of ketone bodies pathways were altered compared to healthy controls. There were no differences in lymphocyte subpopulation numbers. Out of all these biomarkers, only MMP-1 was able to differentiate between early MS and CIS, and was found to correlate with lesion volume and gadolinium enhancing lesions on MRI. CONCLUSION: The immunological and metabolic profile of CIS and early MS is remarkably similar, supporting that these are a continuum of a common underlying pathophysiological process.

D-Lactate and intestinal fatty acid-binding protein are elevated in serum in patients with acute ischemic stroke.

Experimental studies suggest that the intestinal barrier is affected in ischemic stroke. D-Lactate and intestinal fatty acid-binding protein (IFABP) are markers of intestinal mucosa integrity and barrier function. Our purpose was to evaluate the serum concentrations of these markers in patients with acute ischemic stroke (AIS). We included patients with AIS and used healthy subjects as controls. Clinical, demographic and outcome measures were recorded. Blood was drawn within 24 h of symptom onset. Serum concentrations of D-Lactate and IFABP were determined using commercially available colorimetric and ELISA kits, respectively. We included a total of 61 patients (median age of 64 years). The majority of patients were male (57.4%). The most common cause of stroke was atherosclerosis (34.4%), followed by small-vessel disease and cardioembolic (32.7% each). Mean admission NIHSS score was 8. Median IFABP and D-Lactate concentrations were significantly higher in patients than in controls. Concentrations were not associated with stroke severity or 3-month outcome. Patients with large-artery atherosclerosis and cardioembolic etiology had higher D-Lactate values than patients with small-vessel disease. D-Lactate and IFABP were significantly elevated in patients with AIS. This suggests that there is disruption of the intestinal barrier in patients with AIS.

Biomarkers of intestinal barrier function in multiple sclerosis are associated with disease activity.

BACKGROUND: Recent evidence suggests a role for the gut-brain axis in the pathophysiology of multiple sclerosis (MS). MATERIALS AND METHODS: We studied biomarkers of intestinal permeability in 126 people with MS (57 relapsing-remitting multiple sclerosis (RRMS) and 69 progressive MS) and in a group of healthy controls for comparison. Serum/plasma concentrations of zonulin (a regulator of enterocyte tight junctions), tight junction proteins (ZO-1 and occludin), intestinal fatty acid binding protein (IFABP)/ileal bile acid binding protein (IBABP), D-lactate, and lipopolysaccharide (LPS) binding protein were measured. RESULTS: Zonulin concentrations were significantly higher when a concurrent magnetic resonance imaging (MRI) confirmed the presence of blood-brain barrier (BBB) disruption (Gad+ RRMS) and were correlated with tight junction proteins. IBABP and D-lactate were elevated in people with RRMS compared to controls, but did not discriminate between Gad+ and Gad- subgroups. Baseline zonulin concentrations were associated with 1-year disease progression in progressive MS. CONCLUSIONS: People with MS have altered biomarkers of intestinal barrier integrity. Zonulin concentrations are associated with 1-year disease progression in progressive MS and closely mirror BBB breakdown in RRMS. Zonulin may mediate breakdown of both the intestinal barrier and the BBB in gut dysbiosis through the regulation of tight junctions. This could explain how the gut-brain axis modulates neuroinflammation in MS.