The impact of intestinal permeability and intestinal microbiome on cerebral immunological activity and myelination in bipolar disorder

Abstract

Abnormal immune responses have been reported in patients with bipolar disorder (BD), mostly involving number and activity of leucocytes and the balance between pro- and anti-inflammatory cytokines in blood. What lies at the root of the immune system aberrations is still unclear. Intestinal permeability, along with alterations in the intestinal microbiota, may be a significant factor driving the immune dysregulation in BD. In a post-hoc analysis of a study investigating simvastatin augmentation for recent-onset psychotic disorder (SMRI 12T-008)5,, twenty-four patients with recent onset schizophrenia and twenty-four healthy controls were included in the analyses. We found a mean level of LBP of 9.3ng/ml (SD 5.5) in the controls, which was significantly lower than the 13.4ng/ml (SD 7.6) found in the SCZ patients (p=0.05).Although the pattern of LBP levels might be complex in this patient population, it is rational to hypothesize that probiotic treatment may be more effective in patients with higher serum LBP, corresponding to increased intestinal permeability6.In a novel randomized controlled trial we investigate - Whether intestinal permeability improving probiotics have an effect on symptom severity in patients with psychotic or bipolar disorders that have increased intestinal permeability (LBP ≥ median) - Which factors (LBP, intestinal inflammation (fecal calprotectin), intestinal microbiome, and others) can best predict individual treatment response to probiotics- We will also investigate whether treatment with probiotics have a beneficial effect on immune parameters, metabolic syndrome features, cognition, side-effects, general functioning and gastrointestinal complaintsThe probiotic formulation is specifically selected for its beneficial effect on intestinal permeability.Stool and blood samples will be analyzed to identify optimal biomarkers (serum LBP, fecal calprotectin, intestinal microbiome) for response to probiotics.Another unanswered question is how these immune abnormalities exert their effect on the brain. Strikingly few studies have investigated activity of the brain’s immune system in living BD patients. We plan to perform neuroinflammation PET scans and diffusion tensor MRI scans at baseline and after completion in a subsample (n=44) of this RCT to assess the associations between intestinal functioning and glial cell (microglia/oligodendrocyte) functioning