Batra, A. | Search bioRxiv

bioRxiv2020

Inferring intestinal mucosal immune cell associated microbiome species and microbiota-derived metabolites in inflammatory bowel disease

Inflammatory bowel disease (IBD) is a complex, chronic inflammatory disease of the gastrointestinal tract with subtypes Crohns disease (CD) and ulcerative colitis (UC). While evidence indicates IBD is characterized by alterations in the composition and abundance of the intestinal microbiome, the challenge remains to specify bacterial species and their metabolites associated with IBD pathogenesis. By the integration of microbiome multi-omics data and computational methods, we provide analyses and methods for the first time to identify microbiome species and their metabolites that are associated with the human intestine mucosal immune response in patients with CD and UC at a systems level. First, we identified seven gut bacterial species and seventeen metabolites that are significantly associated with Th17 cellular differentiation and immunity in patients with active CD by comparing with those obtained in inactive CD and non-IBD controls. The seven species are Ruminococcus gnavus, Escherichia coli, Lachnospiraceae bacterium, Clostridium hathewayi, Bacteroides faecis, Bacteroides vulgatus, and Akkermansia muciniphila, and a few associated metabolites include the secondary bile acid lithocholate and three short-chain fatty acids (SCFAs): propionate, butyrate, and caproate. We next systematically characterized potential mechanistic relationships between the Th17-involved metabolites and bacterial species and further performed differential abundance analysis for both microbiome species and their metabolites in CD and UC relative to non-IBD controls with their metagenomic and metabolomic data. Based on the deconvolution of immune cell compositions from host intestinal bulk RNA-seq, we investigated changes in immune cell composition and abundance in CD and UC in comparison to non-IBD controls. Finally, we further extended our species and metabolite associations with immune cells from Th17 and Th2 cells to B cells, plasma B cells, plasmablasts, CD4+ T cells, and CD8+ T cells. While a set of associations of immune cells with bacterial species and metabolites was supported by published evidence, the new findings in this work will help to furthering our understanding of immune responses and pathogenesis in IBD.

bioinformatics↗

bioRxiv2020

Maladaptive myelination promotes epileptogenesis in absence epilepsy

Neuronal activity can influence the generation of new oligodendrocytes (oligodendrogenesis) and myelination. In health, this is an adaptive process that can increase synchrony within distributed neuronal networks and contribute to cognitive function. We hypothesized that in seizure disorders, aberrant neuronal activity may promote maladaptive myelination that contributes to pathogenesis. Absence epilepsy is a disease defined by increasingly frequent behavioral arrest seizures over time, thought to be due to thalamocortical network hypersynchrony. We tested the hypothesis that activity-dependent myelination resulting from absence seizures promotes epileptogenesis. Using two distinct models of absence epilepsy, Wag/Rij rats and Scn8a+/mut mice, we found increased oligodendrogenesis and myelination specifically within the absence seizure network. These changes are evident only after seizure onset in both models and are prevented with pharmacological inhibition of seizures. Genetic blockade of activity-dependent myelination during epileptogenesis markedly decreased seizure frequency in the Scn8a+/mut mouse model of absence epilepsy. Taken together, these findings indicate that activity-dependent myelination driven by absence seizures contributes to seizure kindling during epileptogenesis.

neuroscience↗