Chitosan lactate improves repeated closed head injury-generated motor and neurological dysfunctions in mice by impacting microbiota gut-brain axis.

Abstract

The negative impact of repeated-mild traumatic brain injury (rmTBI) is profoundly seen in circadian-disrupted individuals. The unrelenting inflammation, glial activation, and gut dysbiosis are key neuropathological aberrations in the aftermath of rmTBI. In this study, we examined the impact of chitosan lactate (CL) on circadian disturbance (CD) + rmTBI-generated neurological dysfunctions and its prebiotic response on the gut-brain axis. Adult C57BL/6 mice were exposed to circadian disruption (CD) prior to rmTBI insults. The neurobehavioral changes were assessed by rotarod, open-field test (OFT), elevated zero maze (EZM), forced-swim test (FST), Y-maze, and novel object recognition test (NORT). The inflammatory, neuronal, and synaptic markers in the frontal cortex and hippocampus, and cecal gut microbiota phylum were examined using RT-PCR and western blotting. The goblet cells, tight junction proteins (occludin and zona occludens-1), and short-chain fatty acids (SCFAs) were analyzed using immunohistochemistry, alcian-blue PAS staining, and ¹H-NMR methods. Mice exposed to CD + rmTBI (CDR) displayed robust neurological dysfunctions in rotarod, anxiety- and depressive-like behavior in EZM and FST, and cognition deficits in Y-maze and NORT. Administration of CL (1 and 3 mg/kg) mitigated the above neurobehavioral abnormalities. CL treatment also normalized the levels of inflammatory markers (NF-κB, IL-6, IL-18, and TNF-α), brain-derived neurotrophic factor, and neuronal/synaptic proteins (doublecortin, synaptophysin, and postsynaptic density protein-95). Increased goblet cells and tight junction proteins in the colon and SCFAs in the cecal samples indicated improved gut integrity following CL treatment. The results indicate that CL mitigated CDR-inflicted neurological abnormalities in mice by modulating neuroinflammation and gut-brain interactions.