Protective effects of Delta-8-THC against EAE-induced enteric neuropathy and neuroinflammation through regulation of miRNA-mediated signaling networks

Multiple sclerosis has long been associated with neurological symptoms, yet the connection between neuroinflammation and enteric neuropathy remains understudied. To test the complex brain-gut connection, we administered Δ8-THC (10mg/kg) i.p to mice with Experimental autoimmune encephalomyelitis (EAE), animal model of MS. We observed that treatment significantly reduced the clinical score and reversed the weight loss in treated group by suppression of proinflammatory Th1 phenotypes such as Tbet and IFN-g and increase anti-inflammatory phenotype such as Tregs and IL-10.miRNAseq analysis of brain infiltrating CD4+ cells revealed that decrease in neuroinflammation following treatment was associated with downregulation of miRNAs, involved in Pyroptosis, Th1 and Th2 pathway regulation. The EAE mice exhibit persistent gastrointestinal symptoms. To investigate bowel dysfunction miRNAseq analysis was performed for colonic and ileal tissues and contents. A highly dysregulated miRNA6538 found in all four miRNAseq analyses. miRNA6538 downregulation in colonic and ileal tissues, along with ileal content in treated EAE mice, suggests a protective role against EAE-induced bowel symptoms while its upregulation in colonic content could be due to the shedding of cells as a part of homeostasis during cellular turnover.In summary, Δ8-THC's suppression of EAE involves a dual impact on the brain and gut, showing its potential as a therapeutic strategy for mitigating neurodegenerative disorders.