ACS Chemical Neuroscience
In the emerging context of gut–brain control of multiple sclerosis (MS), developing therapeutics targeting proinflammatory proteins controlling the gut–brain immunomodulation is welcoming. One such immunomodulator is glia maturation factor-β (GMF-β). GMF-β activation following GMF-β-ser-83 phosphorylation upregulates proinflammatory responses and exacerbates experimental autoimmune encephalomyelitis (EAE). Notably, GMF-β–/– mice exhibited no EAE symptoms. Thus, we identified 1H-indazole-4-yl-methanol (GMFBI.1) inhibitor which blocked GMF-β-ser-83 phosphorylation critical in EAE suppression. To establish gut GMF-β′s role in EAE in the context of gut–brain involvement in neurodegenerative diseases, we altered gut GMFBI.1 bioavailability as an index of EAE suppression. At first, we identified Miglyol 812N as a suitable biocompatible GMFBI.1 carrier compared to other FDA-approved carriers using in silico molecular docking analysis. GMFBI.1 administration in Miglyol 812N enhanced its retention/brain permeability. Subsequently, we administered GMFBI.1-Miglyol 812N by subcutaneous/oral routes at different doses with differential GMFBI.1 bioavailability in gut and brain to assess the role of local GMFBI.1 bioavailability in EAE reversal by a pharmacokinetic approach. Deprival of gut GMFBI.1 bioavailability led to partial EAE suppression despite having sufficient GMFBI.1 in circulation to inhibit brain GMF-β activity. Restoration of gut GMFBI.1 bioavailability led to complete EAE reversal. Molecular pathology behind partial/full EAE reversal was associated with differential GMF-β-Ser-83 phosphorylation/GM-CSF expression levels in enteric glial cells owing to GMFBI.1 bioavailability. In addition, we observed leaky gut reversal, tight junction protein ZO-1 restoration, beneficial gut microbiome repopulation, recovery from gut dysbiosis, and upregulation of Treg cells. GMFBI.1’s dual gut/brain targeting of GMF-β has therapeutical/translational potential in controlling autoimmunity in MS.