Ursodeoxycholic acid alleviates multiple sclerosis via TGR5-dependent microglial regulation in mice

Multiple sclerosis (MS) causes demyelination of the central nervous system (CNS) because of excessive inflammation of peripheral tissues. The pathophysiological mechanisms remain unclear because of disease background variability; therefore, antibody drugs and disease-modifying agents are ineffective therapeutic options. Alterations in bile acid metabolism correlate with the progression of MS. However, the effects of bile acid supplementation on the amelioration of MS have not been fully elucidated. Thus, in this study, we aimed to investigate the effects of ursodeoxycholic acid (UDCA) on the CNS in a mouse model of MS. Repeated high-dose administration of UDCA significantly improved disease scores and alleviated tissue damage in the spinal cord. The number of Iba1-positive cells increased in the MS spinal cord, which decreased after UDCA treatment. The effect of UDCA ceased with the activation of the TGR5 inhibitor in mice with MS. Proteomic analysis of UDCA-treated activated MG6 cells revealed that the TGR5 inhibitor significantly decreased the expression of 40 proteins, including anti-neuroinflammatory proteins (A2M, AHSG, ALB, APOA1, APOH, and SPP2), and significantly increased the expression of six proteins (Atxn7l3b, Basp1, Plekha3, Ptma, and Rrp15). UDCA may potentially regulate MS progression by modulating microglial activity via TGR5 in the spinal cord. Overall, these findings suggest that UDCA has potential applications as a novel therapeutic agent for MS.