A combination of inhibiting microglia activity and remodeling gut microenvironment suppresses the development and...

Noninfectious (autoimmune and immune-mediated) uveitis is an ocular inflammatory disease which can lead to blindness in severe cases. Due to the potential side effects of first-line drugs for clinical uveitis, novel drugs and targets against uveitis are still urgently needed. In the present study, using rat experimental autoimmune uveitis (EAU) model, we first found that minocycline treatment can substantially inhibit the development of EAU and improve the retinal function by suppressing the retinal microglial activation, and block the infiltration of inflammatory cells, including Th17, into the retina by decreasing the major histocompatibility complex class II (MHC II) expression in resident and infiltrating cells. Moreover, we demonstrated that minocycline treatment can remodel the gut microenvironment of EAU rats by restoring the relative abundance of Ruminococcus bromii, Streptococcus hyointestinalis, and Desulfovibrio sp. ABHU2SB and promoting a functional shift in the gut via reversing the levels of L-proline, allicin, aceturic acid, xanthine, and leukotriene B4, and especially increasing the production of propionic acid, histamine, and pantothenic acid. At last, we revealed that minocycline treatment can significantly attenuate the progression of EAU after inflammation onset, which may be explained by the role of minocycline in the remodeling of the gut microenvironment since selective elimination of retinal microglia on the later stages of EAU was shown to have little effect. These data clearly demonstrated that inhibition of microglial activation and remodeling of the gut microenvironment can suppress the development and progression of experimental autoimmune uveitis. Considering the excellent safety profile of minocycline in multiple clinical experiments, we suggest that minocycline may have therapeutic implications for clinical uveitis.