FIG 7.

SB supplementation modulates the gut microbiota of T2D, increasing the abundance of butyrate-producing bacteria with an upgraded level of butyrate, leading to a strengthened gut barrier. In the stroke context, gut-derived LPS travels through the leaky gut into the circulation, promoting the production of proinflammatory cytokines from leukocytes. The process is more prominent in T2D than in T2D+SB. The cerebral endothelial glycocalyx is the first line of defense of the BBB; it generates an exclusion zone for blood components, such as leukocytes and LPS. Adhesion molecules like VCAM-1 and ICAM-1 are harbored within the glycocalyx, so normally they do not have the chance to contact the circulating blood components. In T2D, the glycocalyx is more structurally degraded under more severe peripheral inflammation. Activated VCAM-1 and ICAM-1 are exposed and allowed to interact with leukocytes, mediating the leukocytic adhesion to the endothelial cells and migration into the brain, where they produce more inflammatory cytokines and activate the microglia, along with inflammatory cytokines and LPS that travel through the BBB. The activated microglia generate MMP-9 that destroys the BBB and glycocalyx in turn as a vicious cycle. The overt inflammatory reaction leads to more neuron death in the brain of T2D, contributing to a larger infarct volume than that in T2D supplemented with SB.