Centrally administered SGLT2 inhibitor improves gut barrier function through the brain orexin, AMPK, dopamine D2 signaling and the vagal pathway in rats

Leaky gut, defined as increased intestinal permeability, has been associated with many diseases. Recent studies suggest the brain is involved in maintaining gut barrier function. Since tofogliflozin, a sodium/glucose cotransporter 2 (SGLT2) inhibitor acts centrally to increase food intake, and feeding and gut functions are deeply associated, this study aimed to clarify the hypothesis that gut barrier function is influenced by centrally administered SGLT2 inhibitors in rats using Evans blue method. Intracisternal SGLT2 inhibitor blocked colonic hyperpermeability in response to lipopolysaccharide dose-dependently (15 μg-). The blockade was cancelled by atropine, vagotomy, intracisternal orexin receptor antagonist, intracisternal compound C, an adenosine monophosphate-activated protein kinase (AMPK) inhibitor, or subcutaneously injected sulpiride, a dopamine D2 receptor antagonist. Subcutaneous SGLT2 inhibitor at much higher doses of 5mg or more could improve colonic hyperpermeability, and the improvement was also blocked by atropine or intracisternal orexin receptor antagonist or compound C. These results indicate SGLT2 inhibitor administered centrally or peripherally reduces colonic hyperpermeability through the vagal pathway although we could not exclude the possibility that peripherally administered SGLT2 inhibitor might act first in periphery. Brain orexin, AMPK and dopamine D2 signaling are involved in this process. SGLT2 inhibitors may be useful to treat leaky gut-related diseases.