We provide evidence that exercise applied prior to the development of colitis, especially in rats with diet-induced obesity as reflected by an increase in weight of colonic tissue and increased MPO activity, resulted in an enhancement in colonic microcirculation as a conglomeration of an increase in CBF, lower colonic tissue weight, an increase of MPO content, and the increased plasma levels of protective myokines, irisin, and IL-6. Here, FNDC5 is linked to colitis.