It is well known that chronic stresses exacerbate illness. However, the molecular mechanism remains poorly understood. Here, we show one of the underlying molecular mechanisms using an adoptive transfer system of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. In general, EAE mice develop tail and hind limb paralysis, but the symptom is not lethal. Under a chronic stress condition, however, EAE mice showed high mortality, associated with severe gastrointestinal failure. Interestingly, while donor pathogenic CD4+ T cells specific for a myelin antigen accumulated at the fifth lumbar spinal cord under a normal condition, the stress condition directed them to invade at the specific vessels of boundary area of the third ventricle, thalamus, and dentate gyrus to establish brain micro-inflammation. Importantly, instead of EAE induction, a direct cytokine injection to induce brain micro-inflammation at specific vessels was sufficient to establish severe gastrointestinal failure in mice with stress. Resulting brain micro-inflammation activated the specific neural pathway including the paraventricular nucleus (PVN), dorsomedial nucleus of hypothalamus (DMH), and vagal neurons to cause severe gastrointestinal failure. Suppression of the brain micro-inflammation or blockage of the neural pathway inhibited the gastrointestinal failure and improved mortality. These results showed a direct link between brain micro-inflammation and gastrointestinal homeostasis via a specific neural pathway under stress. We therefore suggest that brain micro-inflammation(s) could act as a switch to activate the new neural pathway(s) to regulate organ homeostasis.