The aging intestine as a novel front to fight post-stroke inflammation

Age-associated changes in gut permeability are likely to regulate immune response in the elderly, particularly in the setting of stroke. While most of the data on experimental stroke comes from young mice, I study the contribution of the intestinal immune system to post-stroke inflammation in aged mice.

In aged mice, stroke causes a prolonged and sustained gut barrier breach that provokes intestinal immune response, leads to translocation of microbial components across the epithelial barrier and results in exacerbated neurological damage. Time course measurements of intestinal norepinephrine levels and transection of the superior mesenteric nerve, which provides sympathetic innervation to the gut, in young and aged mice post-stroke, showed that a surge of sympathetic signaling to the gut leads to transient gut barrier breach that is being resolved in young mice. However, in aging, maladaptive intestinal immune response aggravates gut permeability, leading to exacerbated systemic inflammation and a severer brain damage. I determined that impaired metabolism in a specific subtype of intestinal macrophages may delay intestinal permeability resolution in aging. In these intestinal macrophages, the lipid messenger PGE2 is a major modulator of immune responses. Its binding to EP2 receptor suppresses metabolism and consequent beneficial myeloid functions. Myeloid-specific deficiency of the EP2 receptor reduced post-stroke gut barrier breach and systemic inflammation by blocking monocytes recruitment form blood to the post-stroke intestinal lamina propria. These results highlight that myeloid cell reprogramming from EP2 inhibition can ameliorate immune cell responses in the aged gut, leading to a better neurological recovery after stroke.