immunogut · Unravelling the role of aging in post-stroke gut-brain axis signalling

Unravelling the role of aging in post-stroke gut-brain axis signalling

Aging is a major risk factor for stroke. Post-stroke inflammation greatly affects its severity and offers an extended therapeutic time window. Age-associated changes in gut permeability are likely to regulate intestinal immune response in the elderly, particularly in the setting of stroke, predisposing elderly stroke patients to infections and poor recovery. In this project, I show that 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. By delineating intestinal norepinephrine dynamics after stroke, and manipulating sympathetic signaling to the gut in young and aged mice, I determined that gut barrier breach fails to recover due to a secondary inflammatory response localized to the gut in aged stroke. Objectives Aim 1: Testing whether aging increases post-stroke gut permeability and bacterial translocation. Here I observed significant increases in early bacterial seeding of organs after sham or stroke surgery in aged mice, indicating a breach of the gut barrier in aged mice. I found a significant and sustained increase in intestinal permeability in aged stroke compared to young. Aim 2: Testing whether aging alters the frequencies and biological functions of intestinal innate immune subsets in response to loss of gut barrier integrity I have showed that a proximal and important consequence of early bacterial translocation is a massive mobilization of local innate immune responses in the intestinal lamina propria. As the intestine harbors ~70% of the body’s Monocytes/Macrophages (Mo/M), and reactive intestinal Mo/M populations generate toxic cytokines, proteases, and ROS that further damage the intestinal epithelium, a conceptually new hypothesis is that this process leads to a feed-forward cycle of bacterial translocation lamina propria innate immune toxic responses further epithelial barrier breakdown. Aim 3. Testing whether aging increases the translocation of microbial metabolites across the intestinal barrier to the systemic circulation after stroke Although the breach in the intestinal barrier is self-limited in young stroke, this is not the case in aged stroke where gut barrier disruption begins earlier and lasts much longer (Fig. 2b). Functional outcomes are worse in aged compared to young stroke (Fig. 1b-d). Indeed, myeloid responses are a major driver of stroke severity. In aged stroke, a critical vulnerability arises from persistent intestinal permeability that is amplified by reactive intestinal innate immune responses. The concept that a dysregulated intestinal innate immune response, enhanced in aged stroke, will worsen stroke outcome is novel and has been investigated in Aims 2-3.

Data: CORDIS, © European Union