Prenatal alcohol alters inflammatory signatures in enteric portal tissues following adult-onset cerebrovascular ischemic stroke.

Prenatal alcohol exposure (PAE) impairs recovery from cerebrovascular ischemic stroke in adult rodents. Since the gut becomes dysbiotic following stroke, we assessed links between PAE and enteric portal inflammation. Adult control and PAE rat offspring received a unilateral endothelin-1-induced occlusion of the middle cerebral artery. Post-stroke behavioral disabilities and brain cytokines were assessed. Mesenteric adipose and liver transcriptomes were assessed from stroke-exposed and stroke-naive offspring. We identified, in the liver of stroke-naive animals, a moderate correlation between PAE and a gene network for inflammatory necroptosis. PAE inhibited the acute-phase brain inflammatory cytokine response to stroke. Post-stroke neurological function was correlated with an adipose gene network associated with B-lymphocyte differentiation and nuclear factor κB (NF-κB) signaling and with a liver pro-inflammatory gene network. Collectively, PAE inhibits brain inflammation but results in an inflammatory signature in enteric portal tissues after stroke, suggesting that PAE persistently and adversely impacts the gut-brain axis following adult-onset disease.

Sex differences in cognitive impairment after focal ischemia in middle-aged rats and the effect of iv miR-20a-3p treatment.

Stroke is a major cause of death and disability worldwide and is also a leading cause of vascular dementia and Alzheimer's disease, with older women experiencing accelerated decline. Our previous studies show that intravenous (iv) injections of miR-20a-3p, a small noncoding RNA (miRNA) delivered after stroke improves acute stroke outcomes in middle-aged male and female rats. The present study tested whether mir-20a-3p treatment would also ameliorate stroke-induced cognitive decline in the chronic phase. Acyclic middle-aged females and age-matched male Sprague Dawley rats were subjected to middle cerebral artery occlusion using endothelin-1 or sham surgery, and treated iv with miR-20a-3p mimics or scrambled oligos at 4 hours, 24 hours, and 70 days post-stroke. Stroke resulted in a significant sensory motor deficit, while miR-20a-3p treatment reduced these deficits in both sexes. Cognitive impairment was assessed periodically for 3 months after stroke using contextual fear conditioning and the novel object recognition task. Overall, the tests of associative and episodic memory were affected by focal ischemia only in female rats, and miR-20a-3p ameliorated the rate of decline.

Intestinal epithelial stem cell transplants as a novel therapy for cerebrovascular stroke.

Almost 2/3rds of stroke survivors exhibit vascular cognitive impairment and a third of stroke patients will develop dementia 1-3 years after stroke. These dire consequences underscore the need for effective stroke therapies. In addition to its damaging effects on the brain, stroke rapidly dysregulates the intestinal epithelium, resulting in elevated blood levels of inflammatory cytokines and toxic gut metabolites due to a 'leaky' gut. We tested whether repairing the gut via intestinal epithelial stem cell (IESC) transplants would also improve stroke recovery. Organoids containing IESCs derived from young rats transplanted into older rats after stroke were incorporated into the gut, restored stroke-induced gut dysmorphology and decreased gut permeability, and reduced circulating levels of endotoxin LPS and the inflammatory cytokine IL-17A. Remarkably, IESC transplants also improved stroke-induced acute (4d) sensory-motor disability and chronic (30d) cognitive-affective function. Moreover, IESCs from older animals displayed senescent features and were not therapeutic for stroke. These data underscore the gut as a critical therapeutic target for stroke and demonstrate the effectiveness of gut stem cell therapy.