RESUMEN
Stroke results in immediate sensory or motor disability and increases the risk for long term cognitive-affective impairments. Thus, therapies are urgently needed to improve quality of life for stroke survivors, especially women who are at a greater risk for severe stroke after menopause. Most current research on stroke therapies target the central nervous system; however, stroke also impacts peripheral organ systems. Our studies using acyclic (estrogen-deficient) middle aged female Sprague Dawley rats show that this group not only displays worse outcomes after stroke as compared to adult females, but also has lower levels of the neuroprotective peptide Insulin-like Growth Factor (IGF1) in circulation. Intracerebroventricular (ICV) administration of IGF1 to this group decreases infarct volume and improves sensory motor performance in the acute phase. In this study, we show that, despite this neuroprotection, ICV-IGF1 did not reduce peripheral inflammation or improve post stroke cognitive impairment in the chronic phase. In view of the evidence that stroke induces rapid gut dysfunction, we tested whether systemic delivery of IGF1 (intraperitoneal, IP) would promote gut health and consequently improve long-term behavioral outcomes. Surprisingly, while IP-IGF1, delivered 4 h and 24 h after ischemic stroke, did not reduce infarct volume or acute sensory motor impairment, it significantly attenuated circulating levels of pro-inflammatory cytokines, and attenuated stroke-induced cognitive impairment. In addition, IP-IGF1 treatment reduced gut dysmorphology and gut dysbiosis. Our data support the conclusion that therapeutics targeting peripheral targets are critical for long-term stroke recovery, and that gut repair is a novel therapeutic target to improve brain health in aging females.
Asunto(s)
Disfunción Cognitiva , Factor I del Crecimiento Similar a la Insulina , Accidente Cerebrovascular , Animales , Femenino , Ratas , Disfunción Cognitiva/etiología , Disfunción Cognitiva/tratamiento farmacológico , Modelos Animales de Enfermedad , Microbioma Gastrointestinal/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/administración & dosificación , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Ratas Sprague-Dawley , Accidente Cerebrovascular/complicacionesRESUMEN
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.
Asunto(s)
Personas con Discapacidad , Trastornos Motores , Accidente Cerebrovascular , Animales , Ratas , Humanos , Accidente Cerebrovascular/terapia , Trasplante de Células MadreRESUMEN
Brain injuries and neurological diseases have a significant impact on the gut microbiome and the gut barrier. Reciprocally, gut disorders, such as Inflammatory Bowel Syndromes (IBS), can affect the development and pathology of neurodegenerative and neuropsychiatric diseases, although this aspect is less well studied and is the focus of this review. Inflammatory Bowel Syndrome (IBS) is a chronic and debilitating functional gastrointestinal disorder afflicting an estimated 9-23% of the world's population. A hallmark of this disease is leaky gut, a pathology in which the integrity of the gut blood barrier is compromised, causing gut contents such as immune cells and microbiota to enter the bloodstream leading to low-grade systemic inflammation. The increased levels of inflammation associated cytokines in circulation has the potential to affect all organs, including the brain. Although the brain is protected by the blood brain barrier, inflammation associated cytokines can damage the junctions in this barrier and allow brain infiltration of peripheral immune cells. Central inflammation in the brain is associated with various neurodegenerative disease such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and neuropsychiatric disorders, namely, depression, and anxiety. Neurodegenerative diseases are of particular concern due to the anticipated rise in the population of the elderly and consequently, the prevalence of these diseases. Additionally, depression and anxiety are the most common mental illnesses affecting roughly 18% of the American population. In this review, we will explore the mechanisms by which IBS can influence the risk and severity of neurological disease.
Asunto(s)
Microbioma Gastrointestinal , Microbiota , Enfermedades Neurodegenerativas , Enfermedades del Sistema Nervioso Periférico , Anciano , Encéfalo/patología , Microbioma Gastrointestinal/fisiología , Humanos , Enfermedades Neurodegenerativas/patología , Enfermedades del Sistema Nervioso Periférico/patologíaRESUMEN
BACKGROUND: Sex differences in experimental stroke outcomes are well documented, such that adult males have a greater infarct volume, increased stroke-induced mortality, and more severe sensory-motor impairment. Based on recent evidence that the gut is an early responder to stroke, the present study tested the hypothesis that sex differences in stroke severity will be accompanied by rapid and greater permeability of the gut-blood barrier and gut dysbiosis in males as compared to females. METHOD: Male and female Sprague-Dawley rats (5-7 months of age) were subject to endothelin (ET)-1-induced middle cerebral artery occlusion (MCAo). Sensory-motor tests were conducted pre- and 2 days after MCAo. Gut permeability was assessed in serum samples using biomarkers of gut permeability as well as functional assays using size-graded dextrans. Histological analysis of the gut was performed with H&E staining, periodic acid-Schiff for mucus, and immunohistochemistry for the tight junction protein, ZO-1. Fecal samples obtained pre- and post-stroke were analyzed for bacterial taxa and short-chain fatty acids (SCFAs). RESULTS: After stroke, males displayed greater mortality, worse sensory-motor deficit, and higher serum levels of proinflammatory cytokines IL-17A, MCP-1, and IL-5 as compared to females. MCAo-induced gut permeability was rapid and severe in males as indicated by dextran extravasation from the gut to the blood in the hyperacute (< 2 h) and early acute (2 days) phase of stroke. This was accompanied by dysmorphology of the gut villi and dysregulation of the tight junction protein ZO-1 in the acute phase. Fecal 16s sequencing showed no differences in bacterial diversity in the acute phase of stroke. Predictive modeling indicated that markers of gut permeability were associated with acute sensory-motor impairment and infarct volume. CONCLUSIONS: These data show that extensive leakiness of the gut barrier is associated with severe post-stroke disability and suggest that reinforcing this barrier may improve stroke outcomes.