Gut repair preserves brain function after stroke
Summary: Transplantation of intestinal epithelial stem cells from healthy donors reduced stroke-related mortality, reduced the volume of dead brain tissue and leaky gut, and prevented stroke-related cognitive decline.
Source: Texas A&M
Stroke is a leading cause of death, dementia and serious long-term disability. According to the American Heart Association, stroke patients also have a higher risk of depression, which negatively affects functional and cognitive recovery.
The only Food and Drug Administration (FDA)-approved stroke drug, which is a type of recombinant tissue plasminogen activator, must be given within a certain time frame after a stroke occurs and has limited success.
To improve stroke outcomes, scientists at Texas A&M University School of Medicine are pioneering research into the link between stroke-induced gut permeability, or leakiness, and cognitive impairment.
A Texas A&M team investigated the novel idea of whether intestinal epithelial stem cell (IESC) transplantation from healthy donors could repair the intestinal barrier after stroke and improve stroke outcomes.
The results of their preclinical study, published in the journal Brain, behavior and immunityshow that IESC transplantation reduced stroke-related mortality, reduced dead tissue volume and leaky gut, and prevented stroke-induced cognitive impairment.
Two-thirds of stroke patients will develop cognitive impairment, while one-third of all stroke patients will develop dementia, according to recent research, so there is a critical need for more effective stroke therapies that preserve cognitive function after acute stroke and remain protective in in the coming weeks.
Although conventional stroke treatment research focuses on the brain, the gut responds early and rapidly to stroke with changes that may precede many of the inflammatory events associated with stroke-induced disease. These changes in the gut, such as increased permeability, likely result in the movement of products synthesized in the gut into the bloodstream.
Many of these products are toxic and therefore in a position to increase inflammation and worsen brain injury caused by stroke.
Evidence from various studies shows that IESCs repair the gut and reduce gut permeability. After a stroke, these repair processes may be critical for preserving cognitive function.
“It is clear that the gut-brain axis is involved in post-stroke injury,” said Farida Sohrabji, PhD, Regents Professor, head of the Department of Neuroscience and Experimental Therapeutics and senior author of the study.
“Tapping into the effects of gut health on the brain after stroke may allow us to more effectively advance stroke therapies.”
With this in mind, Sohrabji and her team transplanted primary IESCs from healthy donors after stroke in a preclinical model. IESCs from young donors repaired gut architecture and reduced gut permeability and consequently reduced levels of proteins and other molecules in the blood that are toxic to brain cells.
IESC transplantation also prevented depressive-like behavior and cognitive impairment in the weeks following stroke. IESC transplantation from older donors did not improve stroke outcomes, indicating that successful transplantation depends on donor age.
Still in the preclinical phase, this research highlights the importance of early therapeutic intervention after stroke and guides future directions of work.
“Future studies will explore refining the dosing and timing of the protocol,” Sohrabji said. “A systematic study of stem cell aging would also be important to explain why older patients experience more severe strokes.”
Sohrabji, a neuroscientist with significant contributions to the stroke pathogenesis literature, explained that this preclinical study was led by Dr. Kathiresh Kumar Mani, a research associate in her laboratory.
Mani, who is trained in gut biology, received a postdoctoral grant from the American Heart Association to support this project. The combination of their expertise has allowed them to move stroke therapy research into new territory with exciting results.
They also received a generous grant from the WoodNext Foundation that facilitates their innovative research.
“This research is expected to ultimately advance the development of new therapies that target and repair the intestinal epithelium to help alleviate the disability of stroke,” said Sohrabji, “but the premise—that intestinal stem cells could be therapeutically valuable outside the gut—could would be considered for a much larger number of neurological diseases.”
About this stroke research update
Original Research: Open access.
“Transplantation of intestinal epithelial stem cells as a new therapy for cerebrovascular strokeby Farid Sohrabj et al. Brain, behavior and immunity
Transplantation of intestinal epithelial stem cells as a new therapy for cerebrovascular stroke
Almost 2/3rds stroke survivors show 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 the adverse effects on the brain, stroke rapidly disrupts the regulation of the intestinal epithelium, resulting in increased levels of inflammatory cytokines in the blood and toxic gut metabolites due to a ‘leaky’ gut.
We tested whether intestinal repair via intestinal epithelial stem cell (IESC) transplantation would also improve stroke recovery.
Organoids containing IESCs derived from young rats transplanted into aged rats after stroke were implanted in the intestine, restored stroke-induced intestinal dysmorphology and reduced intestinal permeability, and reduced circulating levels of the endotoxin LPS and the inflammatory cytokine IL-17A.
Interestingly, IESC transplants also improved acute (4d) stroke-induced sensory-motor disability and chronic (30d) cognitive-affective function. Moreover, IESCs from older animals showed senescence and were not therapeutic for stroke.
These data highlight the intestine as a critical therapeutic target for stroke and demonstrate the efficacy of intestinal stem cell therapy.
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