Altering Gut Flora Could Reduce Stroke Risk

April 04, 2016

Changing the profile of the bacteria in the gut led to a reduction in stroke size, a new study in mice suggests.

"This was a proof-of-concept study," study author Costantino Iadecola, MD, Weill Cornell Medical College, New York, New York, told Medscape Medical News.

"We have demonstrated two important principles: that changes to the microflora in the gut have an effect on how the brain withstands injury, and that changes to the immune system can have a profound effect on stroke," he said. "This could eventually lead to new therapies to prevent stroke."

"The hope is that in future we may be able to reduce an individual's risks of stroke by changing their microbiota profiles in the gut with use of probiotics and/or antibiotics or maybe just with dietary habits," he added. "This could be targeted to patients at very high risk of stroke, such as those undergoing cardiac or brain surgery, but may also be applicable to secondary prevention."

Coauthor Josef Anrather, also from Weill Cornell Medical College, said, "We have shown a new relationship between the intestine and the brain in the setting of stroke. Whatever is going on in the microflora in the gut is contributing to the immune response that controls the damage caused by a stroke. The next step is to address how much of this change is relevant in humans and which bacteria are important."

The study was published online March 28 in Nature Medicine.

''Our findings shed new light on poorly understood immune mechanisms that have an impact on brain injury and have far-reaching and translationally relevant implications for assessing cerebrovascular risk and predicting stroke severity," the researchers conclude in their paper.

Dr Iadecola explained that a substantial amount of evidence suggests that immunologic factors have some control over stroke occurring in the brain. "So we figured that if the immune system is geared in a certain way this may protect against stroke. As the intestine is the major reservoir of immune cells, we focused on changing the environment here and whether this would have any affect on stroke."

For the study, the researchers induced bacteria dysbiosis — changes in the make-up of the bacteria in the gut — by treating mice with antibiotics (amoxicillin and clavulanic acid) for 2 weeks. For controls, they used mice who had been on the same antibiotics for generations, so their flora had become resistant; no bacteria dysbiosis occurred.

When stroke was induced in the mice, the ones that had induced bacterial dysbiosis showed a 60% to 70% reduction in stroke size compared with controls.

As a further verification that it was the dysbiosis rather than the antibiotic itself that was responsible for the reduced stroke, the researchers transplanted the gut contents of the mice with induced bacterial dysbiosis into normal mice and found that these mice also had smaller strokes. "This further suggests that it is the changed composition of the gut flora that is bringing about the benefit on stroke," Dr Iadecola said.

To address the question of how gut flora can affect the brain in this way, the researchers analyzed the lymphocyte profiles of the mice. They found that the animals with induced dysbiosis and smaller strokes had more protective regulatory T cells and fewer harmful gamma delta T cells. Dr Iadecola commented: "So the change in the gut flora appears to bring about a change in the immune system, which favors smaller stroke injury."

He explained that these lymphocytes regulate the influx of inflammatory cells, such as neutrophils, into the brain, thereby controlling inflammation in the brain. On further investigation using flow cytometry, the researchers found normal mice had increased neutrophil counts in the brain, whereas the animals with induced dysbiosis had increased neutrophil counts in the meninges but not in the brain itself.

"Our results suggest that the altered gut flora leads to higher amounts of regulatory T cells and fewer gamma delta T cells in the meninges, which somehow causes fewer neutrophils to enter the brain. We believe the gamma delta T cells help neutrophils enter the brain, whereas the regulatory T cells prevent this process," Dr Iadecola noted.

He added that any clinical application of these findings is still a very long way off. "We need to figure out what is the optimum dysbiotic state in humans. First of all we need to conduct more studies in mice to identify the bacterial species that produce the best changes to the immune system. Then do the same thing in humans."

Dr Anrather referred to efforts underway at present to better characterize the human microbiome on a large scale. "We might be able to use this data to analyze how certain microbiome profiles influence stroke risk. Then in certain high-risk populations we could try and change the composition of the gut flora to the profile most suited to producing beneficial immunological changes for the cardiovascular system."

He agreed with Dr Iadecola that the most obvious target is the prevention of stroke, and it would be more difficult to influence the acute phase of stroke because the immunologic changes take time to come into effect.

"In our current study 1 week of antibiotics did not show any change in stroke risk. The reductions in stroke size only became obvious after 2 weeks of treatment. The changes in the microbiota were there at 1 week but the immune changes did not become apparent until 2 weeks. So this approach does not seem appropriate for use in acute situations. But the immune system also plays a role in regeneration and repair, so there may also be possibilities there," Dr Anrather said.

Nature Med. Published online March 28, 2016. Abstract


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