Could manipulation of gut microbiota affect stroke outcome?

Could manipulation of gut microbiota affect stroke outcomeAlthough it is well documented that gut microbiota may shape brain function and development, little is known about its impact on the outcome of acute brain injury. A recent study, led by Dr. Josef Anrather, an associate professor of neuroscience at the Weill Cornell Medical College in New York (USA), has found that the commensal gut microbiota could influence the immune system to decrease the severity of ischemic stroke in mice.

 

To assess the impact of the commensal microbiota on ischemic stroke outcome, adult mice were treated with the antibiotic amoxicillin, along with clavulanic acid, for 2 weeks. (These mice comprised the AC group.) Middle cerebral artery occlusions (MCAO) were induced after 2 weeks of antibiotic treatment, and brain infarct volume was quantified 3 days later. Rodents with antibiotic-induced gut dysbiosis showed infarct volume reduced by up to 60% when compared to rodents that did not receive antibiotics. To study if these neuroprotective effects were directly mediated by the gut microbiota, mice were pulse-treated with amoxicillin and clavulanic acid for 3 days and gavaged with cecal contents from AC donors. After 2 weeks, MCAO was induced in the faecal transplant (FT) recipient mice, and they were killed 3 days later to quantify infarct volume. Mice that received FT experienced a stroke that was about 54% smaller than mice that did not receive it.

 

The researchers also examined the mechanisms accounting for the protection exerted by altered gut microbiota after antibiotic treatment and FT. Benakis et al. described in the mouse model a gut-brain axis of ischemic stroke, in which the gut microbiota confer a neuroprotective effect by modulating immune cells in the small intestine. In the gut, microbiota induced an expansion of regulatory T (Treg) cells, which secrete the anti-inflammatory cytokine interleukin-10 (IL-10) to suppress the differentiation of gd T cells into IL-17-producing gd T cells (IL-17+ gd T cells). Therefore, neuroprotection conferred by intestinal dybiosis requires a reduction in intestinal IL-17+ gd T cells. In addition, this modulation of immune cells was transmitted to the brain, as IL-17+ gd T cells may have migrated from the gut to the meninges following ischemic stroke, which upregulated cytokines genes that contribute to brain injury through the promotion of neutrophil infiltration. These results suggest that the microbial environment in the gut leverage immune cells to protect the brain, shielding it from the stroke’s full force.

 

In the framework for brain-gut communication after acute brain lesion, it is important to consider potential pitfalls during experimental investigation. These are summarized in a nice recent review in this field:

  • Differences in the gastrointestinal tract anatomy of the rodent and human.
  • Differences in composition of human and rodent microbiota in health and disease.
  • Differences in immunology between rodents and humans.
  • Developmental disturbances in germ-free animals.
  • Effect of antibiotics used to deplete microbiota on nervous and immune system.
  • Influencing effects of gut virome.
  • Effect of housing conditions and animal husbandry.
  • Impact of genetic heterogeneity between humans.
  • Impact of human diets, comorbidities, and pharmacological treatments for stroke, and their changes during stroke care.
  • Sample preparation and bioinformatics of gut metagenomics.
  • Correlation vs. causation.

 

In a study with patients with large-artery atherosclerotic ischemic stroke and transient ischemic attack, the asymptomatic control group did not exhibit a significant change in gut microbiota and blood TMAO levels. However, stroke and transient ischemic attack patients showed significant dysbiosis of the gut microbiota, and their blood TMAO levels were decreased. These results point that as a first step it has been shown that stroke and transient ischemic attack patients showed significant dysbiosis of the gut microbiota, whereas whether these changes occurred before or after the stroke is not proven yet in humans.

 

In conclusion, dysbiosis of the microbiota induced by antibiotic treatment or faecal transplant resulted in an imbalance in the gut-brain axis in mouse models of ischemic stroke, which was responsible for a more than two-fold increase in the volume of necrotic tissue after stroke. Thus, it has been demonstrated in this study that alterations in the gut microbiota may result in neuroprotection in mice. Further research is needed in order to elucidate which bacterial species or components played a neuroprotective role.

 

References: 

Benakis C, Brea D, Caballero S, et al. Commensal microbiota affects ischemic stroke outcome by regulating intestinal gd T cells. Nat Med. 2016. doi:10.1038/nm.4068.

 

Winek K, Meisel A, Dirnagl U. Gut microbiota impact on stroke outcome: Fad or fact? J Cereb Blood Flow Metab. 2016. doi:10.1177/0271678X16636890.

 

Yin J, Liao SX, He Y, et al. Dysbiosis of gut microbiota with reduced trimethylamine-N-oxide level in patients with large-artery atherosclerotic stroke or transient ischemic attack. J Am Heart Assoc. 2015;4(11). doi.10.1161/JAHA.115.002599.

 

Andreu Prados
Andreu Prados
Andreu Prados holds a Bachelor of Science Degree in Pharmacy & Human Nutrition and Dietetics. Science writer specialised in gut microbiota and probiotics, working also as lecturer and consultant in nutrition and healthcare. Follow Andreu on Twitter @andreuprados