[Sciences/BBB] Endothelial TLR4 and the microbiome drive cerebral cavernous malformations (Tang et al., Nature 2017)

You may have heard about this study that showed how your gut bacteria were responsible for stroke. Of course headline news always love to stretch scientific findings as much as I use to stretch my Stretch Armstrong when I was a kid. However, the paper cited was indeed published in Nature and can be found here:
https://www.nature.com/nature/journal/vaop/ncurrent/full/nature22075.html

It is a very interesting paper to read, because a lot of it sounds like a serendipity and lucky strikes. This paper investigated changes in two mouse models of cerebral cavernoma (Ccms). Ccms are a particular type of hemorrhagic stroke because they are mostly genetics (there are three Ccm genes described, in this study they focused on Krit1 and Ccm2) and most of the time go unnoticed. Mutations in those genes result in some alterations in brain microvessels, making some tiny anatomical abnormalities resulting in a higher susceptibility in some of these micro vessels to spontaneously burst and bleed.

The authors of this study have been developing Cre/Lox mice colonies for Ccm2 and Krit1 to better understand the pathology of this disease. The advantage of Cre/Lox is you can knockout a gene in a specific place at a specific time, just by injecting or providing a molecule (usually tamoxifen) that will induce it.

They have been breeding mice that were deficient in Ccm2 or Krit1 and were as expected developing brain micro bleeds (usually around their first two weeks of postnatal age). Following some changes in the animal facility, they observed that a small fraction of their mice colonies suddenly became resistant to cerebral micro bleeds: they still carried the mutations but they fail to develop these microbleeds. Therefore some non-genetic factors were influencing this resistance pattern.
Things became even more interesting as they found that among some of these resistant mice, some developed again the microbleeds within a same littler. The only difference between those developing the microbleeds and those which did not were apparently related to the intraperitoneal (i.p.) injection of tamoxifen. Have the authors provided the tamoxifen through the drinking water, that would have ended the story here.
The authors indeed found that those who reversed their phenotype from resistant to susceptible developed a bacterial infection at the site of the i.p. injection suggesting that such micro bleed was driven by some bacterial factor. They showed that similar results were obtained if they injected LPS (a common Gram-negative antigen) to these mice.

They identified two receptors known to play a role in cellular response to pathogens (we refer such signaling pathways as Pathogen Associated Molecular Patterns or PAMPs): TLR4 (toll-like receptor 4) and CD14 (TLR4 co-receptor). By knocking down these receptors in their Ccm-resistant animals, they were capable to block such bacteria-induced response. The possible interactions of Gram-negative bacteria with these two receptors at the blood-brain barrier maybe enough to trigger the cerebral micro bleeds.

What is also interesting is that mutations in these two genes (some single nucleotide polymorphism or SNP) in patients known to have an history of Ccm also resulted in a higher probability to have brain microbleeds.

I will not spoil the rest of the story but it confirms the presence of a brain-gut axis in Ccm, suggesting the possible effect of the gut microbiota as a risk factor to increased microbleeds in Ccm patients. Let it be clear, these bacteria WILL NOT induce Ccm in normal invididuals. It increase the risk of bleeds in patients already at risk of Ccm.

Another limitation is that in vitro data to confirm the presence of TLR4/CD14 at the BBB and fails to explain how these receptors are triggered by the gut microbiota. The authors suggested a bacteremia (circulating bacteria from gut to the brain via bloodstream) but I remain skeptical about it.

Nevertheless it is a very good paper that worth being read.

 

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