Scanning electron micrograph of Escherichia coli

 

There has been an emergence of research over the last few years focusing on the link between our gut bacteria and brain conditions such as Parkinson’s disease. Recently, an academic research collaboration led by the University of Pennsylvania, published an article in the journal Nature, which reports a causative link between bacteria colonies present in the gut and malformations in the brain, called cerebral cavernous malformations (CCMs). CCMs or CCM lesions are essentially an abnormal group of capillaries or small blood vessels which lead to abnormal blood flow in the brain and can cause haemorrhagic stroke. Currently, there are limited options for people suffering from symptomatic CCMs, and surgical removal remains a common treatment.

 

It has previously been identified that CCMs can be inherited from our parents. They can be caused by a mutation in the genes KLF2 and KLF4, and other proteins expressed in the endothelial cells, which are cells that make up the walls of blood vessels. When researchers used genetically engineered mice to investigate these genetic mutations, they found that some of the mice did not develop lesions. However, within this population of CCM-resistant animals, there were a few pups who continued to develop lesions; interestingly these lesions were associated with intra-abdominal abscesses from an injection the mice were given. The bacteria present in these abscesses were gram-negative bacteria, which have a molecule on their outer membrane called lipopolysaccharide (LPS). LPS is the molecule responsible for many of the deleterious effects on humans and animals.

 

To investigate whether these gram-negative bacteria were driving the CCM disease in these animals, the researchers inoculated CCM-resistant mice with the gut bacteria . A large portion of these mice went on to develop CCM lesions. To further investigate the role of these bacteria, the researchers injected LPS into the CCM-resistant mice and found that they also developed large CCM-lesions. Therefore, the gut bacteria appeared to be directly associated with CCM lesion development.

 

However, the researchers wanted to understand how bacteria in the gut could be affecting the cells lining the blood vessels in the brain. The molecule which is targeted by bacterial LPS, is an immune receptor called Toll-Like receptor 4 or TLR4. TLR4 is present on the endothelial cells of the vessel wall and when they genetically removed TLR4 in these cells they found nearly a complete loss of CCM development in the mice!! What is also interesting is that humans with a mutation in TLR4 also have an increased burden of CCM.

 

These findings presented two options for treatment of CCM disease; targeting the TLR4 receptor or manipulating the gut microbiome. So the investigators initially inhibited LPS from interacting with TLR4 by administering a drug and observed an 80% reduction in CCM lesion volume. They then followed these experiments by comparing CCM-susceptible mice who had grown up in sterile, bacteria-free environment and those which had grown up in a “normal” environment. They found that the majority of the bacteria-free mice failed to develop any lesions at all.

 

Although there are many differences between mice and humans, the evidence here appears to provide hope for an effective treatment for people suffering with CCM related illnesses, as both antibiotics and manipulation of our gut microbiome may be potential treatments. However, as always, further work is needed before a viable treatment strategy can be predicted.

 

The outcomes of this comprehensive study have added to the growing body of evidence that suggests our gut environment can have a significant effect on our health and disease state.