Designer probiotics may able to suppress astrocyte-mediated CNS inflammation that drives the progressive phase of MS, according to a keynote speaker at PACTRIMS 2018 in Sydney.
Dr Francisco Javier Quintana, of the Department of Neurology, Brigham and Women’s Hospital in Boston, opened the conference by saying that his group’s focus was on elucidating the pathways of CNS inflammation mediated by astrocytes and microglia.
While T-cells had traditionally been thought of as having the central role in acute inflammation, attention was now on astrocytes and their role in both inflammation and neurotoxicity in the progressive phase, in conjunction with microglia.
By looking at gene expression in the progressive phase of MS, his group had been able to identify some such as BGALT6 that are upregulated in MS lesions and which are associated with enzymes whose actions suppress inflammation.
Since this enzyme was already associated with Gaucher’s disease, Dr Quintana’s group had been able to exploit repurposed sphingolipid analogues such as miglustatin which were effective inhibitors of MS progression in animal studies.
The group’s next move is to set up trials of this and other more specific inhibitors in people with MS, he told the conference.
Another avenue of research into astrocyte-driven MS pathology has been the search for endogenous molecules that switch off the inflammation pathway. Again using gene expression, the group had identified several pathways that appeared to be controlled by small molecules via a master regulator protein.
Interestingly, the small molecules appeared to be generated from tryptophan in the gut flora, suggesting the gut-brain axis was involved in limitation of the inflammatory activity of astrocytes, said Dr Quintana.
A key feature of this pathway is the regulation of ‘crosstalk’ between microglia and astrocytes, by potential candidate molecules such as TGF alpha limiting the inflammatory action and VEGF-B having the opposite, amplifying effect.
Having identified the gut-brain pathway, the group is now looking at the potential of specially engineered probiotics that would promote production of anti-inflammatory molecules in the CNS and limit the progressive phase of MS, he said.
But he added that candidate anti-inflammatory small molecules did not need to come from a probiotic, and the group was now screening other potential candidate mimics that can penetrate the blood brain barrier.
Dr Quintana said that when ‘zooming out’ and looking at the bigger picture of what drives MS progression, it was becoming apparent that it involves a mix of genetic and environmental factors, such as smoking and exposure to sunlight.
His group had now developed a research platform to investigate elements of the so-called ‘exposome’, such as herbicides and preservatives, and this had also led to other potential pathways of astrocyte-mediate CNS inflammation.
The challenges ahead include the limited knowledge of the astrocyte and its genomic control, and also on the diversity of astrocyte and microglia cells, he said.
“As you know there are pro- and anti-inflammatory T cells and similarly there are pro- and anti-inflammatory astrocytes, so the challenge now is how to identify them, how to study them and to define which ones should be targeted for intervention,” he concluded.