A role for the microbiome in Multiple Sclerosis?
A role for the microbiome in Multiple Sclerosis?
Multiple Sclerosis (MS) is a neurodegenerative disease. In the Netherlands approximately one out of thousand people have MS, affecting women two to three times more often than men. In the onset of the disease there may be two types of MS [1].
Because the exact cause of the disease is unknown, the treatment for MS patients is focused on suppressing the immune system and treating the consequences of MS [2]. Around 85% will develop relapsing remitting MS (RRMS), which starts with inflammation spreading in the nervous system. This will affect the myelin layer surrounding nerve cells, partly blocking the impulse conduction, but this can be restored within weeks to months. This explains why this type is called relapsing remitting MS, because of its attacking nature. RRMS may come to a point where the myelin layer cannot be restored anymore and degeneration of nerve cells occurs. This is called secondary progressive MS (SPMS). In this stage there will be progressive deterioration with no improve. Sometimes patients will have a similar progressive course of disease from the onset. This is called primary progressive MS (PPMS) and affects about 15% of the patients. [1] Patients may suffer from a wide range of symptoms regarding the nervous system. Symptoms include difficulties with walking, feeling and seeing, for example. A disturbance of the immune system leads to inflammation in the onset of the disease. This disturbance is induced by many factors, among which genetic and environmental factors. [3]. The latter is still unknown for a big part. Nevertheless, there has been upcoming proof suggesting a role for the microbiome in the development of MS. Certain microbiota have been linked to either protect against or increase susceptibility for the disease.
The gut microbiome is essential for a healthy life. It occupies the surface of the intestine and protects it from invasion by opportunistic pathogens, keeping the intestinal barrier intact. Besides, these bacteria train our immune system by presenting specific proteins to immune cells populating the gut tissue. This is called immunological education.
We can get more susceptible for certain intestinal diseases, but also systemic diseases like multiple sclerosis, when the microbiome is damaged or changed in its composition. In the immune-mediated disease multiple sclerosis the immune system of a patient is in a pro-inflammatory state. This is partly due to dysbiosis in the gut microbiome in these patients. A meta-analysis of Shailesh K. et al [4] discusses recent microbiome studies and the possible mechanisms which could contribute to the onset of MS. The study lists specific bacteria seen in higher or reduced abundance in multiple sclerosis patients.
Within the phylum Bacteriodetes the genera Prevotella and Parabacteroides are seen in lower abundance. The genus Prevotella is seen in a reduced abundance in MS patients which suggests that this bacterium might have an important anti-inflammatory role. A member of the Prevotella genus, P. histicola, is shown to induce regulatory T-cells and thereby suppress disease [5]. The genus Parabacteroides have also been reported in a lower abundance in MS patients compared to healthy controls. In a different study was seen that the Parabacteroides distasonis bacterium could stimulate naïve T-cells to differentiate into regulatory T-cells [6]. This might imply that this bacterium is beneficial and play a protecting role.Together, the lower abundance of these listed anti-inflammatory bacteria will contribute to less regulation of immune responses. This leads to overactivity in pro-inflammatory responses.
Seen in a higher abundance where, for example, the phyla Firmicutes and Proteobacteria. One study, following pediatric MS patients up to 19 months, detected Firmicutes being in a higher abundance. This was associated with more frequent MS relapses in these patients. But Firmicutes were not in all studies seen in higher abundance. Some genera of Firmicutes were seen in depletion, while others were enriched. Shailesh K. et al. state that these differences might be due to different methods being used in the studies they analyzed. Proteobacteria are not only seen in MS in a higher abundance, but also in IBD and other autoimmune diseases. The authors state that higher prevalence of Proteobacteria in these diseases suggests that they might contribute to autoimmune diseases and that this might be due to promotion of pro-inflammatory responses.
From this meta-analysis we can conclude that the gut microbiota of patients with MS is in dysbiosis. This dysbiosis is characterized by depletion of bacteria which can activate regulatory immune cells and enrichment bacteria which are able to induce pro-inflammatory responses. It is difficult to say whether the dysbiosis in these patients are a cause or a consequence of the disease MS. Patients can have changes in the gut microbiota up to years before onset of the disease. Besides, this meta-analysis is based on studies of which the majority only analyzed fecal samples at one time point. To be sure the disease onset or relapses are linked to a change in intestinal microbiota, studies looking at multiple timepoints must be performed.
Written by Jip de Weijer
Posted on 14 oct 2018
[1] Huisarts en Wetenschap; Multiple sclerose in de huisartsenpraktijk. Available at: https://www.henw.org/artikelen/multipele-sclerose-de-huisartsenpraktijk
[2] Federatie Medisch Specialisten; richtlijn multiple sclerose. Available at: https://richtlijnendatabase.nl/richtlijn/multipele_sclerose/multipele_sclerose_-_startpagina.html
[3] Hersenstichting. Multiple sclerose (MS). Available at: https://www.hersenstichting.nl/alles-over-hersenen/hersenaandoeningen/multiple-sclerose-ms
[4] Shailesh K. et al. Gut microbiome in multiple sclerosis: The players involved and the roles they play. Gut microbes (2017)
[5] Mangalam A. et al. Human Gut-Derived Commensal Bacteria Suppress CNS Inflammatory and Demyelinating Disease. Cell Reports (2017)
[6] Cekanaviciute E. et al. Gut dysbiosis is a feature of MS and it is characterized by bacteria able to regulate lymphocyte differentiation in vitro. ECTRIMS (2016)