PHILADELPHIA—Investigators have identified changes in both pro- and anti-inflammatory microorganisms in the gut of multiple sclerosis (MS) patients, compared with healthy controls. In addition, they found that disease-modifying therapy was associated with a change in the prevalence of those same microorganisms.
These findings, reported here in April at the AAN Annual Meeting, add to a growing body of studies suggesting that the gut “microbiome” may play a role in modulating the immune system in MS, perhaps even contributing to the cause or course of the disease.
The precedent for an effect from the gut on autoimmunity is strong, according to Sushrut Jangi, MD, lead author and post-doctoral fellow in the lab of Howard Weiner, MD, at Brigham and Women’s Hospital in Boston.
Inflammatory bowel disease is an autoimmune disease caused by changes in the microbiome, “so it made sense to think about whether microorganisms in the intestine might influence the immune system beyond the gut,” said Dr. Jangi. “It is actually an old idea that early microbe exposure may influence how the immune system develops.”
In addition, recent work in the mouse model of MS shows that genetically predisposed mice raised in a germ-free environment never develop the disease. “It means you need microbes to have autoimmunity.”
To determine whether there are differences in the gut microbiome in MS, and if changes occur with treatment, Dr. Jangi and colleagues analyzed stool samples from 61 MS patients and 43 healthy controls. They performed two measures of overall richness and diversity, and used two different high-throughput sequencing tools to identify and quantify bacterial and Archaeal families present in each sample. [Archaea microbes are prokaryotes, meaning they have no cell nucleus or any other membrane-bound organelles in their cells.] Individual families were identified by differences in sequence of the 16S hypervariable region of the ribosomal RNA gene, a standard tool for exploring microbial diversity.
They found that while there were no overall differences in richness or diversity, there were significant differences in the microorganisms present between groups. Specifically, they found that MS patients had an increased number of Archaea species, particularly of the familyMethanobrevibacteriaceae, which normally comprises about 10 percent of the gut population. Their mean relative abundance was 6.6-fold higher in MS patients compared with controls.
Dr. Jangi pointed out that the change was not seen in all patients: some had no Methanobrevibacter, and some had levels hundreds of times that of normal.
The cell wall and lipid membranes of these organisms make them strongly immunogenic, “which is consistent with a role in the induction of local and systemic inflammatory processes in the host,” Dr. Jangi said.
The authors also found two organisms with anti-inflammatory properties that were lower in MS patients than in controls: the Butyricimonasgenus from the Bacteroidetes phylum, and the Lachnospiraceae family from the Firmicutes phylum. Both of these produce butyrate, which has been shown to reduce inflammatory signaling. Both bacteria are also low in inflammatory bowel disease and rheumatoid arthritis.
The levels of both these bacteria were increased in patients taking MS treatment, compared with those who were not. The reduction in levels of these bacteria “may be contributing to overactivity of the immune system in the gut,” Dr. Jangi said, “so it makes sense that untreated patients would have less of these.”
For the future, the group plans to expand their sample to include other racial groups (their sample was overwhelmingly Caucasian) and other regions of the country.
“It is possible they have a causative role, but the more likely possibility is that they act as adjuvants, stimulating the immune system,” Dr. Jangi said. “They may also be simply a product of having MS. These are early results, and there is a lot of work to do. The work requires interdisciplinary cooperation between neurologists and gastrointestinal specialists to do it right.”
For the full story with commentary from outside experts, see the June 5 issue of Neurology Today. Browse our collection of articles on MS research:http://bit.ly/NTmultscler