“The most exciting possibility is that the gut holds the key to the cause of MS, especially since it has been theorized that MS may be caused by a virus or bacterium,” said Howard L. Weiner, MD, at the 2015 CMSC Annual Meeting. “It is also possible that the microbiome, diet, oral tolerance, and antibiotic use relates to MS susceptibility. Modulating the microbiome with probiotics or specific bacteria may be a way to treat MS.” These findings could help pave the way toward developing a vaccine to prevent the disease from occurring, Dr. Weiner added.
Modulating the Immune Response
Microbiota in the human body reside in various areas, including the oral cavity, the vagina, and the skin. As many as 500 trillion bacteria and other organisms live in the 300 m² of the intestinal tract, explained Dr. Weiner, Robert L. Kroc Professor of Neurology at Harvard Medical School in Boston; founder of the Partners MS Center in Brookline, Massachusetts; and Codirector of the Center for Neurologic Diseases at the Brigham and Women’s Hospital in Boston.
“There are more genes in our gut than in any other part of our body,” he said. “The gut is probably the largest lymphoid organ in the body and it is where you can induce all kinds of immune responses.”
In a relapsing-remitting mouse model of spontaneously developing experimental autoimmune encephalomyelitis (EAE), animals raised in a normal environment became sick, whereas those raised in a germ-free environment did not. The germ-free animals developed EAE, however, after microbial exposure (ie, consuming feces).
“This [result] is clear proof that the gut is important for immune mechanisms in EAE,” Dr. Weiner said. Other animal research has shown that colonization with Bacteroides fragilis can modulate EAE, he added.
In an ongoing, unpublished study involving an animal model of EAE, Dr. Weiner and colleagues are collecting feces at various stages of disease from onset to recovery. “We then feed the feces to healthy animals. Our preliminary results show that healthy animals fed feces from the peak of disease developed immunity against EAE. It seems that protective organisms develop in the gut as the animals are recovering from disease.”
The Human Microbiome
One study showed that the gut of patients with rheumatoid arthritis is enriched with Prevotella copri. “However, we don’t have a clear handle on the effect of microbiota on human disease because there are so few studies on the subject.”
In a recent study, Dr. Weiner and colleagues collected blood and stool samples from 63 patients with MS and 43 healthy controls. Of the patients with MS, 18 were being treated with beta interferon and 14 with glatiramer acetate; 29 were untreated. Exclusion criteria included antibiotic or probiotic use; recent gastroenteritis; a history of irritable bowel disease, rheumatoid arthritis, or systemic lupus erythematosus; recent travel history; history of bowel surgery; and treatment with prednisone, mycophenolate mofetil, mitoxantrone, rituximab, IV immunoglobulin, or methotrexate.
“We extracted the genetic material from the stool samples and sequenced the hypervariable regions of the 16S using three platforms,” Dr. Weiner said. “We used a Roche 454 sequencing system, as well as Illumina sequencing, which is deeper, but more restrictive. Then we performed validation with quantitative polymerase chain reaction analysis.”
There was no difference in the diversity of bacteria in the gut between patients with MS and controls. However, Methanobrevibacter smithii and Akkermansia muciniphila were increased and Butyricimonas virosa was decreased in patients with MS.
“This is an interesting finding, as Butyricimonas produces butyrate, which typically is reduced in MS and other autoimmune diseases. Because butyrate induces regulatory cells, this [result] goes along with our theories about MS.”
Network analysis indicated that Methanobrevibacter, Akkermansia, and Butyricimonas were linked to the same gene module in monocytes. “This finding implies that the changes in the gut for these organisms in MS patients are not independent of each other,” Dr. Weiner said. “More research is needed to confirm this [finding], but we certainly have found some interesting leads.”
Collinsella aerofaciens, Slackia exigua, and Prevotella were decreased in untreated patients with MS. Patients receiving glatiramer or interferon therapy had increased Prevotella, Sarcina lutea, and Sutterella wadsworthensis. “In the future, we plan to test patients who are on other MS drugs, as well.”
Spotlight on Methanobrevibacter
“We looked closely at Methanobrevibacter, which is not a bacterium, but is actually an archaeon,” Dr. Weiner noted. “We took 10 patients with Methanobrevibacter and 10 patients without it to see if there were any differences in their monocytes and lymphocytes.” The researchers found that monocytes and T cells had unique transcription profiles in Methanobrevibacter-positive patients.