#ACTRIMS2020 – 3 Ways to Treat MS by Altering Gut Microbiome Under Study

Modulating the bacteria that reside in the gut by treating multiple sclerosis (MS) patients with probiotics, fecal transplants, or gut-related microRNAs may help to ease inflammation and disease severity, researchers with Brigham and Women’s Hospital suggest.

Howard Weiner, MD, a group leader at the hospital, presented his team’s findings on this topic at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2020 that ran in Florida on Feb. 27–29. His presentation was titled, “Potential for microbiome as a therapeutic target.”

The gut microbiome — the microorganisms that live in our gut, including bacteria, fungi, and viruses — plays an important role in immune function, and has been implicated in several autoimmune disorders.

In a previous study, Weiner and colleagues observed that people with relapsing-remitting MS (RRMS) have significant alterations in their gut microbiome compared to healthy counterparts, with these changes most evident in certain groups of bacteria.

At ACTRIMS, study results presented by Weiner showed that microbiome changes are specific to RRMS and to secondary progressive MS (SPMS) — including increases in the abundance of Clostridium bacteria, a group associated with several health disorders, and Akkermansia muciniphila, bacteria that may have anti-inflammatory effects and be beneficial for certain conditions.

According to Weiner, Akkermansia muciniphila is linked to lower disability and smaller brain lesions in MS patients, while Clostridium bacteria correlates with worse disability and, possibly, with brain swelling.

Some bacteria appear to also specifically relate to positive (e.g., overall satisfaction and an ability to participate) and negative (e.g., fatigue, anxiety, and depression) aspects that affect patients’ quality of life.

These results may support a current hypothesis that gut microbes communicate with the brain, influencing its development and behavior. For instance, the intestinal microbiome can prompt immune cells to change their activity and produce factors that exert effects in the brain.

Researchers also found that MS therapies, such as anti-CD20 treatments — which include Ocrevus (ocrelizumab, an approved therapy by Genentech), and the off-label therapy rituximab — partly normalized microbiome changes.

Encouraged by these data, the team has been exploring three different approaches to target the microbiome and treat MS: probiotics (live microorganisms that confer a health benefit), fecal microbiota transplants, and gut-related microRNAs.

Probiotics

“Probiotics represent an oral, non-toxic treatment that induces Tregs [regulatory immune cells], affects the microbiome, and could be used in combination with current MS therapy,” Weiner said.

The researchers tested Alfasigma‘s oral probiotic VSL#3, given as a supplement, in a small study with RRMS patients.

VSL#3 is a probiotic that contains Lactobacillus, Bifidobacterium, and Streptococcus bacteria, and has proven benefits in gut inflammatory conditions, including ulcerative colitis, irritable bowel syndrome, and pouchitis.

Of note, VSL#3 positive effects are thought to be mediated by immune regulatory T-cells (Tregs) that produce the anti-inflammatory molecule IL-10. Tregs are important for controlling or suppressing other immune cells, and limit self-attacks as a means of preventing autoimmune diseases.

In the Brigham study, VSL#3 was given to nine RRMS patients and 13 healthy controls twice daily for two months.

Results showed that VSL#3 supplementation increased the amount of ‘good’ bacteria associated with a healthy flora, such as Lactobacillus, while it lowered levels of bacteria tied to microbiome dysregulation in MS, including Akkermansia and Blautia.

At the immune level, VSL#3 counteracted inflammatory responses, as seen by a decrease in certain pro-inflammatory white blood cells (monocytes) and activation markers in certain immune cells.

Fecal Transplants

Another strategy evaluated is called fecal microbiome transplant (FMT), or the transfer of stool bacteria from a healthy person to a recipient.

In FMT, a fecal preparation from a carefully screened, healthy stool donor is transplanted into the colon of the patient. This can be done by multiple routes, including colonoscopy, duodenal infusion, or oral capsules.

Fecal transplants proved highly effective for treating recurrent intestinal infections caused by Clostridium difficile, but apart from this application, the procedure is not routinely performed for other purposes.

Weiner and his group are planning a Phase 1b trial to evaluate the safety and benefits of treating patients with progressive MS with capsules of fecal microbiome.

Patients will start on a single induction dose of 30 capsules (supplied by OpenBiome), followed by monthly doses of 10 capsules for five months.

The trial’s primary goal will be to assess the procedure’s safety, but efficacy measures will also be taken, including changes in the gut microbiome, immune responses, and in the production of short-chain fatty acids — small fats produced by intestinal bacteria that are crucial for intestinal health.

Magnetic resonance imaging (MRI) and positron emission tomography (PET) will be used to follow changes in the brain, including those of microglial cells. These immune cells reside in the brain and spinal cord, are involved in MS, and their function is altered by the gut microbiome.

Treatment with microRNA-30d

A third potential therapeutic approach being analyzed is based on a microRNA (miRNA) — a short RNA molecule that affects the expression or activity of genes — called miR-30d.

In one of its latest studies, Weiner’s group discovered that transferring fecal matter from mice at the peak of an MS-like  disease could ease disease symptoms in mice receiving the transfer, and attributed this effect to miR-30d.

They also found this microRNA at high levels in the feces of MS mice and untreated MS patients, suggesting it was responsible for attenuating the disease.

To confirm their theory, researchers treated mice with oral, lab-made miR-30d. Treatment lessened MS-like symptoms in both relapsing and progressive disease forms in the animals.

“Oral synthetic [lab-made] miR-30d ameliorates established [MS-like disease]” in mice, Weiner said.

Researchers then worked to decipher the mechanism behind this effect, and found that miR-30d leads to an expansion of Akkermansia bacteria in the gut, which in turn stimulates the expansion of Tregs. Subsequently, these immune cells suppress the development of MS-like disease.

These and earlier results, showing that Akkermansia levels correlate with lower disability in MS patients, suggest that the increase in “Akkermansia may be a compensatory mechanism” against MS, the researchers said.

Based on these findings, Weiner believes that “synthetic miR-30d given orally is a novel method to modulate the microbiome.”

The team is now “developing synthetic miR-30d for the treatment of both relapsing and progressive forms of MS.”