New Directions in MS Research
The gut microbiome – the milieu of bacteria found in the digestive tract – is a major component of the immune system, and has emerged in recent years as a focus of MS research. Investigators are exploring how the overall mix of bacteria and different levels of specific types of bacteria may affect the risk for MS and the course of disease. Other researchers are examining whether altering the composition of the microbiome can help reduce relapses, slow MS progression, or otherwise improve outcomes.
One recent study suggests that increasing levels of a fatty acid that typically is reduced in people with MS can affect immune function. It also suggests that in conjunction with disease-modifying therapies (DMTs), it may reduce relapses.81
Propionic acid (PA) is a short-chain fatty acid (SFCA). PA and other fatty acids are produced when bacteria in the gut microbiome process indigestible dietary fibers. Reduced levels of PA, as is seen in MS, are associated with alterations in the composition of the gut microbiome.
Investigators in Germany, Denmark, and Israel recently assessed blood and stool samples from people with MS and healthy controls. They found that the MS patients had reduced amounts of PA and of SCFA-producing bacteria compared to the controls. The people with MS also had reduced amounts of regulatory T (Treg) cells, which play an important role in maintaining immune system function. In MS, Treg cells often are decreased, while two types of pro-inflammatory, autoreactive cells – T helper (Th) 1 and 17 – are increased. Researchers believe that this imbalance contributes to the inflammation and neurodegeneration seen in MS.
The investigators then had 91 people with MS and 24 healthy controls take 1,000 mg per day of PA. After 14 days of taking PA, people with MS saw their Treg cell amounts increase by 30%, while the controls had a 25% increase in their Treg cells. Several people in the initial phase of the study continued on PA for 90 days, as did a separate group of newly diagnosed people with MS who had not initiated any disease-modifying therapy (DMT). Both groups of people with MS saw their Th1 and Th17 cell counts decrease after 14 days and 90 days of PA supplementation. The researchers noted that along with increases in Treg cell amounts, this helped to improve the balance between immune-system modulating Treg cells and inflammatory, reactive Th cells.
To assess the clinical implications of these immune system changes, the investigators studied annual relapse rates in 97 study participants with MS. All of the patients had taken PA continuously for at least one year, and had data on prior relapse rates, with the data in some cases going back six years. The participants were stratified, or categorized, based on their baseline annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) score, and current MS therapy.
The researchers found that 41.2% of patients improved on PA, 47.4% remained stable, and 11.3% had an increase in their ARR. Overall, the annualized relapse rate decreased from 0.24 at baseline to 0.008 after one year or more of PA supplementation, and that difference was statistically significant. Additionally, EDSS scores generally were stable in the patients taking PA. While no severe adverse events were reported, <5% of participants in the long-term group reported mild adverse events, including nausea, flatulence, and abdominal swelling. The investigators concluded, “PA supplementation had a beneficial effect on immunological, neurodegenerative, and clinical parameters in MS patients, including relapse rate and disability progression. The results of our proof-of-concept study reveal not only that purified PA supplementation is a safe add-on to existing immune-modulating drugs but also confirm that one mode of action of this supplemental treatment is because of stimulation of Treg cells.”81 These intriguing results are, as the authors note, generated by a proof-of-concept study, which by its nature calls for validation through a larger trial. With their findings, the investigators have identified several important areas for further research.
Meanwhile, a study from Spain suggests that elevated levels of one family of bacteria, Lactobacillaceae, in the gut microbiome are associated with a greater number of relapses in people with MS. Investigators drew that conclusion after studying 16 people with relapsing-remitting MS and 15 healthy controls. The researchers used sophisticated genetic sequencing to identify the types and levels of bacteria found in each person’s microbiome. They also followed the study participants over a period of 24 months, tracking how often the people with MS had relapses and new or newly enlarged gadolinium-enhancing lesions seen on MRI during that follow-up period.
Investigators found that the healthy controls had more types of bacteria in their microbiome than did the people with MS. Further, in the study subjects with MS, an association was found between increased levels of Lactobacillaceae – particularly the genus Lactobacillus and the genus Lachnoclostridium – and new relapses, new lesions on MRI, or both. Eighty-one percent of study participants with MS were on a disease-modifying therapy (DMT) when they entered the study.82
Another recent study found that one alteration in the gut microbiome seen in early MS appears to be consistent across different ethnic groups. Researchers performed genetic analysis and sequencing on the bacteria in fecal samples from 15 Caucasian, 16 Hispanic, and 14 African-American people with MS, as well as 44 healthy controls matched by ethnicity. They also conducted genomic sequencing involving 24 people with MS – all of whom were newly diagnosed, not on a DMT, and not taking steroids – plus 24 controls.
The researchers found that individuals with MS in all three ethnic groups had an increased abundance of the genus Clostridium in their microbiome relative to controls from the same ethnic groups. The genomic analysis identified specific species within the Clostridium genus that were significantly enriched in the people with MS. Identifying a type of bacteria that has an increased abundance in MS patients across ethnic groups, provides investigators with a valuable target for further research, potentially benefiting a wide range of people.83