The Multiple Sclerosis - Gut Microbiome Connection

Multiple sclerosis (MS) is an autoimmune disease characterized by the breakdown of the myelin sheaths that coat neurons within the central nervous system. The result of this disease is nerve damage and the progressive worsening of neurological function. Both the etiology and pathogenesis of MS largely remains unknown. However, genetic and environmental factors have been identified that contribute to risk.

One risk factor that has both genetic and environmental influences is the gut microbiome, which is known to be a key modulator of immune function. A recent paper research paper in the journal Cell by the international Multiple Sclerosis Microbiome Study (iMSMS) consortium entitled “Gut microbiome of multiple sclerosis patients and paired household healthy controls reveals associations with disease risk and course” demonstrates that key species of bacteria are over-represented in the guts of MS patients, and that MS therapeutics modulated microbial composition and metabolism. In this blog, we will review the findings of this paper and discuss its implications. 

Changes in the gut microbiome have been observed in a variety of inflammatory diseases, and several studies have reported both the enrichment and depletion of specific bacteria in MS patients relative to healthy controls. These findings have implicated certain bacteria in the development and/or progression of the disease, however it was previously unclear if the microbial changes were a driver of disease or if the disease was driving the microbial changes.

Furthermore, few previous studies have probed progressive MS, opting instead to evaluate relapsing-remitting MS (RRMS) patients, and the potential anti-microbial effects of certain MS therapeutics was not considered when assessing the relationship between the microbiota and disease onset and progression. 

To overcome the previously stated uncertainties as well as the small cohort sizes and confounding factors present in other studies on this topic, the iMSMS recruited not only MS patients but also household health controls (HHCs) in the US, Europe, and South America in order to best control for environment and geographic location. The study design is outlined in Figure 1. 

Figure 1. Study design for MS patients and their HHCs [1] 

Patient Stats 

A total of 576 MS patients and their paired, genetically-unrelated HHCs were included within this study. Within these 576 patients, 36% were untreated and 63% were undergoing treatment with a disease-modifying therapy (DMT). The therapies included the oral drugs fingolimod and dimethyl fumarate, the injectable drugs glatiramer acetate and interferon, and the infusion treatments anti-CD20 monoclonal antibodies and natalizumab. Among the patient cohort, 76% had RRMS, 12% had secondary progressive MS (SPMS), and 12% had primary progressive MS (PPMS). Data from the SPMS and PPMS groups were pooled for analysis. 

Results 

Microbiota composition is altered in MS patients 

The research team began by assessing both alpha and beta diversity in patients versus their HHCs. 

• Alpha diversity: the diversity within a sample
• Beta diversity: the diversity between samples (i.e. MS patients vs. HHCs) 

Consistent with previous studies, no difference in alpha diversity was observed between MS patients and their HHCs. However, in contrast to previous studies, a significant difference was noted in beta diversity in MS patients irrespective of treatment status. Moreover, although MS patients exhibited higher beta diversity relative to controls, no difference in beta diversity was observed between treated and untreated MS patients. This observation indicates that the disease likely exerts a more significant effect on the microbiome than do the treatments. 

A total of seven species were significantly lower in untreated MS, while 16 were significantly increased. Some of the most dramatic changes included: 

• Decreased Faecalibacterium prausnitzii
• Decreased Blautia obeum
• Decreased Fusicatenibacter saccharivorans
• Increased Akkermansia muciniphila
• Increased Ruthenibacterium lactatiformans
• Increased Hungatella hathewayi 

In the current study, as well as in some previous reports, Akkermansia muciniphila, which is often regarded as a strictly beneficial microbe, was shown to be enriched in MS patients. A. muciniphila is a mucus-degrading microbe associated with increased metabolic health. However, this bacterium has also been shown to exert pro-inflammatory effects on T cells in in vitro systems, and may also augment inflammation during an infection. Recently, A. muciniphilahas also been shown to secrete peptides that stimulate autoreactive T cells, which implicates molecular mimicry as a mechanism for MS pathogenesis. In other words, these peptides could promote the expansion of these autoimmune-mediating T cells. 

The differing impacts of A. muciniphila in health and disease may relate to differing functional capabilities across different strains of this microbe. For example, at least two strains were identified within the current study that differed in functions including sulfur metabolism. The pathway that was most enriched in untreated MS patients was phytate degradation—a pathway primarily driven by A. muciniphila. This pathway is responsible for converting phytate—a potent binder of minerals like calcium, magnesium, iron, and zinc—into myo-inositol—a simple carbohydrate involved in lipid and glucose metabolism. Interestingly, previous studies have suggested that increased levels of zinc and iron may be a driver of MS, while calcium and magnesium may be protective. The authors postulate that modulation of mineral bioavailability may contribute to disease progression, but state that the role of A. muciniphilain myo-inositol metabolism requires further exploration. 

Faecalibacterium prausnitziiis a primary butyrate producer in the gut and exerts anti-inflammatory effects that can 

1. Block the secretion of inflammatory cytokines
2. Upregulate regulatory T cell production
3. Enhance the integrity of the intestinal barrier 

Overall, the team found a depletion of beneficial bacteria in untreated MS patients that could lead to worsening of inflammation. This may open the door to the development of targeted pre-, pro-, and post-biotics that promote the growth of these key species. 

Influence of treatment on gut microbial composition 

The use of treatment created relative decreases in specific bacterial taxa that are not positively associated with MS. Specifically three taxa were significantly reduced in response to oral medications 

• Bacteroides
• Blautia
• Clostridium 

Patients receiving injectable medications exhibited reductions in 

• F. prausnitzii
• Dialister invisus CAG:218
• R. intestinalis 

Finally, in patients receiving infusion therapies, Bifidobacterium adolescentis was reduced. In a rodent study, reductions in B. adolescentis were shown to promote the accumulation of inflammatory immune cells and worsen autoimmune arthritis. 

Conversely, several species of bacteria were also shown to be increased in response to the various treatment modalities, namely 

• lactatiformans (with fingolimod)
• torques (with fingolimod)
• Eubacterium hallii (with glatiramer acetate)
• Bacteroides uniformis (with interferon)

Like A. muciniphila, R. torques is another major mucus-degrading bacterium and has been associated with decreased integrity of the gut barrier. A recent rodent study showed that this bacterium is associated with aberrations in the motor regions of the brain and worsened symptoms in a rodent model of amyotrophic lateral sclerosis (ALS). Meanwhile, the lactate-producing species R. lactatiformanshas been previously associated with decreased function in the lower extremities and worsening of disability in RRMS and PPMS patients. 

Interestingly, RRMS patients treated with interferon show increased levels of blood propionate levels, and propionate supplementation has been shown to lead to positive immune effects and long-term clinical improvements in these patients. Thus, it is possible that one of the primary mechanisms of action of interferon is its ability to increase cellular transport of bacterially-produced propionate from the gut lumen into the circulation. 

Takeaways 

Although the factors underlying the etiology and progression of MS remain elusive in many ways, changes in gut microbiota composition are common among patients. Namely, 

1. beta diversity is decreased among all MS patients regardless of treatment status
2. increased Akkermansia muciniphila
3. decreased Faecalibacterium prausnitzii 

In the future, pre-, pro-, and/or post-biotic therapies to promote F. prausnitzii and overall butyrate status may be an important point of leverage in the treatment of MS. 

Furthermore, certain standard-of-care MS treatments also impact microbial communities and may exert their clinical benefits in part through this mechanism. In particular, interferon treatment was shown to increase serum propionate levels, which has been independently shown to improve symptoms in RRMS. Thus, the identification of other post-biotic therapies, like propionate, is prudent to provide safe and effective treatment options for MS patients that begin to target root cause issues instead of focusing solely on symptom management.  

Written by: Dr. Alexis Cowan

References 

[1] iMSMS Consortium. Electronic address: sergio.baranzini@ucsf.edu; iMSMS Consortium. Gut microbiome of multiple sclerosis patients and paired household healthy controls reveal associations with disease risk and course. Cell. 2022 Sep 15;185(19):3467-3486.e16. doi: 10.1016/j.cell.2022.08.021. PMID: 36113426.