Study connects lower levels of rare gut bacterium to higher MS risk
Findings offer researchers potential new therapeutic targets
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A large group of probiotic bacteria are seen moving through the human gut. (Photo by iStock)
- Lower Akkermansia massiliensis gut bacteria levels linked to higher multiple sclerosis risk.
- This risk is tied to reduced activity of the immune-regulating FcRL3 gene.
- FcRL3, FcRL5, and NPBWR1 genes are potential therapeutic targets for multiple sclerosis.
Lower levels of a rare gut bacterium called Akkermansia massiliensis may increase the risk of multiple sclerosis (MS) by reducing the activity of an immune-regulating gene called FcRL3, offering researchers potential new therapeutic targets, according to a genetic study.
“The FcRL3 protein plays a key role in linking specific species of microbiota with immune system function and predisposition to autoimmunity,” researchers wrote in the study, “Potential role of Akkermansia massiliensis in multiple sclerosis protection by the FcRL3 gene,” published in Genes & Immunity.
Researchers have long suspected that gut bacteria play role in MS
MS is a chronic disease characterized by inflammatory damage to the brain and spinal cord. It develops through a combination of genetic and environmental triggers, with Epstein-Barr virus infection considered a major environmental factor.
Researchers have long suspected that gut bacteria also play a role in MS, and studies in mice have shown that gut microbes can interact with the immune system in ways that trigger nerve damage similar to that seen in MS.
However, direct studies of gut bacteria in MS patients have generally been small and inconclusive. Also, it’s difficult to separate the effects of the disease and its treatments from any preexisting microbial patterns.
To get around this problem, a group of researchers in Italy used an indirect approach. Instead of directly comparing gut bacteria in MS patients, they cross-compared genetic data from large population studies on the factors that shape gut bacteria levels with genetic data on MS risk.
The team found that a specific genetic signal linked to lower levels of a gut bacterium called Akkermansia massiliensis overlapped closely with a genetic signal for MS risk. This particular genetic signal lies between two genes, FcRL3 and FcRL2, which are part of a cluster of five related genes (FcRL1 through FcRL5) that help regulate the immune system.
The genetic variant linked to both lower A. massiliensis levels and higher MS risk was found to reduce FcRL3 protein levels and to increase production of a related protein, FcRL5.
These data support previous indications of FcRL3 as a target for MS and add FcRL5 and NPBWR1 as further potential targets for therapeutic intervention.
According to the team, FcRL3 plays a complex role across several immune cell types. It has been shown to exhibit distinct activity patterns in certain cell subsets, including antibody-producing B-cells and anti-inflammatory regulatory T-cells. Moreover, a recent study predicted that FcRL3 has causal effects in MS.
The researchers then identified three specific gene variants likely responsible for this effect, one of which changes how a stretch of DNA called an intron is used differently between immature and more mature B-cells. The team believes that this is the “primary molecular mechanism associated with MS risk in this region.”
Beyond its direct effects on the FcRL gene cluster, the same MS-linked signal also affects three other genes located elsewhere in the genome. It reduces the activity of NPBWR1, which is involved in brain signaling, food intake, and behavior, and AZU1, which helps the immune system fight certain bacteria and clear damaged cells. And it increases the activity of TACI, which codes for a receptor that regulates B-cell activity.
“These data support previous indications of FcRL3 as a target for MS and add FcRL5 and NPBWR1 as further potential targets for therapeutic intervention,” the team wrote.
Notably, the same genetic signal has the opposite relationship with several other autoimmune diseases, including rheumatoid arthritis, lupus, and Graves’ disease (hyperthyroidism). In these conditions, it appears protective rather than increasing risk, a pattern the scientists describe as a known genetic phenomenon called antagonistic pleiotropy.
“This phenomenon could help to identify common pathways with opposing consequences in disease predisposition as well as predict potential side effects of therapeutic interventions,” they concluded.
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