ACTRIMS 2023: ‘Bacteria X’ in gut microbiome may drive inflammation
Bacterial strain prevalent in SPMS patients also supports link with progression
A certain bacterial species is enriched in the gut of people with secondary progressive multiple sclerosis (SPMS) and may promote neuroinflammation and drive disability progression in these patients, a study found.
When isolated from SPMS patients and given to a mouse model, this strain led to more pronounced neurological disability and increased numbers of immune cells directly implicated in the inflammation that drives multiple sclerosis (MS).
Researchers suggest that this bacterial species promotes inflammation through the activity of its flagella, the hairlike projections that help bacteria to move around, adhere to, and invade target cells.
Due to ongoing patent protection, the researchers could not disclose the name of the bacteria, dubbing it “bacteria X.”
Study in gut microbiome differences across MS types, disease transition
“The selective elimination of pathogenic bacteria, including this bacteria X, might lead to innovate therapies for SPMS patients,” Daiki Takewaki, MD, said in the presentation “Identification of Pathogenic Gut Bacteria Underlying Multiple Sclerosis Progression.”
Takewaki, with the National Center of Neurology and Psychiatry in Japan, presented the findings at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2023, held Feb. 23-25 in San Diego.
A growing body of evidence has linked the gut microbiome — the billions of bacteria, fungi, and viruses living in the intestinal tract — to immune dysregulation in MS. Abnormalities in the balance of these microbes is commonly observed in MS patients, and changes in gut bacteria are linked to earlier and more severe disease in animal models of MS.
How the gut microbiome differs across MS types, and whether certain bacteria might be responsible for the transition from a relapsing to a progressive disease course, however, is still unclear.
Whether there is a “causal relationship between gut dysbiosis and MS progression … [also] remains elusive,” the researchers wrote, adding that should such a relationship be confirmed, the specific “disease-enhancing causative bacteria” remain to be identified.
Takewaki and his team previously analyzed fecal samples from relapsing-remitting MS (RRMS) and SPMS patients, finding a distinct microbiome profile associated with each MS type.
They now sought to identify the specific gut bacteria linked with MS progression, and the likely mechanisms that drive neuroinflammation.
Using bacterial DNA obtained in fecal samples from 62 RRMS and 15 SPMS patients, the researchers found 12 bacterial species that were particularly enriched in the SPMS samples. Of them, bacteria X levels showed the strongest correlation with patients’ disability levels, as assessed using the Expanded Disability Status Scale (EDSS).
Genomic data from public databases in the International Multiple Sclerosis Genetics Consortium (IMSGC) confirmed the relative increase in bacteria X among people with progressive MS, particularly in patients with an EDSS score of 3 to 5, indicating moderate to severe disability.
This observation “confirms that bacteria X is highly enriched in the progressive stage of MS,” Takewaki said.
On further examination, two different strains, or subtypes, of bacteria X were identified. While strain A1 levels were similar among healthy people and RRMS and SPMS patients, strain B1 was significantly more abundant in SPMS samples compared with the other two groups.
Researchers then worked with mice engineered to lack all microorganisms, called germ-free mice. These animals are normally resistant to the neurological disability that marks experimental autoimmune encephalomyelitis (EAE), a common mouse model of MS.
Significant disability rise seen in mice given strain B1 from SPMS patients
When strain B1 of bacteria X — isolated from SPMS patients — was delivered to the germ-free mice, their disability significantly increased. A similar degree of disability was not observed when the bacteria’s strain A — isolated from RRMS patients — was given these mice.
SPMS-derived bacteria also led to a relative increase of Th17 cells, a type of pro-inflammatory immune cell considered a main driver of inflammation in MS, in the large intestine and brain. Strain A also led to significant increases in these cells, although to a lesser extent.
Looking at differences between strains A1 and B1 that could explain the more severe disease mechanisms with SPMS-derived bacteria, the team found that strain B1 expressed more genes associated with flagella. Under a microscope, these bacteria were observed to have flagella-like structures, and they attached to cells of the large intestine.
“After bacterial transfer into the germ-free mice, we confirmed that bacteria X strain B1 can colonize in the colon of the transplanted mice,” Takewaki said.
Notably, certain types of flagella in bacteria are thought to activate receptors called toll-like receptor 5 (TLR5). This prompts the release of the pro-inflammatory molecule interleukin-6 (IL-6) from certain immune cells, which in turn activate Th17 cells.
This could be one way that bacteria X promotes inflammation in SPMS, the researchers noted, and supported in experiments. Specifically, the SPMS-derived bacteria significantly stimulated TLR5 activity in cell cultures, and promoted the secretion of IL-6 from immune cells.
This rise in IL-6 levels was suppressed in the presence of a molecule that blocks toll-like receptor 5.
“We confirmed that bacteria X has the capacity of inducing Th17 cells in the gut and subsequently exacerbate neuronal inflammation,” Takewaki said, adding that this is “possibly associated with disease progression from RRMS to SPMS.”
Note: The Multiple Sclerosis News Today team is providing in-depth coverage of the ACTRIMS Forum 2023 Feb. 23–25. Go here to see the latest stories from the conference. Follow along on Facebook, Twitter, and Instagram for live updates using the hashtag #actrims2023.
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