Gut Bugs That May Trigger MS Relapses
- Gary Birnbaum, MD
- 6 hours ago
- 6 min read
Multiple sclerosis and gut microbiota: Lachnospiraceae from the ileum of MS twins trigger MS-like disease in germfree transgenic mice-An unbiased functional study.
Yoon H, Gerdes LA, Beigel F, et al.
Proc Natl Acad Sci U S A 2025;122:
e2419689122.
Introduction:
Research on finding a “cure” for MS has mostly involved studies of the immune system. While the immune system plays a major role in the disease, and great success has been achieved in reducing disease activity in relapsing forms of multiple sclerosis, focusing only on the immune system ignores many other facets of the illness that must be addressed to truly achieve a cure.
Several of these facets were discussed previously in this blog, including the increasing likelihood that the central nervous systems in persons with MS are different than those without the illness and that the multiple populations of bacteria (microbiomes) that reside in different body compartments may also play an important role. The bacterial populations of the gut, the “gut microbiome”, has particular relevance for MS.
The above cited paper presents new and persuasive evidence that particular bacteria in the gut are a possible trigger for inducing acute central nervous system inflammation in persons with MS, a trigger that must be better understood and controlled if a true “cure” for MS is to be achieved.
Key Points:
1. There are more bacteria in our bodies than there are human cells. Almost all these bacteria are either harmless or serve important bodily functions, such as helping with digestion.
2. Bacterial colonies, or microbiomes, are different in different areas of the body, such as the skin, mouth, and gut. Gut microbiomes vary in individuals based on their genetic background, their geographic location and their diet. Most importantly, cells in the central nervous system are affected by changes in the gut microbiome, with bacteria in the gut able to stimulate immune cells, such as T cells and central nervous system cells, such as microglia and astrocytes, that result in central nervous system inflammation.
3. Gut microbiomes in persons with MS are different than in non-affected individuals. However, results between studies have varied and it wasn’t clear whether the changes noted were the result of the illness or were directly involved in causing the disease.
4. To further complicate the issue, bacteria are different in different areas of the gut and in different layers of the gut (ileal lumen, ileal mucosa, colonic lumen, and colonic mucosa). These differing populations may have different effects on immune cells and on the central nervous system.
5. To address these multiple issues the authors of the above paper studied a unique population of 81 genetically identical twins, only one of whom had MS. They asked the question “are there differences in the gut microbiomes of affected and non-affected twins, and if so, what are the differences and how do they relate to possibly triggering the disease?”.
6. Differences between twins’ gut microbiota were found. The diversity or number of bacterial species did not differ in the two groups, but 51 genus, or groups of bacteria did differ, especially a group called “Firmicutes”.
7. To study differences in the geography of gut bacteria, and after obtaining consent, the researchers placed tubes into the intestines of two pairs of twins. One set of twins was older with the affected twin in the progressive phase of her illness and off disease-modifying therapy for over ten years. The other set of twins was male, younger, with the affected twin having recent onset of relapsing MS and on the disease-modifying therapy interferon-beta.
8. Bacteria were obtained from the different parts of the gut (duodenum, ileum, colon) and from stool to see where the bacterial differences were most prominent. Most differences were noted in bacteria obtained from the ileum.
9. Bacteria from the ilea were then transferred to germ-free mice that were genetically susceptible to the MS-like disease, experimental autoimmune encephalomyelitis (EAE). More specifically, they were genetically engineered to express receptors on 70% of their T cells that reacted with a myelin protein, myelin oligodendrocyte glycoprotein (MOG).
10. Mice had to be germ free since mouse bacteria in their gut could induce EAE.
11. Inoculation of bacteria from the ilea of twins with MS induced substantially more EAE in the mice than did bacteria from the ilea of the twins without MS. This effect was even more prominent in female mice.
12. The researchers then went on to identify the particular species of bacteria that were associated with EAE in the mice. Patterns of bacterial species in mice that received ileal samples from normal twins remained stable for weeks, with no onset of EAE. Patterns of bacteria in the guts of mice inoculated with bacteria from the twins with MS changed rapidly over 2-6 weeks, with a reduction in the number of species and with a marked preponderance of two members of the Lachnospiraceae family of bacteria. Findings were similar using bacteria from both sets of twins.
13. How these particular strains of bacteria triggered episodes of acute central nervous system inflammation is not clear. One theory the authors suggested was that there were proteins on the surfaces of the bacteria that were similar to those on cells of the central nervous system and that this “cross-reactivity” or “molecular mimicry” triggered immune cells that then entered the central nervous system and attacked it. Another possibility is that infection with these specific bacteria resulted in a decreased number of regulatory T cells, called Foxp3-positive T cells, thus allowing the expansion of disease causing autoimmune T cells.
14. In that context the authors did note an increase in numbers of T-cells secreting the inflammatory compound Il-17, and observation also seen in another study. Direct visualization of these cells, in another different study showed them traveling from the gut to the central nervous system of mice.
15. The study authors were very cautious in interpreting their findings. As noted in my previous blogs, the immune systems of humans and mice are very different and relapsing EAE is not MS. Nevertheless, these findings establish in an unbiased way, that gut bacteria from persons with MS are different, even in genetically identical persons, and that particular populations of MS gut bacteria can stimulate immune cells in genetically altered mice that can travel to the central nervous system and induce central nervous system inflammation.
Discussion:
The more scientists learn about MS, the more complex the disease becomes. While it’s clear that the immune system plays a critical role in the disease, what remains unknown is what triggers the disease and how genetic and environmental factors contribute to disease susceptibility and severity.
The observations of Yun and colleagues, described in the above paper, provide an important new insight into the pathogenesis of MS. While multiple researchers have suggested that the gut microbiomes of persons with MS are different, this study is the first to demonstrate that particular bacteria from genetically similar persons with MS are able to induce an MS-like illness in mice. Bearing in mind that mice are not humans and that experimental autoimmune encephalomyelitis is not MS, these observations now can lead to discovering the mechanisms that result in the triggering of acute central nervous system inflammation by particular strains of bacteria.
This issue is complicated by the fact that the gut microbiomes of individuals vary greatly based on their genetics, their diets, geographic locations, and by medications, such as antibiotics and disease-modifying therapies. Nevertheless, if one is to find a true “cure” for MS, all aspects of the disease must be addressed, including the possibility that the central nervous systems of persons with MS are intrinsically different (see my blog from June 4, 2020 and these articles).
Once we understand how certain bacteria are able to stimulate immune and central nervous system cells that can trigger an attack on the central nervous, system it should be possible to eliminate these organisms and replace them with bacterial strains that have been shown to repress central nervous system inflammation. Since gut microbiomes can change over time, with aging and diet, probiotics containing disease-repressing bacteria may need to be administered as adjunctive therapy to other disease-modifying therapies.
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