The human gut microbiome comprises approximately 100 trillion microbes representing the most complicated interaction between microbiota and the human body. Collectively, these microbes inhabiting your gut are termed symbionts, which means “fellow travelers” or species different from us that live within us (1). Amongst these symbionts are mutualists, commensals, and pathogens, that is, microbes that are helpful and some that are harmful (1). Due to intense selection pressure by the host (humans in this case), of the 1,200 to 1,500 estimated bacterial phyla (major bacterial groups) greater than 90% of microbiota in the human gut fall within 2 phyla, Bacteroidota and Firmicutes. Put another way, during health, your body has the capacity to decern amongst one trillion bacterial species on earth and chose just ~100 core species to inhabit the gut. Why is this selection of microbes “invited” to inhabit the human gut so critical to health?
First, it is important to understand that the gut represents the largest immune organ in the human body (Gut Associated Lymphoid Tissue, GALT) impacting immune responses in all other organs including the brain and spinal cord. After birth, microbes begin to inhabit your gut working to organize and shape the characteristics of the gut immune system. Specific groups of microbes are required for development of pro-inflammatory immune cells, while others function to enhance regulatory immune cells which dampen immune responses. In adulthood changes in the balance of gut microbial composition can lead to a heightened pro-inflammatory state and autoimmunity. A goal in Multiple Sclerosis (MS) treatment is to boost the regulatory function of the immune system thereby dampening inflammation and autoimmunity (immune tolerance). A key cell type functioning in immune tolerance are T regulatory cells or Tregs for short. Tregs are present in both the small and large intestine, however they are most abundant in the large intestine.
What’s the connection between gut microbes*, gut Tregs, and immune tolerance? Certain classes of microbes generate metabolites (molecules produced through metabolism) that directly influence immune cells. A class of metabolites termed short chain fatty acids (SCFA) induce and maintain Treg populations within the gut, mostly the large intestine (2). Only a subset of bacteria has the cellular machinery to make SCFA and these fall within the phylum termed Firmicutes. It has been shown in model systems that increasing the proportion of Firmicutes, and thus SCFA producing bacteria, markedly reduces autoimmunity through induction of Tregs that travel to the central nervous system (CNS). For a nice review on gut microbes and MS models of autoimmunity please see (3) and (4).
Bacterial metabolites such as SCFA and aryl hydrocarbons also have direct effects on the CNS. A critical function is on the blood-brain barrier. The blood-brain barrier functions to create an environment in which the nervous system functions optimally by limiting entry of cells and molecules from the blood into the CNS. SCFA and other bacterial metabolites help induce and maintain barrier function in the CNS which is important for overall brain health as well as limiting the potential for autoimmunity. For review please see (5).
In studies of the MS gut microbiome, one consistent finding is a relative reduction in the proportion of Firmicutes compared to other bacteria. The reason for this shift is not clear but likely is the consequence of the persons genetics and their environment. Environment in this case is crucially geographic location and diet. Bacteria that produce metabolites important for overall health require food for growth and survival. Important components of our diet, suboptimal for many people, are insoluble dietary fiber and resistant starch. Firmicutes feed on these dietary components through the process of fermentation and generate beneficial metabolites. It’s important to talk with your doctor about diet and how you can optimize it to tip the balance in favor of beneficial microbes.
In addition to metabolites, some bacteria produce toxins that may be detrimental to the CNS. One toxin of interest is Clostridium perfringens epsilon toxin which targets and alters the blood-brain barrier in model systems of MS. In addition, epsilon toxin directly targets myelin and in model systems causes demyelination. Research is still underway, but it appears that people with MS are more likely to harbor this organism (6). Further work needs to be done to determine if there is a causal role for epsilon toxin in MS.
Understanding the relationship between gut microbes and multiple sclerosis is an active area of research in laboratories and clinics throughout the world. There is hope that through modulating and optimizing beneficial gut microbiota we can reduce or even prevent injury to the nervous system in people with MS. Be sure to talk with your health care provider about ways to improve your gut health.
- For a very nice explanation of symbionts, commensals, mutualists, and pathogens (parasites) please see: https://www.youtube.com/watch?v=vMh-zxBlrUE&t=351s
- https://www.nature.com/articles/s41423-023-00987- 1
- https://pubmed.ncbi.nlm.nih.gov/35931825/
- https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-022-...
- https://pmc.ncbi.nlm.nih.gov/articles/PMC9954192/
- https://www.jci.org/articles/view/163239
*We use the terms microbiota or microbes as a general designation that includes Bacteria and Archaea.
Content is educational only and does not represent medical advice.