Multiple Sclerosis & Autoimmunity: The Impact of the Microbiome Keeps Getting Larger
MICHAËL FRIEDMAN, ND
Multiple sclerosis (MS) is a chronic inflammatory, demyelinating, and neurodegenerative disorder of the central nervous system (CNS). It is estimated that MS affects 2.8 million people globally,1 including approximately 1 million people in the United States.2,3 The etiology of MS is poorly understood, but is likely the result of a complex interplay between genetic polymorphisms and environmental exposures, as evidenced by its increasing incidence worldwide. The clinical presentation and course of MS can vary greatly, but it is characterized by uncontrolled activation of immune cells that infiltrate the CNS and attack the myelin sheath, leading to demyelination and axonal loss. MS clearly has autoimmune features, but as yet no specific autoantibodies have been consistently identified in every person with MS.4 This may be a consequence of its complex and varied etiology.
MS is also described as an immune-mediated condition,5 meaning it does not have a definitive etiology but is distinguished by common inflammatory pathways that are instigated by a dysregulated immune response. The distinction between autoimmune and immune mediated may largely be moot for naturopathic physicians, as our therapeutic approaches aim to support the body at deep, multisystem levels. Neuroinflammatory autoimmune (or immune-mediated) conditions do not begin in the CNS. Increasing evidence points to the central importance of the gut microbiome in its capacity to both mitigate and promote neuroinflammatory reactivity.
The Gut-Brain Axis & Neuroinflammation
The gut-brain axis (GBA) is a complex array of interactive neurochemical signaling pathways. It encompasses the neuroendocrine system, neuroimmune system, enteric nervous system, and autonomic nervous system. The GBA regulates multiple processes that are crucial for healthy functioning and homeostasis. In fact, scientific evidence continues to demonstrate the importance of the interplay between the gut and the brain for physical and mental health, as well as in the development of certain disease states. The gut microbiome (or gut microbiota; the terms are often used interchangeably) is a dynamic component of the GBA. The gut microbiome is actively involved in a process known as tolerogenic signaling with the immune system, which establishes and maintains immune privilege, or non-reactivity to both commensal flora and dietary antigens.6
The brain, another major organ subject to immune privilege, is protected from substances such as cytokines and metabolic or microbial byproducts, in large part by the blood-brain barrier. The blood-brain barrier is closely monitored by macrophages and microglia that are resident in the CNS. It has been shown that the healthy maturation and function of CNS microglia are dependent on a healthy and diverse gut microbiome. Furthermore, the maturation and function of microglia are regulated on an ongoing basis by short-chain fatty acids (SCFAs) synthesized by gut flora.7 This means the gut microbiome is involved with crosstalk with the immune system beyond the gut. It also means the health of the microbiome can have a direct impact on the integrity of the blood-brain barrier.
Microglia & the Gut Microbiome
Microglia are the foremost innate immune cells of the CNS. They are involved in many processes integral to CNS development and function, including the regulation of inflammation, apoptosis, and synaptic connectivity. Recent studies have shed light on a fascinating property of activated microglia: they can be polarized into 2 different forms, or phenotypes, in response to the CNS environment in which they find themselves. This means they are capable of shifting into having either proinflammatory/neurotoxic effects or anti-inflammatory/neuroregenerative effects, based on their microenvironment.8 The proinflammatory factors produced by microglia can damage local brain tissue. When a disordered immune response or damage to the blood-brain barrier persistently activates microglia, the inflammatory homeostasis is disrupted. As a consequence, microglia may not shift sufficiently toward their “resolution” phenotype. This situation induces more inflammation and further microglial activation, potentially leading to a vicious cycle of neuroinflammation. Prolonged activation of microglia and the resultant state of chronic neuroinflammation are thought to be linked to the development of neurodegenerative disorders such as Alzheimer’s disease9 and Parkinson’s disease,10 and may be a cofactor in the development and clinical course of MS.
Considering the significant role that the gut microbiome plays in microglial development and function, as well as the vital importance of communication between the microbiome and the immune system within and beyond the gut, it is not a big leap to say that gut dysbiosis may increase susceptibility to dysfunctional immune activity in the CNS.
Gut Microbiome & MS
The link between CNS autoimmunity and the gut microbiome was first shown in studies using the experimental animal model of MS (experimental autoimmune encephalomyelitis, or EAE). Some of these studies showed that gut bacteria from people with MS exacerbated the symptoms of EAE in mice11 and even induced EAE in mice that did not already have it.12
The gut microbiome appears to have its immunomodulatory influence beyond the gut in a number of ways. Several studies using the EAE model suggest that interleukin-17 (IL-17) may be a significant cofactor in the development and severity of MS.13 IL-17 is a family of proinflammatory cytokines produced by Th17 cells. Many MS patients have elevated levels of IL-17 in their serum and cerebrospinal fluid.14 Along with playing a crucial role in the maturation and function of microglia, the gut microbiome is involved in the activation of T cells by modulating the balance of Th1/Th17 and regulatory T cells (Tregs), even outside of the gut. Tregs are crucial for preventing autoimmune reactions because they inhibit T-cell proliferation and cytokine production, thereby restoring homeostasis and maintaining self-tolerance. It’s not fully understood how Th1 and Th17 cells in people with MS become myelin-specific and are able to cross the blood-brain barrier; however, the presence of T cells in the CNS has many detrimental effects, including promoting microglial activation and the release of cytotoxic agents that break down myelin, as was demonstrated in a mouse model.15
Clinical Relevance for MS Patients
Even though our understanding of the microbial species and ratios that constitute a healthy microbiome is still evolving, it is known that the gut microbiota in people with relapsing-remitting MS is different from that of healthy controls. The restoration of a healthy microbial population in these patients was shown to result in a decrease in inflammatory episodes and immune reactivity.16 A healthy gut microbiome establishes and maintains physiological balance through a number of mechanisms, such as preventing colonization by pathogenic microbes; modulating host immunity within and beyond the gut; and ensuring the integrity of the intestinal barrier (thereby contributing to the integrity of the blood-brain barrier).
A particularly simple approach that, over the long term, has the potential to address many of these mechanisms is having your MS patients add high-fiber prebiotics to their diet. These can be taken in the form of supplements, but they are also readily available in the diet and can be incorporated with a view to being a permanent lifestyle change. High sources of dietary fiber include legumes (such as black beans, lentils, and chickpeas), fruits (in particular avocados, berries, apples, bananas, and oranges), lightly cooked vegetables, whole grains (in patients without gluten sensitivity), seeds, and nuts (in particular walnuts and raw almonds).
The gut microbiome breaks down insoluble fibers into short-chain fatty acids such as acetate, propionate, and butyrate. SCFAs have innumerable beneficial effects on inflammation, including neuroinflammation. They exert this effect in part by reducing levels of IL-1ß, and because of their role in microglial maturation and function. High-fiber diets can also differentially affect the preponderance of microbial strains and widen the range of beneficial flora. For example, the prebiotic inulin selectively influences the abundance of Anaerostipes, Bilophila, and Bifidobacterium. Beneficial alterations to the gut microbiome of mice fed inulin included increased microbial production of SCFAs and improved neurological outcomes.17 High-fiber diets have also been shown to increase circulating levels of butyrate, as well as to reduce the risk for chronic inflammatory conditions such as type 2 diabetes, obesity, stroke, and cardiovascular disease, which themselves are linked to an increased risk of dementia and other neurological disorders.18
One caveat to be aware of is that adding prebiotic fiber to the diet of a patient who already has dysbiosis may cause intestinal discomfort. This discomfort is usually temporary while the microbiome environment adjusts, but it may be advisable to have your patient supplement for a time with probiotics first. Although the mechanisms of autoimmunity in Alzheimer’s disease and Parkinson’s disease are different from those in MS, it’s worth noting the benefits of addressing imbalances in the microbiome with probiotics in these conditions that do have neuroinflammation and neurodegeneration in common. An in-vitro study in which immune cells isolated from people with Parkinson’s disease were cultured with Lactobacillus and Bifidobacterium found that these probiotic strains significantly reduced proinflammatory cytokines (including IL-17) and increased anti-inflammatory cytokines.19 In a randomized, double-blind trial, participants diagnosed with Alzheimer’s disease, who received a mix of probiotics for 12 weeks, showed significant improvements in their scores on the Mini-Mental State Exam compared to controls.20 Many patients can benefit from adding fiber to their diet whether or not they are also supplementing with probiotics.
As naturopathic doctors, we have a panoply of options to offer patients to mitigate the clinical course of MS and potentially promote remyelination. These approaches include directly addressing systemic inflammation, hormone imbalances, mitochondrial dysfunction, and neurotransmitter deficiencies using the wide array of therapeutic modalities in our toolbox. We are also experts at supporting gut health. Incorporating dietary fiber into a daily wellness regimen is a relatively inexpensive and easy thing for MS patients to do, whether or not they are supplementing with probiotics as well. It is also a simple yet powerful therapeutic strategy in support of neurological health.
- Walton C, King R, Rechtman L, et al. Rising prevalence of multiple sclerosis worldwide: Insights from the Atlas of MS, third edition. Mult Scler. 2020;26(14):1816-1821.
- Wallin MT, Culpepper WJ, Campbell JD, et al. The prevalence of MS in the United States: A population-based estimate using health claims data. Neurology. 2019;92(10):e1029-e1040.
- National Multiple Sclerosis Society. Prevalence of MS More Than Doubles Estimate. 2020. Available at: https://www.nationalmssociety.org/About-the-Society/MS-Prevalence. Accessed December 21, 2020.
- Kuerten S, Lanz TV, Lingampalli N, et al. Autoantibodies against central nervous system antigens in a subset of B cell–dominant multiple sclerosis patients. Proc Natl Acad Sci U S A. 2020;117(35):21512-21518.
- National Multiple Sclerosis Society. What is an immune-mediated disease? Available at: https://www.nationalmssociety.org/What-is-MS/Definition-of-MS/Immune-mediated-disease. Accessed December 21, 2020.
- Rescigno M. Gut commensal flora: tolerance and homeostasis. F1000 Biol Rep. 2009;1:9.
- Erny D, Hrabě de Angelis AL, Jaitin D, et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci. 2015;18(7):965-977.
- Hornedo-Ortega R, Cerezo A, de Pablos R, et al. Phenolic Compounds Characteristic of the Mediterranean Diet in Mitigating Microglia-Mediated Neuroinflammation. Front Cell Neurosci. 2018;12:373.
- Krause DL, Müller N. Neuroinflammation, microglia and implications for anti-inflammatory treatment in Alzheimer’s disease. Int J Alzheimers Dis. 2010;2010:732806,
- Hunot S, Hirsch EC. Neuroinflammatory processes in Parkinson’s disease. Ann Neurol. 2003;53 Suppl 3:S49-S58.
- Cekanaviciute E, Yoo BB, Runia TF, et al. Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models. Proc Natl Acad Sci U S A. 2017;114(40):10713-10718.
- Berer K, Gerdes LA, Cekanaviciute E, et al. Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice. Proc Natl Acad Sci U S A. 2017;114(40):10719-10724.
- Lee YK, Menezes JS, Umesaki Y, Mazmanian SK. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2011;108 Suppl 1(Suppl 1):4615-4622.
- Matusevicius D, Kivisäkk P, He B, et al. Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult Scler. 1999;5(2):101-104.
- Reyes REN, Zhang Z, Gao L, Asatryan L. Microbiome meets microglia in neuroinflammation and neurological disorders. Neuroimmunol Neuroinflammation. 2020;7:215-233. Available at: http://dx.doi.org/10.20517/2347-8659.2020.13. Accessed December 21, 2020.
- Esmaeil Amini M, Shomali N, Bakhshi A, et al. Gut microbiome and multiple sclerosis: New insights and perspective. Int Immunopharmacol. 2020;88:107024.
- Matt SM, Allen JM, Lawson MA, et al. Butyrate and Dietary Soluble Fiber Improve Neuroinflammation Associated with Aging in Mice. Front Immunol. 2018;9:1832.
- Schepici G, Silvestro S, Bramanti P, Mazzon E. The Gut Microbiota in Multiple Sclerosis: An Overview of Clinical Trials. Cell Transplant. 2019;28(12):1507-1527.
- Magistrelli L, Amoruso A, Mogna L, et al. Probiotics may have beneficial effects in Parkinson’s disease: in vitro evidence. Front Immunol. 2019;10:969.
- Akbari E, Asemi Z, Daneshvar Kakhaki R, et al. Effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer’s disease: a randomized, double-blind and controlled trial. Front Aging Neurosci. 2016;8:256.
Michaël Friedman, ND, is the founder of the Association for the Advancement of Restorative Medicine and the Journal of Restorative Medicine. He also formulates herbal and nutritional supplements, and is cofounder and president of the Restorative Formulations supplement company. He is the author of the textbook Fundamentals of Naturopathic Endocrinology, a contributing author of Evidence-Based Approach to Restoring Thyroid Health, and co-author of Healing Diabetes. He has treated patients with illnesses ranging from lymphoma to liver cancer. He lives with his family in Montpelier, VT. His latest book, There’s No Pill for This: A Naturopathic Physician’s Personal Prescription for Managing Multiple Sclerosis, is now available at: https://www.chelseagreen.com/product/theres-no-pill-for-this/.