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THE potential roles of intestinal microbiome in triggering relapses of multiple sclerosis

Neurology
10 months ago, OP Editor

The cause of multiple sclerosis (MS) involves environmental exposure and genetic susceptibility.1 Differences in intestinal microbiome between MS patients and healthy people had been identified in previous studies.2-5 Two recently published studies in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) have further demonstrated a potential role of specific intestinal microbiome in the progression of MS.6,7 The research findings may have important implications not only for the pathogenesis, but also for the treatment and prevention of MS.6,7

MS is an idiopathic, putatively autoimmune, chronic inflammatory disorder of the central nervous system (CNS) in which focal lymphocytic infiltration through the blood-brain barrier (BBB) leads to acute inflammation of myelin and axons.1,8 Over time the pathological changes become dominated by widespread microglial activation with extensive and chronic neurodegeneration, resulting in disability.1

The etiology of MS involves both environmental and genetic factors.1 The exact nature of the environmental factors responsible for predisposition to MS remains elusive; however, emerging evidence has suggested that gastrointestinal commensal microbiota may have a role in the pathogenesis of MS.2-5 Previous studies had already shown that Acinetobacter, Akkermansia, Psuedomonas, Mycoplana, Hemophilus, Blautia and Dorea genera were more abundant in MS patients, and Parabacteroides, Adlercreutzia and Prevotella genera were more abundant in healthy people.3-5 The role of variability in intestinal microbial abundance and composition in the progression of MS has been further established in two recent studies.6,7

In a study recently published in PNAS, Dr. Egle Cekanaviciute and her collaborators compared the intestinal microbial profiles of 34 monozygotic twin pairs discordant for MS.6 A remarkable increase in certain taxa including Akkermansia was observed in untreated MS twins.6 When transplanted to a transgenic mouse model of spontaneous brain autoimmunity, intestinal microbiota from MS-affected twins induced CNS-specific autoimmunity at a higher incidence than microbiota from healthy co-twins.6 A high intraindividual and remarkable temporal stability with several differences, including Sutterella, an organism shown to induce a protective immunoregulatory profile in vitro, was observed in the microbial profiles of the colonized mice.6 IL-10 may have a regulatory role in spontaneous CNS autoimmunity, as neutralization of the cytokine in mice colonized with healthy-twin fecal samples increased disease incidence.6 The findings were consistent with previous reports describing enhanced IL-10 production in the intestinal immune system driven by bacterial polysaccharide A and protection from actively induced CNS autoimmune disease.9,10

In another recent study published in the same issue of PNAS, Dr. Egle Cekanaviciute and her collaborators sequenced the intestinal microbiome of 71 MS patients as well as 71 healthy control subjects.7 Akkermansia muciniphila and Acinetobacter calcoaceticus, both were more prevalent in MS patients, resulted in proinflammatory responses in both human peripheral blood mononuclear cells and monocolonized mice.7 Parabacteroides distasonis, which was found at low levels in MS patients, induced IL-10+FoxP3+ Tregs and anti-inflammatory IL-10–expressing human CD4+CD25+ T cells in mice.7 Microbiota transplants from MS patients into germ-free mice caused more severe symptoms of experimental autoimmune encephalomyelitis, and reduced proportions of IL-10+ Tregs compared with mice “humanized” with microbiota from healthy controls.7

“Two different groups, using two separate cohorts of patients and controls, and two distinct mouse models of the disease, saw very similar results,” Dr. Cekanaviciute said in a statement.11 These results suggest that the intestinal microbiome may play a crucial role in MS pathogenesis.6,7

The findings of these studies provide possibilities for characterizing the precise role and functional mechanisms by which the human intestinal microbiota contributes to the pathogenesis of neuroinflammatory diseases. It is believed that the results may eventually provide a basis for the development of microbiome-based therapeutics in autoimmune diseases, and novel therapies for patients with MS.

“To be clear, we don’t think the microbiome is the only trigger of MS,” added Dr. Cekanaviciute. “But it looks like these microbes could be making the disease progression worse or better — pushing someone with genetic predisposition across the threshold into disease or keeping them safe.”11

1. Compston A, Coles A. Multiple sclerosis. Lancet 2008; 372(9648): 1502-17.

2. Jangi S, Gandhi R, Cox LM, et al. Alterations of the human gut microbiome in multiple sclerosis. Nature communications 2016; 7: 12015.

3. Ebringer A, Hughes L, Rashid T, Wilson C. Acinetobacter immune responses in multiple sclerosis: etiopathogenetic role and its possible use as a diagnostic marker. Arch Neurol. 2005 Jan;62(1):33-6.

4. Tremlett H, Waubant E. The multiple sclerosis microbiome? Ann of Trans Med 2017; 5(3): 53.

5. Chen J, Chia N, Kalari KR, et al. Multiple sclerosis patients have a distinct gut microbiota compared to healthy controls. Sci Rep 2016; 6: 28484.

6. Berer K, Gerdes LA, Cekanaviciute E, et al. Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice. PNAS 2017; 114(40): 10719-24.

7. Cekanaviciute E, Yoo BB, Runia TF, et al. Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models. PNAS 2017; 114(40): 10713-8.

8. Wingerchuk DM, Carter JL. Multiple sclerosis: current and emerging disease-modifying therapies and treatment strategies. Mayo Clin Proc 2014; 89(2): 225-40.

9. Wang Y, Telesford KM, Ochoa-Reparaz J, et al. An intestinal commensal symbiosis factor controls neuroinflammation via TLR2-mediated CD39 signalling. Nat Commun 2014; 5: 4432.

10. Round JL, Mazmanian SK. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci U S A. 2010; 107(27): 12204-9.

11. Gut Bacteria May Impact Multiple Sclerosis Progression. Genomeweb. 2017 (Accessed October 6 2017, at https://www.genomeweb.com/autoimmune-disease/gut-bacteria-may-impact-multiple-sclerosis-progression).

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