An Influence of the Microbiome in Multiple Sclerosis?
Three Lines of Evidence Suggest So
Growing evidence points to a role of the microbiome in multiple sclerosis, an autoimmune disorder of the central nervous system.
Research over the past decade implicates the intestinal microbiome in multiple autoimmune diseases—inflammatory bowel disorder (IBD), Crohn’s, and type 1 diabetes (T1D). But could the microbiome also play a role in multiple sclerosis (MS), an autoimmune disorder of the central nervous system (CNS)? While involvement of the commensal gut microbiome in GI disorders is intuitive, the idea that gut bacteria and their metabolites underly a disease of the CNS seems further afield. The next three blogs in our microbiome series delve into emerging evidence that the bacterial gut microbiome may play a role in a constellation of CNS disorders—both neurological and psychiatric—via immune, metabolic, and endocrine signals transmitted along the gut-brain axis. In MS specifically, understanding the role of the microbiome holds the promise of better understanding the large interpatient variation in severity, progression, and presentation of MS and of uncovering new therapeutic interventions. Here, we outline three lines of evidence implicating the gut microbiome in MS.
#1--Microbiome Differences in MS Patients
Microbiomes of MS patients appear less diverse and with a different composition (i.e., dysbiosis, which is either a reduction of normal gut bacteria or an increase in pathological ones) than in healthy individuals. Dysbiosis also occurs in IBD or T1D patients. However, no group has identified a consistent “MS microbiome profile” thus far. Instead, the microbiome of MS patients appears generally shifted toward a more pro-inflammatory and less anti-inflammatory state than that of healthy individuals. For instance, multiple research groups have identified increases in Akkermansia and Actinobacter and reductions in Parabacteriodes distasonis in MS patients compared with healthy patients. In vitro and in vivo studies demonstrate that Akkermansia and Actinobacter elicit proinflammatory responses in human peripheral blood monocytes in vitro and in mice. Conversely, Parabacteriodes stimulates anti-inflammatory cytokine IL-10-expressing T cells in vitro and IL-10-producing regulatory T cells (Tregs) in mice (Cekanaviciute E, 2017). Studies in discordant twins—one with MS and the other not—confirm an increase in Akkermansia in MS patients (Berer K, 2017). Other studies show that microbiome richness is reduced in patients experiencing relapses (Chen, 2016), while it appears unaffected in patients in remission (Miyake S, 2015). It is still unclear whether dysbiosis precedes the development of MS symptoms or whether changes to MS patients’ immune systems cause dysbiosis.
#2--Microbiome Studies in EAE Mice
Truly intriguing results implicating the microbiome in MS and CNS autoimmunity emerge from studies in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. EAE is attenuated in mice raised under germ-free conditions and these animals have lower levels of the proinflammatory cytokine IL-17 in the gut and in the CNS while having an increase in anti-inflammatory Treg cells in the periphery (Lee Y, 2011). However, when these animals are recolonized by a normal gut microbiome, EAE can be induced once again (Berer K, 2011), suggesting a necessary role for the intestinal bacteria in the initiation of EAE. In addition, treating mice with antibiotics leads to a dampening of EAE severity compared with untreated EAE animals, though a protective effect only occurred if animals were treated within 2 weeks after EAE induction.
In an elegant experiment, Berer and colleagues colonized the guts of transgenic mice (capable of spontaneously developing EAE) with the microbiomes of 34 MS patients and their unaffected twins (Berer K, 2017). Mice inoculated with the microbiota of MS patients experienced a significantly higher incidence of EAE and greater EAE severity than controls, suggesting the microbiomes of MS patients can induce more autoimmune reactions and more severe reactions than healthy patients. In addition, levels of IL-10-producing-Treg cells were reduced in mice treated with MS microbiomes compared with healthy control microbiomes, suggesting a protective role of IL-10 in EAE. Moreover, when researchers neutralized IL-10 using antibodies in mice with healthy twin microbiomes, the incidence of EAE increased, further supporting the hypothesis that IL-10 and IL-10-producing Treg cells play a protective role against relapses in CNS autoimmunity. Finally, experiments from a separate group demonstrated that when germ free mice were colonized with a gut bacterium, P histicola, known to decrease pro-inflammatory Th1 and Th17 cells while increasing Treg levels, the severity of EAE was reduced as would be expected if Tregs play a protective role against EAE (Mangalam, 2017).
#3--Intestinal Permeability Changes in MS Patients and EAE Mice
One of the most interesting effects of the microbiome is on the permeability of the intestinal epithelial wall of the host’s gut. Commensal bacteria can reduce gut permeability by strengthening the adhesion between neighboring epithelial cells forming the gut wall. There is evidence of a more permeable gut wall under conditions of dysbiosis such as is seen in MS. Researchers have histological evidence of disrupted intestinal barrier function in biopsies of MS patients (i.e., evidence of intestinal inflammatory cell infiltration). Moreover, several groups have shown evidence of abnormal gut wall permeability in MS using a lactulose/mannitol permeability test: Buscarinu and colleagues showed that 73% of MS patients vs. 28% of controls had abnormal gut permeability (Buscarinu M, 2017). Given the structural similarities between the intestinal epithelial wall and the blood brain barrier (BBB), it would not be surprising that circulating metabolites from commensal bacteria would also affect the permeability of the BBB, as has been documented in MS patients. The fact that IBD and Crohn’s patients also show signs of CNS demyelination supports this hypothesis. EAE mice also show evidence of intestinal permeability and the degree of permeability is associated with the severity of EAE symptoms (Secher T, 2017). Moreover, treatment with the probiotic E. coli strain Nissle 1917, known to reduce intestinal wall permeability, also reduced the severity of EAE in mice. This reduction in permeability was also associated with a reduction in pro-inflammatory cytokines, an increase in IL-10, and a reduction in the migration of inflammatory T cells into the CNS, suggesting an effect on the permeability of both the intestinal wall and of the BBB.
Finally, MS treatments also affect patients’ microbiomes and gut permeability, although these effects have not been fully evaluated. Interferon-beta has been shown to stabilize biological barriers, including the BBB, the intestinal barrier, and the lung-blood barrier (Kraus J, 2004; Camara-Lemarroy C, 2018). Glatiramer acetate also stabilizes the intestinal barrier and shifts the immune profile of mouse models of colitis to an anti-inflammatory state (Aharoni R, 2005). Biogen’s Tysabri—an MS therapy also indicated for the treatment of Crohn’s disease—targets integrin α-4, preventing the passage of lymphocytes through the BBB and through the intestinal wall.
Our understanding of the role of the microbiome on MS is still nascent and large therapeutic trials targeting the microbiome in MS patients are several years away. The most prominent initiative in this arena, the International MS Microbiome Study (iMSMS), is a multinational collaboration of research labs across the United States, U.K., Spain, and Argentina. Its goal is to better understand changes in the composition of the microbiome in MS patients and the fundamental influences of altering the microbiome in patients, before selecting agents for trials. iMSMS expects to enroll 2,000 patients within three years and to begin clinical trials for therapeutic agents four to five years after. Meanwhile, a study by Sheba Medical Center in Israel will enroll 520 patients to evaluate microbiome changes in MS patients and the potential to use the microbiome transcriptome as a diagnostic or prognostic tool for MS, although the status of the trial is uncertain (NCT02580435; anticipated completion: December 2021). Other academic initiatives led by Washington University in St Louis and Oregon Health and Science University in Portland are assessing the influence of fasting and of low fat diets on MS. Anecdotal evidence of the influence of diet on MS is scant, although a recent study has demonstrated beneficial effects of intermittent fasting in EAE mice (Cignarella F, 2018).
Small but promising studies have evaluated the effect of probiotics on MS (Camara-Lemarroy C, 2018). Use of the helminth T. suis in patients with relapsing-remitting MS was associated with favorable MRI and immunological outcomes (Fleming J, 2011). Another study showed that treating MS patients with a probiotic for 12 weeks was associated with small improvements in patients’ disability, anxiety, and depressive symptoms (Kouchaki E, 2017). Finally, two small studies on fecal microbial transplantation are in progress at the London Health Science Centre in Ontario Canada (NCT03183869; completion: December 2018, although a recent report at the ECTRIMS conference suggests the completion date will be later given 16 out of 40 patients are enrolled thus far [Wing A., 2018]) and at the University of California-San Francisco (NCT03594487; completion: July 2020). Fecal transplantation has already yielded promising efficacy and safety results in GI indications.
Companies exploring microbiome therapeutic approaches have not aggressively pursued MS—none list the indication in their pipelines. This lack of focus on MS could be due to the market being well served by a large and growing number of immunomodulating therapies. However, unmet need remains for safe and well tolerated therapies which could be used adjunctively with currently approved therapies in hopes of added--perhaps synergistic--efficacy. In addition to therapeutic approaches, studies that identify a gut microbiome profile specific to MS patients, and/or map that profile to disease progression could lead to welcomed diagnostic and prognostic tools. For now, we eagerly await results from the fecal microbial transplantation trials for additional clues as to the efficacy and safety of this novel therapeutic approach in MS.
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