Gut Bacteria and Its Emerging Role in Multiple Sclerosis

A growing body of research is unraveling a multitude of ways in which the human gut microbiome has a major impact on health. Microbial dysbiosis has been linked with a variety of diseases, including diabetes, rheumatoid arthritis, cardiovascular disease, colorectal cancer, and more, underscoring the diffuse role of intestinal bacteria in biological functioning.¹

“Humans have evolved with these gut bacteria over millions of years and have a symbiotic relationship with them,” according to Ashutosh Mangalam, PhD, an assistant professor of pathology at the University of Iowa. “The human host provides them with food and space, and the bacteria help to digest food and extract energy from foods that we cannot digest,” he told Neurology Advisor. Clues to the role of the gut microbiota in the development of a healthy immune system have been revealed in various research initiatives, especially in a rodent study in which mice were raised in a germ-free facility.^2,3 Their immune systems were initially impaired but were restored via colonization of gut microbes from normal mice.

Though the precise mechanisms are not yet clear, the current hypothesis is that “gut microbiota regulate or influence our immune system either directly or indirectly by producing small chemicals that train our immune system to deal with different kind of pathogens,” he explained. Because multiple sclerosis (MS) is an immune-mediated disease, it has been proposed that the gut microbiome may be an important environmental risk factor for the disease, and findings of several recent studies highlight its potential role in MS pathogenesis.

A study by a multidisciplinary team at the Mayo Clinic in Rochester, Minn., found that patients with relapsing remitting MS had altered fecal microbiota compared to matched healthy controls, which supports the hypothesis that patients with MS have microbial dysbiosis.⁴ Gut microbiota contribute to the development and regulation of effector and regulator cells, and while there is balance between the 2 cell types and the gut microbiota in healthy individuals, numerous factors can disturb this balance.  Although researchers are still trying to pinpoint these, they can “speculate that factors such as stress, food habits, too much cleanliness, sunlight, smoking, or certain infections, for example, can cause a shift in this balance,” leading to an increase in harmful bacteria or a decrease in beneficial bacteria, said Dr Mangalam, who co-authored the study. “Any one of these factors – either alone or in combination – might be the reason for altered microbiota in MS,” he noted.

A new study published in the European Journal of Neurology found similar results in a pediatric MS population, as did another recent investigation involving an adult Japanese sample, with significant differences found between MS patients and healthy controls in 21 species “comprised primarily of clostridial species belonging to Clostridia clusters XIVa and IV and Bacteroidetes,” according to the paper.^5,6 None “of the clostridial species that were significantly reduced in the gut microbiota of patients with MS overlapped with other spore-forming clostridial species capable of inducing colonic regulatory T cells (Treg), which prevent autoimmunity and allergies,” wrote the authors. “This suggests that many of the clostridial species associated with MS might be distinct from those broadly associated with autoimmune conditions,” they concluded.

Other new research notes that the gut microbiota metabolizes dietary tryptophan into aryl hydrocarbon receptor (AHR) agonists that act on astrocytes to limit inflammation of the central nervous system. However, the researchers found that individuals with MS have reduced levels of circulating AHR.⁷

Taken together, these findings hold promise for the ultimate development of MS treatment methods that target the gut microbiome, but it is “exceedingly complex, and research is only just beginning, so there are no established or proven treatment methods,” Dean Wingerchuk, MD, FRCP(C), a professor of neurology and director of the Division of MS and Autoimmune Neurology at the Mayo Clinic in Scottsdale, Arizona, told Neurology Advisor. Based on current evidence, dietary approaches may be one way to correct dysbiosis in people with MS, which may result in more favorable immune responses that maintain remission. The use of probiotics and fecal transplantion are additional avenues for exploration, though much more research will be required first. The findings of altered microbiota in pediatric MS “raise the possibility that early-life maintenance of a normal microbiome could play a role in disease prevention, though it is not clear how to achieve this in an effective and sustainable way,” he said. According to Dr Mangalam, gut bacteria-based drugs – or Brugs – may be available in the near future to restore normal gut flora in the treatment of MS patients.

The next steps in this line of inquiry will involve piecing together the prolific ongoing findings with an eye toward the development of strategies to correct microbial dysbiosis for MS prevention and treatment.  

References

1. Shreiner AB, Kao JY, Young VB. The gut microbiome in health and in disease. Curr Opin Gastroenterol. 2015; 31(1): 69–75.
2. Wu HS, Wu E. The role of gut microbiota in immune homeostasis and autoimmunity. Gut Microbes. 2012; 3(1): 4–14.
3. Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol. 2009; 9:313-323
4. 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.
5. Tremlett H, Fadrosh DW, Faruqi AA, et al. Gut microbiota in early pediatric multiple sclerosis: a case-control study. Eur J Neurol. 2016; 23(8):1308-21.
6. Miyake S, Kim S, Suda W, et al. Dysbiosis in the Gut Microbiota of Patients with Multiple Sclerosis, with a Striking Depletion of Species Belonging to Clostridia XIVa and IV Clusters. PLOS ONE. 2016; doi:10.1371/journal.pone.0137429
7. Rothhammer V, Mascanfroni ID, Bunse L, et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med. 2016; 22:586–597.