Gut microbiota at a young age contribute to multiple sclerosis development in mice

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) in which both genetic and environmental factors (including age and microbial infections) can contribute to the dysregulation of immune tolerance. Although recent studies have suggested that alterations in the gut microbiota (dysbiosis) are related to MS, it is still unknown how gut dysbiosis impacts the onset and progression of MS.

A recent study, led by Dr. Kouichi Ito from the Department of Neurology at the Rutgers-Robert Wood Johnson Medical School (Piscataway, New Jersey), has found that gut microbiota dysbiosis is involved in the initiation and progression of MS during young adulthood in mice.

The researchers investigated the effects of age and gut dysbiosis on the development of MS in a model of genetically engineered mice that have a pre-disposition for this autoimmune disease. Humanized transgenic mice used in the experiments (called 3A6/DR2a transgenic mice) expressed MS-associated risk genes (MS-associated human histocompatibility leukocyte antigen (HLA)-DR2a and T-cell receptor (TCR) genes specific for MBP87-99/DR2a) that were derived from an MS patient.

In this animal model, spontaneous experimental autoimmune encephalomyelitis (EAE) developed most frequently between 5 and 8 weeks of age, whereas it could not be observed after 18 weeks of age. Besides this, both the development of myelin basic protein (MBP)-specific T cells -which are involved in the initiation of EAE- and their proliferation in response to the MBP antigen in the thymus and spleen was more vigorous during the 5- to 10-week-old period while significantly decreased in 21- to 35-week-old transgenic mice. These results indicate that adolescence and young adulthood (5-10 weeks of age) are the most risky period for the development of CNS autoimmunity in 3A6/DR2a transgenic mice.  

When genetically modified mice were grown in a germ-free environment, they did not develop EAE. However, when assessing how immune tolerance to MBP was interrupted during young adulthood in this MS animal model, the authors found that the induction of gut dysbiosis -which was attributed to expansion of enteric pathogenic bacteria such as Bacteroides vulgatus and decrease of bacteria that promote intestinal integrity and mucosal tolerance including Akkermansia muciniphila– through antibiotic administration exacerbated the development of spontaneous EAE during adolescence and young adulthood.

Mechanisms that took part in antibiotic-induced exacerbation of gut dysbiosis involved increased gut leakiness that resulted in the translocation of microbial products into systemic circulation including lipopolysaccharide (also known as endotoxin), which is the major component of the outer membrane of Gram-negative bacteria. Besides this, gut dysbiosis also up-regulated the expression of complement C3 in the spleen, which was correlated with anaphylatoxin C3a production -both complement factor C3 and C3a are involved in autoimmunity and inflammatory responses-. Finally, gut dysbiosis also led to a reduction of the development of Foxp3⁺ Treg cells -a subpopulation of T lymphocytes that maintain tolerance to self-antigens and prevent autoimmune disease by suppressing or downregulating induction and proliferation of effector T cells- and expression of anergy-related E3 ubiquitin ligase genes involved in protection from autoimmune diseases. On the whole, these data suggest that gut dysbiosis can induce gut barrier leakiness and complement activation in the periphery involving extra-gastrointestinal immune system, through modulation of genes that are common in autoiummune diseases, including multiple sclerosis.

Furthermore, high faecal IgM levels were associated with spontaneous EAE compared with non-EAE mice, which suggests that an increase in faecal IgM levels could be used as a marker of spontaneous EAE in transgenic mice. Besides this, an increase in immunological tolerance with aging suppressed EAE onset after late young adulthood in mice.

The study’s co-author and Director of the Rutgers-Robert Wood Johnson Centre for Multiple Sclerosis said in a news release: “The findings could have therapeutic implications on slowing down MS progression by manipulating gut bacteria.” The press release specifies: “Future research could lead to the elimination of harmful types of gut bacteria that were shown to cause MS progression, or conversely enhance beneficial bacteria that protects from disease progression”.

In conclusion, this study suggests that gut dysbiosis may play a pathological role in the initiation and progression of MS during young adulthood in a mouse model. This is the first study elucidating mechanisms involved in how the gut microbiota may modulate MS development and further research is needed in order to elucidate its clinical impact.

Reference:

Yadav SK, Boppana S, Ito N, et al. Gut dysbiosis breaks immunological tolerance toward the central nervous system during young adulthood. Proc Natl Acad Sci U S A. 2017; 114(44):E9318-27.