Previous research has found that multiple sclerosis (MS) patients may have a specific microbial signature in their gut microbiota that could impact disease pathogenesis. However, it is not known to what extent structural and functional changes in the gut microbiota are primary contributors to MS pathogenesis and which underlying mechanisms are involved.
A new study, led by Dr. Sergio Baranzini from the Department of Neurology at the University of California San Francisco (USA), has found that specific gut bacteria from multiple sclerosis patients regulate immune responses and exacerbate MS-like symptoms in mice.
The researchers used 16S ribosomal ribonucleic acid (rRNA) gene sequencing of stool samples from 71 untreated relapsing-remitting MS patients and 71 healthy controls.
Although they did not find shifts in the gut microbiota structure, specific bacterial taxa were significantly associated with MS. Both Akkermansia muciniphila and Acinetobacter calcoaceticus were increased in MS patients. Although the role of A. muciniphila has been extensively studied in the context of metabolism, little is known about its role in regulating immune responses and these results are in agreement with previous research supporting A. muciniphila as a bacterial species that exacerbates inflammation during infection. In contrast, MS patients exhibited decreased levels of Parabacteroides distasonis.
When researchers stimulated peripheral blood mononuclear cells (PBMCs) -consisting of lymphocytes (T cells, B cells and natural killer cells) and monocytes- from MS patients or healthy controls using self bacterial extracts isolated from the stool samples, they reported that PBMCs from MS patients could not differentiate to CD25+FoxP3+ T regulatory (Treg) cell populations; these are immunosuppressive and downregulate induction and proliferation of effector T cells. Altogether, these findings show that MS patient gut microbiota alters self-Treg differentiation despite similar bacterial community structure. To further assess the role of the gut microbiota in regulating immune responses, the researchers evaluated T lymphocyte differentiation and proliferation under different stimulating conditions in an in vitro model system by exposing PBMCs from healthy donors to MS-associated bacterial species. Extracts from A. calcoaceticus inhibited Treg differentiation and stimulated pro-inflammatory T helper 1 (Th1) lymphocyte differentiation in vitro. A. muciniphila also increased Th1 lymphocyte differentiation in vitro, but in a more pronounced way. Besides this, P. distasonis skewed in vitro T lymphocytes toward anti-inflammatory IL-10-expressing human CD4+CD25+T cells and IL-10+FoxP3+ Treg cells with strong immunoregulatory properties. Both increased A. calcoaceticus and A. muciniphila and decreased P. distasonis in MS patients contributed to the creation of a pro-inflammatory effector immune profile.
Monocolonization of germ-free (GF) mice with single species (either A. calcoaceticus, A. muciniphila or P. distasonis) also mediated T lymphocyte differentiation in vivo (in cervical lymph nodes, mesenteric lymph nodes and spleens), thereby supporting in vitro data.
Finally, gut microbiota transplants from MS patients into GF mice led to more severe symptoms of experimental autoimmune encephalomyelitis -a MS-like autoimmune disease- and reduced proportions of interleukin (IL)-10+ Tregs in mouse mesenteric lymph nodes, compared with gut microbiota transplants from healthy controls.
In conclusion, this study has identified specific human gut bacteria involved in modulating MS-linked immune responses both in vitro and in vivo, and contributing to symptoms of experimental autoimmune encephalomyelitis in mice.
Another recent study, led by Dr. Hartmut Wekerle from the Max Planck Institute of Neurobiology in Martinsried (Germany) and Munich Cluster for Systems Neurology at Ludwig-Maximillians University in Munich (Germany), has found that MS-derived gut microbiota may elicit a MS-like autoimmune disease in mice through immune and metabolic pathways.
The researchers compared, by 16S rRNA and metagenomics shotgun sequencing, the gut microbial composition of 34 monozygotic twin pairs discordant for MS -in each pair, one twin had clinically definite MS, and the other was unaffected.
As reported in the study mentioned above, there were no differences in the overall gut microbiota composition between twin pairs, although there was a significant increase in some bacteria—most notably Akkermansia muciniphila—in untreated twins with MS.
MS twin-derived gut microbiota led to a higher incidence of autoimmunity when it was transferred to a transgenic mouse model of spontaneous brain autoimmunity, compared with the healthy twin-derived gut microbiota. These results suggest that the gut microbiota is a factor contributing to the severity and course of MS. When studying which factor made MS-derived gut microbiota more pathogenic, the researchers found that the most significant difference in mice colonized with gut microbiota from MS twins was a reduced abundance of the genus Sutterella compared with recipients of gut microbiota from healthy twins. Several metabolic pathways (pyruvate fermentation, L-tyrosine biosynthesis, and chondroitin sulfate degradation) were also altered in mice that received faecal samples from MS individuals; these results show that metabolic factors should also be considered in MS disease risk.
Finally, immune cells from mouse recipients of MS-twin samples produced less IL-10 than immune cells from mice colonized with healthy-twin samples. When IL-10 was neutralized in mice colonized with healthy-twin faecal samples, disease incidence increased; this suggests IL-10 may have a protective role in central nervous system autoimmunity.
In conclusion, this study shows that MS-derived gut microbiota increases the incidence of MS-like symptoms in mice compared with healthy-individual-derived gut microbiota.
On the whole, both studies suggest that the gut microbiota has a role in the development of MS. Further studies are needed in order to investigate potential gut microbiota-based therapeutics in MS.
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. doi: 10.1073/pnas.1711233114.
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. doi: 10.1073/pnas.1711235114.
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