A combination of two intestinal bacteria significantly exacerbated symptoms in a mouse model of multiple sclerosis (MS), researchers at the RIKEN Center for Integrative Medical Sciences (IMS) in Yokohama, Japan, reported in a study by published in the August 26, 2020, issue of Nature.
The two specific gut bacteria were demonstrated to enhance synergistically the activity of a subset of CD4+ T lymphocytes that attack the myelin sheath lining brain and spinal cord neurons, which may have implications for treating MS and other inflammatory autoimmune diseases.
Demyelination affects how rapidly neurons communicate with each other and with muscles, leading to the characteristic symptoms of MS, including numbness, muscular weakness, tremors and immobility.
"MS remains essentially incurable, with only symptomatic treatments being available, such as steroids to control inflammation," said study leader Hiroshi Ohno, team leader of the Laboratory for Intestinal Ecosystem at RIKEN IMS.
"Although I am an intestinal immunologist and not a specialist in MS, I firmly believe that more effective causal therapies are needed for MS," Ohno told BioWorld Science.
Gut microorganisms are known to affect MS symptoms, but exactly how they affect brain and spinal cord myelin has remained unknown, prompting Ohno and his team to investigate this connection in mouse models of MS.
These mice exhibit similar spinal cord demyelination to that due to autoimmune attacks by the T helper subset producing IL-17A (Th17).
"IL-17A is a strong inducer of inflammation, which is important in protecting against extracellular pathogen infections such as bacteria and fungi, but sometimes the cytokine is also involved in autoimmune inflammation."
In the MS mouse models, ampicillin treatment was shown to reduce demyelination and prevent the activation of this particular Th17 cell subset.
Of note, "we found that only ampicillin treatment selectively reduced the activity of the T cells attacking the protein, myelin oligodendrocyte glycoprotein [MOG], which helps myelin to adhere to neurons," explained Ohno.
The researchers then confirmed this by taking immune cells from the small intestines and other regions and measuring cytokine production in the presence of MOG.
This research showed that MOG production was only reduced by ampicillin and only in T cells from the small intestine, establishing that small intestinal microorganisms activate MOG-specific T cells, which then attack myelin.
The researchers then had to determine which bacteria were responsible and, since only ampicillin reduced symptoms in the mouse models, they looked for bacteria that were almost completely eradicated only in ampicillin-treated mice.
New bacterial strain
They identified a new bacterial strain, OTU002, "which is a member of the family Erysipelotrichaceae and the most resembled genus is Allobaculum, but belongs to a new genus that has not yet been officially reported," said Ohno.
The RIKEN IMS team then examined mice that lacked all bacteria except OTU002, to confirm whether OTU002 was responsible for MS symptoms.
These mice also had significantly more severe symptoms than those seen in germ-free mice, which rarely have symptoms, demonstrating that OTU002 was indeed responsible for exacerbating MS symptoms.
However, symptoms in the OTU002-only mice were less severe than in the normal controls, suggesting the involvement of another microbe possibly cross-reacting with MOG-specific Th17 cells by mimicking the region on MOG recognized by Th17 cells.
Shotgun DNA sequencing of the small intestinal microbiome revealed that a protein expressed by Lactobacillus reuteri contained a region similar to MOG, which weakly activated MOG-specific T cells.
MS symptoms in mice with joint L. reuteri and OTU002 colonization were approximately twice more severe than those in OTU002-only mice and as severe as those in the original model mice, suggesting the two bacteria work synergistically to worsen symptoms.
"Other studies have focused on fecal microbes, or a single microbe, in MS patients or in model mice," said study lead author, RIKEN IMS research scientist Eiji Miyauchi.
"Our findings stress the need to consider the synergistic effects of intestinal microbes on autoimmune diseases and inspire research into the development of more effective MS treatments," said Miyauchi.
Moreover, while these findings were made in mice, "OTU0002-like bacteria do exist in human feces, so in terms of antigen-mimicking bacteria, we need to investigate these for human MS self-antigens," said Ohno.
In future, "it may be possible to prevent or cure MS based on the control of gut microbiota, and possibly other inflammatory autoimmune diseases."
"For example, gut microbiota have also been proposed to be involved in other autoimmune diseases, such as rheumatoid arthritis and type 1 diabetes, and could have relevance in these diseases.
"We will continue to study both MS and type 1 diabetes, and other allergic diseases that have been reportedly associated with gut microbiota." (Miyauchi, E. et al. Nature 2020, Advanced publication).