People with MS have a specific microbial profile in the gut, but how do gut bacteria influence the progression of the disease?
An estimated 2.3 million people around the world are affected by multiple sclerosis (MS), which is an autoimmune disease characterized by a "misfiring" of the immune system - a process in which myelin, the insulation around nerves, is perceived as a "foreign body" and erroneously attacked.
Unfortunately, despite its high prevalence, little is known about what causes MS and there is currently no cure. Treatments are largely symptomatic, aimed at facilitating the management of the condition.
Previous research has pointed out that people diagnosed with MS have a specific gut microbial profile, showing that some bacteria are more abundant in the guts of people with MS while the levels of other bacteria are unusually low.
A new study from the University of California, San Francisco, led by Dr. Sergio Baranzini, went one step further and sought to investigate what the significance of some of those microbes is to the immune system.
Dr. Egle Cekanaviciute, another investigator involved with the study, explains that she and her colleagues were interested in going beyond just ascertaining an association.
"A lot of microbiome studies say, 'These bacteria are increased in patients with a disease, and those bacteria are reduced.' And then they stop. We wanted to know more: should we care about the ones that are increased because they are harmful or the ones that are decreased because perhaps they are helpful?"
Dr. Egle Cekanaviciute
The researchers' findings are now published in the online issue of PNAS.
Gut microbiome 'talks' to immune system
As part of the study, the researchers analyzed the gut microbiomes of 71 people who had been diagnosed with MS. They did the same for 71 healthy people with no MS history (the controls).
After pinpointing which microbes were more present in the guts of people with MS, and which ones tended to be present to a lesser degree, the scientists used in vitro experiments to try to identify the specific roles of those microbes.
First, they tested whether these microbes could interact with human immune system cells to render them pro- or anti-inflammatory. The team noted that Akkermansia muciniphila and Acinetobacter calcoaceticus, which were commonly found in the guts of people with MS, prompted a pro-inflammatory response.
At the same time, Parabacteroides distasonis - which is found at abnormally low levels in the systems of people with an MS diagnosis - determined immune-regulatory responses.
Next, to try to understand the role that these bacteria play when interacting with the whole immune system, the researchers carried out tests in mice.
The results were similar: A. muciniphila and A. calcoaceticus stimulated an inflammatory response, while P. distasonis led to an anti-inflammatory effect.
From here, they wanted to see how an MS-specific gut microbiome in its totality might influence neurodegeneration. Using mice in which MS had been induced artificially, they performed fecal microbiota transplants and studied the effect of the microbe levels on the animals' system.
It was found that the transplanted MS-specific microbiome led to the loss of important immune-regulatory cells. It also facilitated neurodegeneration, which, the team suggested, may point to a causal link between the gut microbiome and the development of MS.
The researchers told Medical News Today that, to their knowledge, this is the first study to look at the function of gut microbiota both in vitro and in vivo. Yet they acknowledge that they faced some limitations, including the restrictions of RNA sequencing, a technique they used to identify relevant bacteria.
"This is the first study in MS," explained Dr. Baranzini, "that provides mechanistic (in vitro and in vivo) information on microbiota differences. One limitation is that the [RNA] sequencing is only at 16S resolution, thus we cannot identify every bacteria. Also, larger studies are needed to evaluate heterogeneity and eliminate confounders."
Other important limitations that will need to be addressed in the future, the scientists explained for MNT, are to do with the specific interaction between gut bacteria and cells of the immune system.
As Dr. Cekanaviciute told us, "[A]lthough we have shown that immune cells respond to different bacteria by becoming either more pro-inflammatory or more regulatory, we don't know exactly how the bacteria interact with the immune cells."
'On the right track' for better treatment
These findings are reinforced by another study whose results are also published in the online issue of PNAS. This second study - conducted by researchers at the Max Planck Institutes in Germany and to which Drs. Cekanaviciute and Baranzini also contributed - had very similar findings.
It noted that transplants of MS-specific microbiomes aggravated MS symptoms in laboratory mice in which the disease had been induced.
"Two different groups, using two separate cohorts of patients and controls, and two distinct mouse models of the disease, saw very similar results. This is very promising evidence that we're on the right track," explains Dr. Cekanaviciute.
The scientists say that, while they do not suggest that the gut microbiome is the sole culprit in the case of MS, it may play an important role in the evolution of the disease.
"To be clear, we don't think the microbiome is the only trigger of MS. But it looks like these microbes could be making the disease progression worse or better - pushing someone with genetic predisposition across the threshold into disease or keeping them safe," says Dr. Cekanaviciute.
Dr. Baranzini suggests that the studies' findings, aided by further research, may help scientists to devise better, more effective MS therapies. He told MNT that future treatments for MS may well consider fecal transplants from healthy individuals. "One could speculate that transplanting fecal microbiota from healthy donors may ameliorate [the] disease," he suggested.
"The microbiome is very malleable. You could relatively easily change it in an adult who has MS or is susceptible - something you cannot do with their genetics. This is not a magical approach, but it is hopeful," he says.
Dr. Cekanaviciute also added that, in the future, "studying the functions of specific bacteria that are reduced in MS patients may help identify specific bacterial compounds that are beneficial and could later be used to design new therapies."