In an astonishing new study published in Nature today, researchers at the Max Planck Institute of Neurobiology in Martinsried in Munich, Germany say they have found evidence that suggests multiple sclerosis (MS) is triggered by natural intestinal flora, the so-called friendly bacteria that reside in the gut. They found genetically engineered mice with normal gut bacteria developed brain inflammation similar to MS in humans. They say the bacteria first activated the immune T-cells, then the B-cells, which resulted in an attack on the myelin layer in the brain. The same could happen in humans with a corresponding genetic predisposition, they say.
The human gut is home to some 100 billion bacteria from 2,000 different species, comprising 10 to 100 times more genes than in our entire genome. Some scientists refer to this world within a world as an “extended self”.
These microorganisms not only help us digest food, they are also essential for gut development. And they also play a role in promoting autoimmune disease, say the Max Planck researchers.
MS is an autoimmune disorder where the body’s own immune system attacks and damages the myelin sheath that insulates the axons which are like the “cabling” that connects nerve cells or neurons to one another. The term multiple sclerosis refers to the numerous scars that result from loss of myelin: particularly in the white matter of the brain and spinal cord, most of which is made of myelin.
Although we know quite a lot about the mechanisms of myelin loss, we know very little about the causes of MS. Some have said it is genetic, others that it is triggered by environmental factors like infections, and many say it’s probably a bit of both.
In their background information, the Max Planck researchers refer to previous research that shows active MS lesions have “inflammatory changes suggestive of a combined attack by autoreactive T and B lymphocytes against brain white matter.” (Lymphocytes are the white blood cells of the immune system).
They explain that T and B cells are normally innocuous members of a healthy immune system, but it appears something triggers them to become “autoaggressive”, and the cause is commonly assumed to be environmental, with infection (ie an external pathogen) being the most common reason given.
So, they decided to investigate further using a new type of laboratory mice that have been genetically engineered to spontaneously develop relapsing-remitting autoimmune brain inflammation that is similar to MS in humans.
They found that the gut microorganisms that are necessary to keep the gut and the body healthy (the so-called “commensal gut flora”) were essential to triggering the immune processes that led to “a relapsing-remitting autoimmune disease driven by myelin-specific CD4+ T cells”.
They discovered this by allowing some of the genetically modifed mice to continue with their normal gut bacteria intact, while removing the intestinal flora in the others and keeping them under sterile conditions.
In time, the mice that kept their gut bacteria developed MS-like symptoms.
But the mice that had their gut bacteria removed remained healthy, despite their genetic predisposition to MS. They also had fewer T-cells in their gut, their spleens produced fewer inflammatory substances like cytokines, and their B-cells produced few if any antibodies against myelin.
However, when they then inoculated these mice with normal gut flora, their T-cells and B-cells increased, as did their cytokine and antibody production, and they eventually developed symptoms and fell ill.
In a final experiment the researchers also found that a protein called MOG has to be present for the immune cells to be able to trigger the autoimmune process:
“We show further that recruitment and activation of autoantibody-producing B cells from the endogenous immune repertoire depends on availability of the target autoantigen, myelin oligodendrocyte glycoprotein (MOG), and commensal microbiota.”
“Our observations identify a sequence of events triggering organ-specific autoimmune disease and these processes may offer novel therapeutic targets,” concluded the researchers.
Senior author Gurumoorthy Krishnamoorthy told the press:
“It appears that the immune system is activated in two stages: to begin, the T cells in the lymph vessels of the intestinal tract become active and proliferate. Together with the surface proteins of the myelin layer, these then stimulate the B cells to form pathogenic antibodies.”
“Both processes trigger inflammatory reactions in the brain which progressively destroy the myelin layer – a process that is very similar to the way multiple sclerosis develops in humans.”
Krishnamoorthy and colleagues are convinced that the gut flora can also trigger an overreaction of the immune system against the myelin in people who are genetically predisposed to MS.
This study indicates that nutrition may play a key role in the development of MS, since diet largely determines the types of bacteria that colonize the gut.
The researchers suggest the recent increase in MS in Asia could be because of changes in eating habits.
It is not clear exactly which bacteria are involved in the development of MS. The researchers propose the clostridiums, because they have direct contact with the wall of the gut, are naturally present in the flora, and could be a trigger for T-cell activation in people with a genetic predisposition.
The team now wants to investigate the complete microbial genomes of people with MS and compare them to people without MS.
Written by Catharine Paddock PhD