Multiple sclerosis is an autoimmune disease of the central nervous system, which affects more than 2,9 million people worldwide and for which currently there is no cure.

In multiple sclerosis, the immune system attacks myelin, damaging it and thus compromising neural transmission.

In relapsing-remitting multiple sclerosis, which is the most common form of the disease, phases of immune system activation, inflammation and myelin damage (relapse) alternate with phases of inflammation resolution and repair or deposition of new myelin (remission). During remission phases, neurological symptoms are mild or absent.  

A study published this year in Cell Reports Medicine by the team of Dr. Marika Falcone, group leader of the Autoimmune Pathogenesis lab at IRCCS San Raffaele Hospital, investigated the role of secondary biliary acids, produced by gut microbiota, in mitigating inflammation in relapsing-remitting multiple sclerosis.

In observance of World Multiple Sclerosis Day (May 30 2025), we met with Dr. Falcone to discuss the study and new perspectives on disease pathogenesis and treatments.

The role of microbiota in the modulation of the immune system

Gut microbiota is a set of bacteria, fungi, viruses and protozoa populating the intestine, whose health is crucial for the entire organism as shown by substantial research evidence of the last 20 years.

Around 2010, research began to study the role of gut microbiota in modulating the activity of the immune system, both in physiology and pathologies like infections, cancer and autoimmune diseases.

For years, Dr. Falcone’s research group has been studying the correlation between alterations of gut microbiota and immune system dysfunctions at the basis of autoimmune diseases, including multiple sclerosis.

“Back in 2017, we had already published a study that showed the correlation between alterations of gut microbiota and increased frequency of pro-inflammatory T lymphocytes in the gut of patients with multiple sclerosis”, tells Dr. Marika Falcone. “This increased frequency of pro-inflammatory T lymphocytes was associated with increased disease activity- that is, with the appearance of new neurological signs and new active lesions identified by magnetic resonance”, continues the researcher.

The new study

In their recently published paper in Cell Reports Medicine, Dr. Falcone and her lab continued to investigate the relationship between altered gut microbiota and the immune as well as the inflammatory profile in patients with relapsing-remitting multiple sclerosis. They observed a reduced presence of bacteria that released the enzymes producing secondary biliary acids in the gut of examined patients.

Secondary biliary acids derive from the metabolism of biliary acids, which are produced by liver to emulsify fats. Recently, it has been found that secondary biliary acids, in addition to emulsifying fats, play a crucial immune-regulatory role: they promote the differentiation of regulatory T lymphocytes at the expense of pro-inflammatory T cells.

The authors showed that in the gut of patients with relapsing-remitting multiple sclerosis the concentration of secondary biliary acids (in particular, deoxycolic acid) was reduced and associated with a higher frequency of pro-inflammatory T lymphocytes.

The exposure of naïve T lymphocytes to the microbiota of patients resulted in the differentiation of pro-inflammatory T lymphocytes. “This observation indicates that microbiota alterations observed in these patients could directly cause the increased presence of pro-inflammatory T lymphocytes in the gut”, says Dr. Falcone.

Moreover, the administration of secondary biliary acids in a preclinical model of the disease resulted in the reduction of pro-inflammatory T cells and the increase of regulatory T cells in the gut. These improvements in the gut immune profile were accompanied by reduced overall inflammation and increased presence of regulatory T cells in the animal model.

Dr. Falcone adds: “Bacteria that produce secondary biliary acids thus seem to be important to prevent inflammation also at the level of the central nervous system. We are now working to confirm these results in additional preclinical models of the disease.”

Health of the nervous system depends also on the gut

But how do altered gut microbiota and subsequent immune dysfunctions impact the central nervous system?

“In animal models of the disease, it has been already shown that the activation of autoimmune T lymphocytes against myelin could occur at the gut level”, explains Dr. Falcone, who continues: “however, this has not been proven in humans yet”.

For this reason, Dr. Falcone’s team is working on a project that aims at studying the set of proteins, genes, and metabolites of the human gut microbiota:

“We have preliminary results indicating that gut viruses and bacteria have some components that are similar to myelin and can activate autoimmune T lymphocytes in the gut. We hypothesize that this phenomenon, associated with an inflammatory profile of the intestine, could cause the activation and acquisition of an inflammatory profile of T lymphocytes against myelin, which from the gut go to the central nervous system.”

In other words, if the gut is healthy, and has no sign of inflammation (defined as altered microbiota and immune cell profiles), activated T lymphocytes will take on an anti-inflammatory and protective role.

Instead, if the gut already shows signs of inflammation, due to altered microbiota or other factors, T lymphocyte activation will lead them to acquire a pro-inflammatory and autoimmune profile.

“However, these are just hypotheses that must be confirmed in humans”, explains the researcher. “Moreover, we cannot exclude that inflammatory mediators coming from the gut microbiota could directly act on the central nervous system that they reach via peripheral nerves”.

Prevention first

Nowadays immunosuppressors help to control symptoms of multiple sclerosis, but they present significant side effects, given that they need to be taken chronically.

For this reason, research aims at setting strategies to complement the use of available drugs, which include, for example, restoration of a balanced microbiota composition and an anti-inflammatory environment in the gut.

“The idea is to test the introduction of bacteria consortia that have anti-inflammatory action in patients’ gut, to help response to existing drugs and prevent or mitigate relapses in relapsing-remitting multiple sclerosis. However, it must be noted that gut microbiota is influenced not only by its composition, but also by environmental factors, such as the diet and physical exercise, as well as by genetics and numerous other factors that are too complex to keep under control”, explains Dr. Falcone.

In this context, primary prevention remains the most important strategy against multiple sclerosis.

In recent years, physicians have reported a significant increase in gut inflammation among the general population, mainly due to lifestyles, like an unbalanced diet (rich of animal fats and poor in fibers) and little physical exercise.

“We think that intestinal inflammation is diffused in the general population and that, in those subjects who are already genetically predisposed to multiple sclerosis and present a higher disease risk, an inflamed gut increases the probability of activation of autoimmune T lymphocytes in the gut”, comments Dr. Falcone.

Studying the activation of the immune system is fundamental to understanding disease pathogenesis and intervening early with available therapies, but research never goes in one direction.

“Indeed, I’m convinced that prevention in medicine is as important as therapy, and this is why it’s imperative to give the message that having a healthy lifestyle, by following balanced diets and practicing constant exercise, is indispensable to reduce and prevent the risk associated with numerous pathologies not only multiple sclerosis, that depend on the alterations of the microbiota,”, concludes Dr. Falcone.

Published on 30/05/2025