Gut Inflammation Could Contribute to Multiple Sclerosis

The autoimmune condition multiple sclerosis (MS) is caused by immune cells attacking the myelin sheath that coats neurons in the brain and spinal cord. Myelin helps conduct brain signals, and in MS, damage to this transmission causes brain fog, vision problems, and mobility issues.

Genetic and environmental triggers are thought to contribute to MS. Recent data suggest that infection with the Epstein-Barr virus may play a significant role.¹ But some researchers are studying another potential contributor: the gut microbiome.

Patients with MS have changes in their gut microbiota.² Metabolites released from the gut microbiota shape the body’s immune responses, and in mice, changes in the gut microbiota accelerate the MS-like condition experimental autoimmune encephalomyelitis (EAE). However, it had not been clear how signals from the gut could influence autoimmune attack in the brain.

Now, in a new study published in Science Immunology, researchers found that gut cells that interact directly with the microbiota can boost the production of immune cells that then migrate to the spinal cord in mice.³ The finding provides the missing link between the gut and MS.

“Increasing evidence shows that the gut microbiota influences neurological diseases such as Parkinson’s, Alzheimer’s, and MS,” said Tomohisa Sujino, a biologist at Keio University and coauthor of the new study, in a statement. “We were keen to identify how gut immune responses contribute to neuroinflammatory diseases.”

Tracking the Path of Inflammation in the Gut

The researchers took intestinal biopsies from mice with EAE and patients with MS, and they analyzed the samples using single-cell RNA sequencing. They found that a subset of T helper cells called Th17 cells, which are pro-inflammatory, were found in higher numbers in the guts of MS patients and mice with EAE as compared with healthy controls.

The researchers also saw that intestinal epithelial cells (IECs) in the guts of EAE mice had elevated activity in their antigen presentation pathways as compared to healthy control mice. This is a key process in ramping up immune activity. IECs line the gut and are directly exposed to metabolites released by the microbiota. When the researchers deleted glycoproteins involved in antigen presentation, called major histocompatibility complex class II, from the mice IECs, disease severity and inflammation decreased in their EAE mice.

Certain T cells, called CD4+ cells, can adopt pro-inflammatory or anti-inflammatory states depending on their surrounding environment. The researchers showed that IECs could drive CD4+ cells down a pro-inflammatory pathway via antigen presentation.

Pathogenic Cells Migrate to the Spinal Cord

In a final set of experiments, the authors tracked what happened to these riled-up immune cells. Would they stay in the gut or contribute to a brain-based disease?

The team used transgenic mice with Th17 cells that they could track precisely in the body. The cells emitted red fluorescence when exposed to violet light. They saw that some of these cells migrated from the intestine to the spinal cord, where the cells stimulated brain inflammation. While they are similar, EAE and MS are not the same disease, and the authors only showed this immune cell migration in mice. But the study still provides evidence of a potential mechanism by which changes in the gut could drive autoimmune neuroinflammatory disease.

“While current therapies for MS often target B cells, our study highlights the gut as an important therapeutic site. Modulating intestinal microbiota or antigen-presenting activity of IECs represents new approaches to treating autoimmune neurological diseases,” said Shohei Suzuki, a study coauthor and a gastroenterologist at Keio University, in the statement.