Engineered probiotic found to ease symptoms in mouse model of MS

These probiotics have the potential to help people with autoimmune diseases

by Lindsey Shapiro, PhD | August 16, 2023

A lab-engineered probiotic, composed of live bacteria that colonize the gut, was able to ease signs of disease in a mouse model of multiple sclerosis (MS), according to recent research.

After discovering that a metabolite called lactate could activate immune signaling pathways that help to curb autoimmunity, scientists specifically engineered the bacteria to release it.

With further study, scientists believe that these specialized probiotics could be beneficial for patients living with many different autoimmune diseases, including MS.

“Engineered probiotics could revolutionize the way we treat chronic diseases,” Francisco Quintana, PhD, Harvard professor of neurology, member of the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital in Boston, and the study’s lead author, said in a university news story.

“By using synthetic biology to get probiotic bacteria to produce specific compounds relevant to diseases, we can take the benefits of probiotics and amp them up to the max,” Quintana added.

The study, “Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells,” was published in the journal Nature.

In MS, an overactive immune system causes damage to healthy tissue in the brain and spinal cord, leading to neurodegeneration.

Dendritic cells (DCs) are important for regulating immune function, including the activity of self-reactive T-cells that are implicated in diseases like MS, positioning them as potential therapeutic targets.

In this study, Harvard scientists identified a signaling pathway in DCs that ultimately inhibits self-attacking T-cells. A protein called HIF-1-alpha (HIF-1a) was critical for this process.

Moreover, HIF-1a could be activated by lactate, a metabolite produced in the body when food is being turned into energy that serves a number of different biological functions. Treatment of DCs with lactate significantly decreased the production of pro-inflammatory molecules in both CDs and T-cells.

“The mechanism we found is like a brake for the immune system,” Quintana said. “In most of us, it’s activated, but in people with autoimmune diseases, there are problems with this brake system, which means the body has no way to protect itself from its own immune system.”

Next, the scientists looked for a way to therapeutically activate this protective system.

The gut microbiome — the constellation of bacteria, fungi, and viruses that inhabit the gastrointestinal tract — can have significant influence on both immune and brain function, leading researchers to believe that targeted probiotics could be a promising approach.

Most readily available probiotics are mixtures of bacteria that are generally thought to be beneficial to the body. While these probiotics have shown anti-inflammatory effects, the team needed one with a more specific function.

Therefore, they modified a bacteria called Escherichia coli to cause it to produce lactate, in the hope that it would stimulate the anti-autoimmune functions of DCs.

Engineered probiotics could revolutionize the way we treat chronic diseases.

In a mouse model of MS, treatment with the probiotic eased clinical signs of disease and reduced the number of pro-inflammatory T-cells in the brain and intestines.

Notably, these benefits in the brain were observed even though the bacteria lived mainly in the gut and were not found in the bloodstream.

Additional experiments indicated that the probiotic likely activates protective signaling pathways in DCs of the intestines, in turn influencing the direct communication between cells in the gut and brain — a relationship that has come to light in recent years.

“We’ve learned in recent decades that the microbes of the gut have a significant impact on the central nervous system [brain and spinal cord],” Quintana said. “One of the reasons we focused on multiple sclerosis in this study was to determine whether we can leverage this effect in treating autoimmune diseases of the brain. The results suggest we can.”

Probiotics can also offer advantages relative to traditional medications, helping to maximize therapeutic benefit and avoid side effects.

Quintana noted that when medicines are taken, their levels peak in the bloodstream, then go back down. On the other hand, the live bacteria can keep producing lactate in the body, “which is essential when we consider lifelong diseases that require constant treatment,” he said.

Overall, the data indicate that “probiotics engineered to activate immunoregulatory signalling pathways could provide new tools for the clinical management of autoimmune and allergic disorders,” according to the team.

While more preclinical work will be needed, the scientists are optimistic that the probiotic could translate well into the clinic. Indeed, E. coli has already been safely tested in people.

Although this study focused on MS, the benefits of the probiotic could be harnessed to treat other diseases.

“The ability to use living cells as a source of medicine in the body has tremendous potential to make more personalized and precise therapies,” Quintana said.

“If these microbes living in the gut are powerful enough to influence inflammation in the brain, we’re confident we’ll be able to harness their power elsewhere as well,” he added.