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At a glance:
- Engineered probiotic bacteria suppressed autoimmunity in the brains of mice with a condition similar to MS.
- The engineered bacteria release a substance to modulate the activity of dendritic cells, which rein in the activity of other immune cells to prevent autoimmunity.
- The researchers say that if affirmed in future studies, the approach could be adapted to treat an array of autoimmune conditions.
Harvard Medical School researchers at Brigham and Women’s Hospital have designed a probiotic to suppress autoimmunity in the brain, a condition that occurs when the immune system attacks the cells of the central nervous system.
The work, conducted in mice, is described Aug. 9 in Nature.
Autoimmunity in the brain is at the core of several neurodegenerative diseases, including multiple sclerosis. In a new study, researchers demonstrated the treatment’s potential using preclinical models of these diseases, finding that the technique offered a more precise way to target brain inflammation, while minimizing negative side effects compared with standard therapies.
“Engineered probiotics could revolutionize the way we treat chronic diseases,” said study lead author Francisco Quintana, HMS professor of neurology and a member of the Ann Romney Center for Neurologic Diseases at Brigham Women’s.
“When a drug is taken, its concentration in the bloodstream peaks after the initial dose, but then its levels go down. However, if we can use living microbes to produce medicine from within the body, they can keep producing the active compound as needed, which is essential when we consider lifelong diseases that require constant treatment.”
Autoimmune diseases affect between 5 and 8 percent of the U.S. population. Despite their prevalence, there are limited treatment options for most of these conditions. Autoimmune diseases that affect the brain, such as MS, are particularly challenging to treat because many pharmacological therapies cannot get through the blood-brain barrier, a protective network of cells that filters out many blood-borne substances to shield the brain from toxins and pathogens.
Looking for new ways to treat autoimmune diseases, the researchers studied dendritic cells, a type of immune cell that is abundant in the gastrointestinal tract and in the spaces around the brain. These cells help control the rest of the immune system, but scientists don’t yet understand their role in autoimmune diseases. Analyzing dendritic cells in the central nervous system of mice, the researchers identified a biochemical pathway dendritic cells use to stop other immune cells from attacking the body.
“The mechanism we found is like a brake for the immune system,” said Quintana. “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.”
The researchers also found that this biochemical brake can be activated with lactate, a molecule involved in many metabolic processes. Next, the researchers genetically engineered probiotic bacteria to produce lactate.
“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 said.
The team tested the designer probiotic in mice with a disease closely resembling MS and found that even though the bacteria live in the gut, they reduced the effects of the disease in the brain. The scientists did not detect the bacteria in the bloodstream of the mice, suggesting that the effect they observed was a result of biochemical signaling between cells in the gut and in the brain.
“We’ve learned in recent decades that the microbes of the gut have a significant impact on the central nervous system,” said Quintana. “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.”
The researchers caution that mice are not people, and the findings remain to be replicated in larger models and, eventually, in humans. But the researchers said they are optimistic the approach could be translated into the clinic for human use because the strain of bacteria they used to create their probiotic has already been tested in people.
The team is also working to modify the approach for autoimmune diseases that affect other parts of the body, particularly gut diseases like inflammatory bowel syndrome.
“The ability to use living cells as a source of medicine in the body has tremendous potential to make more personalized and precise therapies,” said Quintana. “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.”
Authorship, funding, disclosures
Additional authors included Liliana M. Sanmarco, Joseph M. Rone, Carolina M. Polonio, Gonzalo Fernandez Lahore, Federico Giovannoni, Kylynne Ferrara, Cristina Gutierrez-Vazquez, Ning Li, Anna Sokolovska, Agustin Plasencia, Camilo Faust Akl, Payal Nanda, Evelin S. Heck, Zhaorong Li, Hong-Gyun Lee, Chun-Cheih Chao, Claudia M. Rejano-Gordillo, Pedro H. Fonseca-Castro1, Tomer Illouz, Mathias Linnerbauer, Jessica E. Kenison, Rocky M. Barilla, Daniel Farrenkopf, Nikolas A. Stevens, Gavin Piester, Elizabeth N. Chung, Lucas Dailey, Vijay K. Kuchroo, David Hava, Michael A. Wheeler, Clary Clish, Roni Nowarski, Eduardo Balsa, and Jose M. Lora.
This study was supported by grants from the National Institutes of Health (NS102807, ES02530, ES029136, AI126880, 1K99NS114111, F32NS101790, T32CA207201), the Multiple Sclerosis Society (RG4111A1 and JF2161-A-5), the American Cancer Society (RSG-14-198-01-LIB), the International Progressive MS Alliance (PA-160408459), the German Research Foundation (CRC/TRR167 “NeuroMac.”), the Swedish Research Council (2021-06735), and the National Research Foundation of Korea (2021R1A6A3A14039088). Further support was provided by fellowships from FAPESP BEPE (2019/13731-0), the European Molecular Biology Organization (ALTF 610-2017 and ALTF: 1009-2021), and the Ministry of Science and Technology, Taiwan (104-2917-I-564-024).
Ning Li, Anna Sokolovska, David Hava, and Jose M. Lora were employees of Synlogic Therapeutics during the performance of some of these studies. Additional authors in this manuscript declare no competing financial interests.
