9th August 2023
Harvard researchers and collaborators have uncovered a novel biological pathway that quiets immune attacks that lead to damage to the central nervous system (brain and spinal cord) in multiple sclerosis. They have also found a way to manipulate this pathway by engineering an experimental probiotic to reduce inflammation in mice with an MS-like disease.
The idea of custom-engineering probiotics is an emerging strategy being tested in several disorders, including cancer. Further work will be needed to confirm and apply this finding to develop therapies for MS. This research, led by Francisco Quintana, PhD, was supported by several funders including the International Progressive MS Alliance.
This work focused on “dendritic cells,” which are key regulators of immune activity. These cells command other immune cells, determining what gets attacked as a foreign invader and what gets deemed harmless and ignored, such as the body’s own tissues. In immune-mediated disorders like MS, for some reason dendritic cells play a role in targeting the body’s own brain and spinal cord tissues.
Through a series of studies, the investigators found a key feedback mechanism inside dendritic cells that can limit their damaging activity.
- The team found that lactate, a substance produced by cells when food is turned into energy, is a driver of this feedback mechanism.
- They took advantage of recent knowledge pointing to the gut as a source of immune cells that damage the central nervous system and the potential of the bacteria that live in the gut (microbiome) to regulate these cells.
- The team manipulated harmless bacteria to have them produce lactate. These bacteria were fed to mice as a probiotic, and the bacteria produced lactate in the gut.
- The mice had less inflammation in the central nervous system than is typical of the mouse model of MS.
- Having too much lactate build up in the body can cause serious harm, so the team purposely engineered the probiotic to release lactate gradually rather than just feeding the mice lactate. (This experimental probiotic has not yet been tested in people and is not yet available.)
This innovative approach may have potential for developing new therapies for reducing immune activity in MS and in other immune-mediated and autoimmune disorders. Further work will be needed to confirm this approach and translate it into new treatments for people.
“Lactate limits CNS autoimmunity by stabilizing HIF-1a in dendritic cells,” by 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-Castro, 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, Jose M. Lora, Francisco J. Quintana, was published online in Nature on 9 August 2023.