ACTRIMS 2024: Molecule made by gut bacteria seen to ease MS in mice
Indole 3-lactate supplement 'a potentially safe new remyelination agent'
Supplements of indole 3-lactate (ILA), a molecule made by gut bacteria, significantly reduced disease severity and promoted myelin repair in mouse models of multiple sclerosis (MS).
That’s according to new findings presented by Larissa Jank, PhD, a postdoctoral researcher at Johns Hopkins University, at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2024, held Feb. 29-March 2 in Florida and virtually.
“Our results imply that ILA could be a potentially safe new remyelination agent,” Jank said. “It might be particularly interesting to administer it in a personalized medicine approach where we can identify … patients with particularly low ILA levels and select [them] for supplementation.”
Jank’s talk was titled “Restoring the Multiple Sclerosis Associated Imbalance of Gut Indole Metabolites Promotes Remyelination and Suppresses Neuroinflammation.”
Gut bacteria can affect health and disease outcomes
The human digestive system is home to billions of bacteria and other microscopic organisms, collectively called the gut microbiome. It’s become clear that gut bacteria can play major roles in influencing health and disease, not just in the intestines but throughout the entire body.
One of the main ways the gut microbiome affects health in other parts of the body is via metabolites — molecules made by gut bacteria that end up in the bloodstream — circulating through the whole body.
ILA is a gut microbiome metabolite that’s been shown to be dysregulated in people with MS. Specifically, previous data have suggested MS patients tend to have lower-than-normal ILA levels in their blood and fewer ILA-producing bacteria in their guts.
Jank and colleagues set out to test whether increasing ILA levels might be beneficial in MS using two mouse models. ILA was given to mice by putting supplements of the metabolite in their drinking water.
In one mouse model, experimental autoimmune encephalomyelitis (EAE), mice are essentially vaccinated to induce an immune attack against myelin, a fatty covering around nerve fibers. In MS, inflammation damages myelin, causing nerve cell damage that drives disease symptoms.
In the other model, mice were treated with cuprizone, a toxic chemical that causes myelin damage.
ILA supplementation decreased disease severity in both mouse models
Results indicated ILA supplementation decreased disease severity in both models. In EAE, mice given ILA had fewer mobility issues and fewer immune cells in their brains, indicating a reduced inflammatory response.
Consistently, additional experiments in cell models showed exposure to ILA decreased the number and inflammatory activity of immune cells in the spinal cord. This had an impact on T-cells and myeloid cells, which are both involved in the inflammatory attack that drives MS.
“Overall, we can conclude that ILA dampens neuroinflammation and has a direct effect on [immune cells], reducing their activation,” Jank said.
In the cuprizone model, mice given ILA had more extensive myelin repair (remyelination) after the toxin was withdrawn.
Additional experiments in cell models, using both human and mouse cells, suggested ILA promotes the maturation of oligodendrocytes, which are the main cells responsible for making and repairing myelin in the brain. These effects were dampened when the cells lacked a protein receptor called AhR, implying that ILA binds to AhR to trigger oligodendrocyte growth.
ILA supplementation may help restore gut metabolite imbalance in MS
“This study identifies a novel mechanism by which gut metabolite imbalance in MS impacts neuroinflammation and repair and suggests ILA supplementation as a treatment to restore this balance,” the researchers wrote in their abstract.
In the mouse models, the researchers found ILA supplementation led to lower levels of another gut microbiome metabolite called indole 3-acetate (IAA). Prior research has suggested the ratio of IAA to ILA is abnormally high in MS patients.
Additional experiments indicated IAA reduced remyelination in mice, and it lessened maturation of myelin-making oligodendrocytes in cell models.
These results suggest, in addition to its direct effects on immune cells and brain cells, “ILA also reduced the circulating levels of IAA, a remyelination-blocking metabolite,” Jank said.
Based on the findings, Jank proposed it may be beneficial to give supplements of ILA to people with MS, especially individuals who have low levels of the metabolite. She stressed, however, that further research will be needed to translate these findings into clinical practice.
https://multiplesclerosisnewstoday.c...s-mice/
Indole 3-lactate supplement 'a potentially safe new remyelination agent'
Supplements of indole 3-lactate (ILA), a molecule made by gut bacteria, significantly reduced disease severity and promoted myelin repair in mouse models of multiple sclerosis (MS).
That’s according to new findings presented by Larissa Jank, PhD, a postdoctoral researcher at Johns Hopkins University, at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2024, held Feb. 29-March 2 in Florida and virtually.
“Our results imply that ILA could be a potentially safe new remyelination agent,” Jank said. “It might be particularly interesting to administer it in a personalized medicine approach where we can identify … patients with particularly low ILA levels and select [them] for supplementation.”
Jank’s talk was titled “Restoring the Multiple Sclerosis Associated Imbalance of Gut Indole Metabolites Promotes Remyelination and Suppresses Neuroinflammation.”
Gut bacteria can affect health and disease outcomes
The human digestive system is home to billions of bacteria and other microscopic organisms, collectively called the gut microbiome. It’s become clear that gut bacteria can play major roles in influencing health and disease, not just in the intestines but throughout the entire body.
One of the main ways the gut microbiome affects health in other parts of the body is via metabolites — molecules made by gut bacteria that end up in the bloodstream — circulating through the whole body.
ILA is a gut microbiome metabolite that’s been shown to be dysregulated in people with MS. Specifically, previous data have suggested MS patients tend to have lower-than-normal ILA levels in their blood and fewer ILA-producing bacteria in their guts.
Jank and colleagues set out to test whether increasing ILA levels might be beneficial in MS using two mouse models. ILA was given to mice by putting supplements of the metabolite in their drinking water.
In one mouse model, experimental autoimmune encephalomyelitis (EAE), mice are essentially vaccinated to induce an immune attack against myelin, a fatty covering around nerve fibers. In MS, inflammation damages myelin, causing nerve cell damage that drives disease symptoms.
In the other model, mice were treated with cuprizone, a toxic chemical that causes myelin damage.
ILA supplementation decreased disease severity in both mouse models
Results indicated ILA supplementation decreased disease severity in both models. In EAE, mice given ILA had fewer mobility issues and fewer immune cells in their brains, indicating a reduced inflammatory response.
Consistently, additional experiments in cell models showed exposure to ILA decreased the number and inflammatory activity of immune cells in the spinal cord. This had an impact on T-cells and myeloid cells, which are both involved in the inflammatory attack that drives MS.
“Overall, we can conclude that ILA dampens neuroinflammation and has a direct effect on [immune cells], reducing their activation,” Jank said.
In the cuprizone model, mice given ILA had more extensive myelin repair (remyelination) after the toxin was withdrawn.
Additional experiments in cell models, using both human and mouse cells, suggested ILA promotes the maturation of oligodendrocytes, which are the main cells responsible for making and repairing myelin in the brain. These effects were dampened when the cells lacked a protein receptor called AhR, implying that ILA binds to AhR to trigger oligodendrocyte growth.
ILA supplementation may help restore gut metabolite imbalance in MS
“This study identifies a novel mechanism by which gut metabolite imbalance in MS impacts neuroinflammation and repair and suggests ILA supplementation as a treatment to restore this balance,” the researchers wrote in their abstract.
In the mouse models, the researchers found ILA supplementation led to lower levels of another gut microbiome metabolite called indole 3-acetate (IAA). Prior research has suggested the ratio of IAA to ILA is abnormally high in MS patients.
Additional experiments indicated IAA reduced remyelination in mice, and it lessened maturation of myelin-making oligodendrocytes in cell models.
These results suggest, in addition to its direct effects on immune cells and brain cells, “ILA also reduced the circulating levels of IAA, a remyelination-blocking metabolite,” Jank said.
Based on the findings, Jank proposed it may be beneficial to give supplements of ILA to people with MS, especially individuals who have low levels of the metabolite. She stressed, however, that further research will be needed to translate these findings into clinical practice.
https://multiplesclerosisnewstoday.c...s-mice/