Neuroimmunity works again! Cell reveals that propionic acid inhibits the occurrence of multiple sclerosis through immunomodulatory mechanisms
The relationship between multiple sclerosis and gut microbiota
Multiple sclerosis (MS) is the most common non-traumatic neurological disorder in industrialized countries, characterized by the destruction of myelin around axons in the central nervous system through an autoimmune response. After onset, the number of pro-inflammatory Th17 and Th1 cells increases, while the number and function of regulatory T (Treg) cells are impaired. Recent studies suggest that multiple sclerosis may be associated with diet-induced changes in the gut microbiome, but the mechanism and impact on the specific course of multiple sclerosis remain unclear.
Research Background
On March 10, 2020, the Aiden Haghikia research team at Ruhr University Bochum, Germany, published a research paper entitled "Propionic Acid Shapes the Multiple Sclerosis Disease Course by an Immunomodulatory Mechanism" online on Cell, which found that patients with multiple sclerosis can further reverse the imbalance of Treg cells/Th17 cells by supplementing propionic acid to induce an increase in the number and function of Treg cells, and ultimately improve the process of multiple sclerosis.
Research content
Analysis of differences between patients and healthy groups
Firstly, the author compared the serum and stool samples of patients and healthy groups to find differences in MS patients. From the results of high performance liquid chromatography-mass spectrometry analysis, it can be seen that the relative abundance of intestinal microbiota in MS patients has changed, the content of propionic acid in feces and serum has been significantly reduced, and the content of propionic acid in patients who have not been treated with drugs is lower.
Immunomodulatory effects of propionic acid
So what immunomodulatory role does propionic acid play as a gut microbial metabolite in MS patients?
In order to solve this problem, the authors performed immunophenotypic analysis and T cell subgroup function analysis in MS patients after propionic acid supplementation. The analysis results showed that the number of Treg cells increased in both the control group and MS patients after propionic acid supplementation, while the number of Th17 cells and Th1 cells decreased significantly.
And further isolation of Treg cells and co-culture of peripheral blood mononuclear cells found that the inhibitory ability of Treg cells in MS patients was weakened, while the inhibitory ability of Treg cells in patients supplemented with propionic acid was enhanced. Therefore, the function of Treg cells was also enhanced after propionic acid treatment.
Effect of propionic acid on MS patients
How does this regulatory effect of propionic acid affect patients? By taking propionic acid for a long time, it was found that the annual recurrence rate and disease progression of MS patients were greatly improved, and MRI analysis showed that the subcortical gray matter of patients after propionic acid treatment also increased.
Mechanism Exploration
To further explore the mechanism, the authors examined fecal samples before and after propionic acid treatment in the intestinal organ culture system. After propionic acid treatment, the expression of genes positively associated with Treg cell induction was increased, while the expression of genes negatively associated with Treg cell induction was suppressed.
Subsequently, the authors conducted in vitro inhibition tests using Treg cells from healthy groups and found that propionic acid treatment can improve the in vitro inhibition ability of Treg cells. This suggests that the microbiota of MS patients after propionic acid treatment has the effect of inducing Treg development
It is worth noting that IL-10 was significantly increased in patients after propionic acid treatment, and the use of IL-10 antibodies can reduce the regulatory effect of propionic acid on Treg, so it is necessary for propionic acid to regulate the function of Treg cells.
We know that cell metabolism plays an important role in the function of various immune cells. To determine the potential mechanism of Treg cell inhibition and IL-10 increase, the authors examined the oxygen consumption rate of Treg cells in MS patients before and after propionate supplementation.
The results showed that propionic acid could restore mitochondrial respiration in Treg cells to the level of the control group in MS patients. And long-term dietary supplementation of propionic acid reversed the morphological phenotype of mitochondrial damage. These findings suggest that the pathogenesis of MS is related to the impairment of mitochondrial function and integrity.
Finally, the author analyzed the gene expression of peripheral blood cells in MS patients before and after propionic acid treatment.
The results showed significant changes in genes related to specific T cell regulation, including upregulation of some T cell activation-related genes such as CD28, IL-2R and CD3e. Network connectivity analysis revealed that IL-10 and TNF are two major gene interaction centers after propionic acid supplementation, so they have biological significance in coordinating cell response to propionic acid therapy.
Research Summary
In conclusion, the authors found that propionic acid levels in serum and feces were significantly reduced in MS patients. When patients took propionic acid, functional regulatory T (Treg) cells increased significantly and persistently, and intestinal Treg cells induced increased gene expression while Th1 and Th17 cells were significantly reduced. Long-term propionic acid treatment can reduce the recurrence rate of multiple sclerosis and stabilize the course of the disease. And propionic acid normalizes the mitochondrial function and morphology of Treg cells in MS patients.
Therefore, this study provides a potential drug supplement for the treatment of related diseases such as multiple sclerosis.
Author-related research papers
2015 Study
As early as October 20, 2015, Aiden Haghikia, a postdoctoral fellow, published a research paper entitled "Dietary Fatty Acids Directly Impact Central Nervous System Autoimmunity via the Small Intestine" in Immunity as the first author.
In this paper, the authors found that long-chain fatty acids promote the differentiation and proliferation of T helper cell 1 (Th1) and/or Th17 through the p38-MAPK pathway, thereby impairing the isolation of the gut, which provides new ideas for the treatment of autoimmune diseases such as multiple sclerosis.
2017 Study
In February 2017, Aiden Haghikia published a research paper entitled "Severe B-cell-mediated CNS disease secondary to alemtuzumab therapy" in The Lancet Neurology as the first author.
In this paper, the authors found that alenzumab treatment caused severe B-cell-mediated central nervous system diseases, which raised the alarm about the overuse of alenzumab.
