Metabolite of Gut Bacteria, as Supplement, May Regulate Immune System

Metabolite of Gut Bacteria, as Supplement, May Regulate Immune System
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A short-chain fatty acid produced by gut bacteria helps to counteract inflammatory responses in multiple sclerosis (MS) by promoting greater numbers of regulatory immune cells, a study reports.

But the bacterial composition of the gut (its microbiome) of MS patients is deficient in bacteria that produce this acid — called propionic acid — particularly in earlier disease stages, its researchers said.

Dietary supplements can help to restore normal levels of this acid, preventing the likelihood of relapses and better protecting the brain, they added. They recommend studying supplement use in clinical trials of people with MS and other autoimmune diseases.

The study “Propionic Acid Shapes the Multiple Sclerosis Disease Course by an Immunomodulatory Mechanism” was published in the journal Cell.

The autoimmune reaction in MS involves an increase of pro-inflammatory immune cells, like Th17 cells, and a reduction in cells that work to stop an immune response, like immune regulatory T-cells (Tregs). The autoimmune reaction damages myelin, the protective coat of nerve fibers — or axons — leading to loss of sensory and motor function.

Previous preclinical studies have shown that diet and gut bacteria (called gut microbiome) play an important role in modulating this inflammatory auto-reaction. Bacteria produce short-chain fatty acids like propionic acid (PA), which influence the composition of immune cells populating the microbiome by increasing the numbers of Tregs.

“These cells [Tregs] stop excessive inflammatory processes, and reduce auto-immune cells in autoimmune diseases like MS,” Ralf Gold, director of the department of Neurology at Ruhr University Bochum, St. Josef Hospital Bochum, in Germany, and one of the study’s co-lead authors, said in a press release.

To confirm these lab findings in people, researchers compared blood and stool samples from a group of MS patients (268 patients) and 68 people with this disease, serving as controls.

Results showed lower levels of PA in patients regardless of disease type — relapsing-remitting MS, secondary progressive or primary progressive MS; no differences were seen between the subtypes.

Reduced PA levels were found in MS patients using disease-modifying therapies (DMT) and those naïve to treatment. “However, larger sample sizes are needed to verify whether disease-modifying therapies have an effect on PA amounts,” the researchers wrote.

Bacteria that produce short-chain fatty acids were also found to be in lower than usual amounts in the gut of MS patients, despite treatment.

“Because of an apparent reduced availability of PA in blood and fecal samples of MS patients, we investigated whether the gut microbiome composition of MS patients is altered,” the researchers said.

Analysis of the gut microbiome of a new group of MS patients and healthy controls showed changes in the numbers of certain gut bacteria in patients: specifically, lower levels of the short-chain fatty acid-producing bacteria Butyricimonas, and higher levels of disease-associated bacteria, like Flavonifractor, Escherichia, and Shigella.

These observations led researchers to wonder if PA supplements could help modulate the gut microbiome, particularly the imbalance in Tregs — significantly lower in patients — and Th17 cells observed in MS samples relative to controls.

They tested various doses, then treated 91 MS patients and 24 controls with 1,000 milligram (mg) of PA daily for 14 days.

After two weeks of treatment, the number of Tregs rose by 25% in healthy controls and by 30% in MS patients. Among the 52 patients who chose to continue taking PA supplements, the increase in Tregs remained constant regardless of MS subtype.

To confirm these findings, researchers tested PA supplementation in another patient group. Again, they saw Tregs increase in number, while the high levels of Th17 cells seen in MS patients prior to treatment dropped significantly after 14 and 90 days of  taking PA supplements.

To better understand how Tregs were affected by PA, researchers studied immune cells isolated from patients’ blood. At the beginning, they observed that MS-derived Tregs were not able to suppress the proliferation of other immune cells, but started to show suppressive capacity with PA treatment .

They also analyzed long-term effects of supplementation by looking retrospectively at clinical outcomes for 97 MS patients taking PA continuously for at least one year.

This analysis showed a lower annual relapse rate (ARR) in 41.2% of patients on long-term supplement use, and a stable ARR in another 47.4% remained stable. An increase in ARR was seen in 11.3% of these patients.

A comparison between two groups of MS patients — matched by parameters like age, sex, disease duration and severity, and type of therapy — also found those given PA supplements for up to three years had a lower risk of disease progression than did those not taking these supplements.

Researchers then used magnetic resonance imaging (MRI) to determine effects of about 1.5 years of PA supplement use on the brain. A total of 22 patients underwent MRI brain scans, with results showing that the striatum, a region known to shrink (brain atrophy) in MS, actually increased in volume compare to scans taken before starting this treatment.

An analysis of cerebrospinal fluid (CSF; the fluid surrounding the brain and spinal cord) taken from three MS patients who consented to a lumbar puncture also showed an increase in propionic acid levels with supplementation.

These results led the team to suggest that the gut microbiome can influence the immune system and the brain via their metabolites, like PA.

“This is how intestinal bacteria can directly and indirectly affect anatomically distant structures such as the brain,” said Aiden Haghikia, the study’s co-lead author.

“Accordingly, the gut microbiome acts like a self-sufficient endocrine organ that interacts with the environment,” Haghikia added. “Further research into this largely unknown organ and the knowledge gained from it will enable us to develop innovative dietary measures to complement the known therapeutics in the future.”

Researchers also confirmed that PA supplementation significantly enhanced the levels of the anti-inflammatory molecule IL-10 in MS patients, while the pro-inflammatory IL-17 and interferon gamma were significantly reduced. The increase seen in IL-10 by PA was necessary for the suppressive capacity of Tregs.

They also demonstrated that IL-10 is important for mitochondrial function. Mitochondria work as the energy plant of a cell, using oxygen and sugars to produce energy molecules. Long-term PA supplement use increased the oxygen consumption rate of MS Tregs.

Overall, the findings show that “PA supplementation had a beneficial effect on immunological, neurodegenerative, and clinical parameters in MS patients, including relapse rate and disability progression,” the researchers wrote.

“Our proof-of-concept study reveal not only that purified PA supplementation is a safe add-on to existing immune-modulating drugs, but also confirm that one mode of action of this supplemental treatment is because of stimulation of Treg cells,” they added.

These “results provide solid groundwork for prospective clinical phase 2 trials for supplemental PA treatment not only in MS but also for other autoimmune diseases,” the team suggested.

Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.
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Patrícia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.
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Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.
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