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

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 .

“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.