Supplement lowers marker of nerve damage in small MS trial

Daily intake of propionic acid, a substance naturally made by gut bacteria when they break down fiber from food, significantly reduced blood levels of neurofilament light chain (NfL), a marker of nerve cell damage, in people with multiple sclerosis (MS).

That’s according to data from a small Phase 2b clinical trial, dubbed MADAI (NCT06402487), that also showed that the supplement, taken twice daily for 90 days (about three months) as an add-on to standard MS treatment, was generally well tolerated.

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The findings suggest propionic acid may help reduce neuroaxonal injury — damage to nerve fibers — in MS, but researchers said larger and longer studies are needed to confirm whether the supplement can lead to meaningful clinical benefits.

The study, “Propionic acid in multiple sclerosis: a phase 2b, double-blind, randomized placebo-controlled trial,” was published in Brain.

MS is an autoimmune disease marked by inflammation and damage to myelin, the protective sheath around nerve cell fibers, called axons. This can lead to the formation of lesions — areas of tissue injury that can be detected on MRI scans — in the brain and spinal cord, as well as gradual neurodegeneration, or the loss of nerve cells.

“While current disease-modifying therapies (DMTs) effectively control inflammatory activity, including clinical relapses and … lesion formation on MRI, they do not primarily act within the [brain and spinal cord],” the researchers wrote, adding that some patients continue to experience “disability accumulation unrelated to overt inflammatory activity.”

Growing evidence suggests that the gut microbiome — the community of microbes living in the intestines — may influence MS. Past research suggests that patients have lower levels of propionic acid, a short-chain fatty acid produced when gut bacteria break down dietary fibers and indigestible carbohydrates.

Propionic acid is thought to help maintain the intestinal barrier, regulate immune responses, and support nerve cell function.

Study tested supplement as add-on treatment

Earlier data from an open-label clinical study suggested that propionic acid supplementation (500 mg twice a day) may provide benefits for MS, specifically in relapses and disability. However, its effects had not been evaluated in a placebo-controlled trial.

To address this, a team of researchers conducted the MADAI study. A total of 101 adults (64% women, mean age 45) with clinically stable MS, defined as no relapse in the three months prior, were enrolled at a single MS center in Austria.

Participants were randomly assigned to receive either 500 mg of propionic acid (67 patients) or a matching placebo (34 patients), twice daily for 90 days. The supplement was used as an add-on approach, meaning participants continued their existing MS therapies during the trial.

The trial’s main goal was to assess changes in blood levels of NfL, a protein released when axons are damaged. Higher NfL levels are associated with MS disease activity and long-term progression. Secondary goals included changes in cognition, walking speed, hand dexterity, fatigue, sleepiness, and quality of life.

Most participants (95%) completed the study. Data showed that after 90 days, blood NfL levels fell significantly, by 17.9%, in the propionic acid group, but remained largely unchanged in the placebo group. The difference in NfL levels between the two groups at follow-up was statistically significant.

Among participants who had not started or changed DMTs within 12 months before the trial began, NfL levels fell significantly in the propionic acid group, but not in the placebo group. At follow-up, NfL levels were significantly lower in the propionic acid group, suggesting that the observed effect was not mainly due to recent changes in MS medication.

NfL reductions seen in treatment subgroups

Also, propionic acid supplementation was associated with a significant reduction in NfL levels among patients receiving moderate-to-high efficacy DMTs, including those targeting B-cells, immune cells involved in MS. This raises the possibility that propionic acid may provide additional benefits beyond standard MS treatments, which mainly work by controlling inflammatory disease activity.

There were no significant differences between the groups in terms of secondary outcomes. Still, motor fatigue, as assessed with the motor domain of the Fatigue Scale for Motor and Cognitive Functions, showed a significant reduction within the propionic acid group, but not in the placebo group. However, the researchers described secondary outcome findings as preliminary and said they need to be confirmed in future studies.

Propionic acid was generally well tolerated. Adverse events were reported by 31% of participants in the propionic acid group and 18% of those in the placebo group, a difference that was not statistically significant.

Bloating was significantly more common in the propionic acid group than in the placebo group (13% vs. 0%). No serious adverse events occurred, and no clinically relevant changes in kidney function were observed.

The researchers noted that taking propionic acid with food may improve tolerability.

Overall, these preliminary findings provide “evidence for the short-term effectiveness and safety of PA [propionic acid] supplementation in reducing [serum NfL],” and lay “the groundwork for future long-term, phase 3 clinical studies,” the researchers wrote. “Future research should examine the effects of long-term PA supplementation on clinical outcomes.”