Gary Birnbaum, MD
A most important observation!
Recent work in persons with MS suggests that the gut microbiome (the population of bacteria in the gut) is altered in MS, resulting in changes in immune function that affect central nervous system inflammation. The gut microbiome affects immune function via production of compounds made by bacteria as they metabolize food. This landmark paper is the first to show that by correcting a deficiency of a bacterial food metabolite in persons with MS, namely propionic acid, the course of MS is improved, both clinically and on central nervous system MRIs. These benefits correlated with biologically plausible changes in immune function. Propionic acid is a product of bacterial metabolism of food fiber and is decreased in the blood and stool of persons with MS. The authors showed that feeding persons with MS propionic acid resulted in an increase in immune cells that regulate immune function associated with a decrease in cells that increase inflammation. They also demonstrated in a small number of individuals with MS that taking propionic acid for up to three years was safe and well tolerated, resulted in decreased MS-related disease activity, and was associated with an increase in volume in certain areas of the brain. They propose that propionic acid supplementation may be a treatment for some individuals with MS, especially those with low levels of this compound. However, persons with MS should not self-administer this still experimental therapy without the supervision of a health care provider experienced in the care of persons with MS, and ideally, only as part of a clinical trial.
1. While a person’s genes play a major role in determining susceptibility to MS, the environment also plays a major role (e.g. smoking, low vitamin D levels and diet).
2. The association between one’s diet, one’s immune system and MS-related disease activity is much debated. What is clear is that the gut contains large numbers of immune cells, called the “gut associated lymphatic tissue” or GALT.
3. Immune cells in the GALT are affected either directly by one’s diet or by the breakdown products of one’s diet by gut bacteria. Of particular importance are the breakdown products of fatty acids.
4. There are two forms of fatty acids produced by gut bacteria as they metabolize our food. They are long chain fatty acids and short chain fatty acids.
5. Long chain fatty acids increase numbers of inflammatory cells. Short chain fatty acids decrease numbers of inflammatory cells. Short chain fatty acids also increase numbers of immune cells that regulate or control the immune response.
6. An important population of such regulatory cells are regulatory T cells, called “Tregs.” Tregs are both decreased in numbers in persons with MS and have decreased regulatory ability.
7. Studies of animal models of MS, such as experimental autoimmune encephalomyelitis, showed that short-chain fatty acids, in particular propionic acid, increased numbers of Treg cells and reduced the severity of disease.
8. The authors of this paper studied levels of short chain fatty acids in the blood and stool of over 300 persons with MS and compared results to 68 normal individuals. They also studied populations of gut bacteria (the gut microbiome) in persons with MS and in normal controls.
9. The scientists found that levels of propionic acid were significantly decreased in the blood and stool of persons with MS regardless of their pattern of disease (relapsing forms of multiple sclerosis, secondary progressive MS or primary progressive multiple sclerosis). No significant changes were noted in the levels of other short chain fatty acids such as acetic acid or butyric acid.
10. Levels of propionic acid were lowest in persons not on disease-modifying therapies but being on a disease-modifying therapy did not restore normal propionic acid levels.
11. Next the scientists studied populations of bacteria in the gut microbiome of persons with MS and controls. While no major changes in overall bacterial populations were noted between persons with MS and controls, certain subpopulations of bacteria were either missing from persons with MS or certain populations of bacteria were increased compared to controls. These changes were not affected by disease-modifying therapy nor by MS disease pattern but did vary with disease activity, an important observation also noted by another group of MS investigators.
12. Populations of gut bacteria that could produce short chain fatty acids were reduced in persons with MS with increases in populations of bacteria that could cause serious infections.
13. The scientists next studied the effects of adding propionic acid to the diet of 91 persons with MS and normal controls. Disease-modifying therapies were not changed.
14. There were two major observations. At baseline numbers of Treg cells were decreased in persons with MS compared to controls. Within two weeks of taking supplemental propionic acid there were significant increases in Tregs in both persons with MS and controls, but increases were greater in persons with MS. These changes persisted while taking supplemental propionic acid for as long as three months.
15. At baseline numbers of disease-inducing T cells called Th17 cells were increased in persons with MS compared to controls. Following propionic acid supplementation, numbers of these cells were reduced, as were numbers of another potentially disease-inducing population of T cells called Th1 cells.
16. After one year of propionic acid supplementation the researchers assessed whether propionic acid offered any clinical benefit to a group of 97 persons with MS. They found that numbers of relapses were significantly reduced in relapsing forms of multiple sclerosis in 41% of individuals. Forty-seven percent of persons with MS remained stable, and only 11% of persons with MS had an increased annual relapse rate.
17. In addition to decreased numbers of relapses while on propionic acid, persons with MS also noted a decreased risk for disease progression over a three-year observation period.
18. There were no serious side effects from taking propionic acid, though some individuals noted abdominal discomfort and more gas.
19. Central nervous system MRIs were obtained in a subgroup of persons with MS on supplemental propionic acid and compared to a matched group of persons with MS not on propionic acid. While there was an overall reduction in brain volume over time in both groups, there was an increase in volume in a part of the brain called the “striatum” in individuals receiving supplemental propionic acid. It’s not clear what this means.
20. Stool samples were obtained from persons with MS fed supplemental propionic acid for two weeks. Samples were added to organ cultures of normal gut. Samples from individuals responding to propionic acid, that is those that made more Tregs with propionic acid, activated genes in these organ cultures that increased numbers of Tregs while suppressing genes that prevented development of Tregs. Samples from persons with MS that did not respond to propionic acid, that is those individuals that did not increase Tregs after propionic acid supplementation, had the opposite effect on these gene populations.
21. Thus, feeding propionic acid to persons with MS caused changes in gut microbiomes that, in responding individuals, had the potential to increase production of Treg cells.
22. The authors next studied the ability of Tregs to regulate and suppress white blood cell proliferation. At baseline this regulatory ability was decreased in persons with MS. After two weeks of taking propionic acid, the ability of Tregs to prevent white blood cell proliferation was increased. These effects were blocked by neutralizing the actions of a cytokine called IL-10, showing the importance of this compound in allowing Tregs to function.
23. Finally, oxygen metabolism by Tregs was measured in normal individuals and persons with MS. Oxygen consumption was lower in Tregs from persons with MS but increased to normal levels after 90 days of propionic acid consumption. These changes were associated with activation of genes linked to increased T cell proliferation, especially genes involved in IL-10 production and genes involved in increasing the metabolism of Treg cells.
24. The authors concluded that supplementation with propionic acid may prove to be a safe and effective treatment for persons with MS who have low levels of this compound. However, numbers of persons studied were relatively small, there was no placebo control, and persons with MS were not randomized. Thus, these data, while very exciting and informative, must be considered preliminary, or a “proof of concept.”
25. Supplementation with propionic acid outside of a clinical trial and without the supervision of an MS-experienced health care provider should not be considered.
The effect of diet on the course of MS has been a subject of interest for at least the past 70 years. Many diets have been proposed, with claims of great benefit, but most observations have been anecdotal, with no controls and no objective validation. More recent work has clearly shown that immune function in persons with MS is not well regulated, that the gut microbiome, is different in persons with MS and that the two abnormalities are linked.
The above paper is the first to objectively show that a dietary supplement, in this case propionic acid, has a beneficial effect on the course of MS, and that propionic acid may exert such benefit in a biologically valid, scientifically demonstrable fashion.
The authors demonstrated that levels of propionic acid are lower than normal in blood and stool of persons with MS, that levels and functions of regulatory immune cells, Tregs, are decreased in persons with MS, that gut bacteria able to produce propionic acid from food are decreased in persons with MS, and that supplementation with propionic acid not only corrects the immune defect, but is associated with a lower annualized relapse rate, less risk of disease progression, and changes on central nervous system MRIs that suggest an effect on brain degeneration, an important component of progressive forms of MS.
Administration of propionic acid is not a cure for MS. Eleven percent of persons with MS on propionic acid continued to have relapses and some individuals did not change their immune status with taking propionic acid. Clearly, persons with MS represent a diverse group of individuals with potentially different disease-causing pathways for their illness. Nevertheless, this is a landmark paper, validating the concept that the gut microbiome and the immune system are linked, that abnormalities of these systems play a role in MS, and that correcting some of these changes may be of benefit to a large number of persons with MS. What is needed now is a Phase 3, randomized, placebo controlled clinical trial to more firmly establish the benefits of propionic acid supplementation. Such trials are very costly and with limited available funding and little if any potential for pharmaceutical corporate profit initiation of such a trial may be difficult.