• Gary Birnbaum, MD

A gut feeling for the brain

Paper #1: An overview of the current state of evidence

for the role of specific diets in multiple sclerosis.

Evans E, Levasseur V, Cross AH, Piccio L.

Mult Scler Relat Disord. 2019;36:101393.

Paper #2: Pilot study of a ketogenic diet in relapsing-remitting MS.

Brenton JN, Banwell B, Bergqvist AGC, Lehner-Gulotta D, Gampper L, Leytham E, Coleman R, Goldman MD.

Neurol Neuroimmunol Neuroinflamm. 2019;6:e565.

Paper #3: Recirculating Intestinal IgA-Producing Cells

Regulate Neuroinflammation via IL-10.

Rojas OL, Probstel AK, Porfilio EA, Wang AA, Charabati M, Sun T, Lee DSW, Galicia G, Ramaglia V, Ward LA, Leung LYT, Najafi G, Khaleghi K, Garcillan B, Li A, Besla R, Naouar I, Cao EY, Chiaranunt P, Burrows K, Robinson HG, Allanach JR, Yam J, Luck H, Campbell DJ, Allman D, Brooks DG, Tomura M, Baumann R, Zamvil SS, Bar-Or A, Horwitz MS, Winer DA, Mortha A, Mackay F, Prat A, Osborne LC, Robbins C, Baranzini SE, Gommerman JL.

Cell. 2019;176:610-24 e18.

Bottom Line: Bacteria in the gut can affect the immune system in multiple ways, either quieting inflammation or increasing it. Particular diets can influence gut bacteria. Two of the cited papers deal with efforts to change the course of MS with diet. Paper #1 describes the current state of knowledge regarding multiple diets proposed to alter the course of MS. The paper concludes that studies to date have not been sufficiently rigorous to persuasively show that dietary changes alter the course of disease. The second paper describes a small, 6-months pilot study of one such diet, the “ketogenic diet,” in persons with MS. The results of this small study showed the diet to be safe and well tolerated, resulting in mild weight loss, improvement of both fatigue and depression, and a reduction in blood levels of an inflammatory protein. The study was too short and too small to determine effects on neurologic function. The third paper describes very elegant experiments in a mouse model of MS showing that a population of immune cells called plasma cells that secrete a class of antibodies called IgA can leave the gut, enter an inflamed brain and reduce inflammation and the severity of disease by secreting a protein called IL-10. Most interestingly, the authors also showed that levels of bacteria coated with IgA antibodies in the gut of persons with active MS were significantly lower compared to those with stable MS, suggesting, but not proving, that a similar passage of IgA-secreting cells may leave the gut and enter the brain in persons with MS. This paper adds to the list of other papers that describe strong effects of gut bacteria on a body’s immune response. Understanding the role of gut bacteria (the gut microbiome) in the development of MS and in shaping the course of disease is in early stages but promises to be an important one in understanding the cause of MS and also possibly treating it.

Key Points:

1. Diet has been used as a means of modulating health for decades. Its value in controlling illnesses such as heart disease, high blood pressure and diabetes are well established. Its value in controlling inflammatory central nervous system diseases such as MS is less established.

2. Many studies have been performed regarding diet as a means of controlling or changing the pattern of disease in MS. The paper by Evans and colleagues (Paper #1) summarizes the results from multiple studies of diets in both persons with MS and rodents with the MS-like disease, experimental autoimmune encephalomyelitis (EAE).

3. Paper #1 reviews the data from the ketogenic diet, Swank’s diet, caloric restriction diet, intermittent fasting diet, paleolithic diet, Wahl’s diet, gluten free diet, Mediterranean diet, high fat diet, and sodium restriction diet.

4. Most of the human studies involved small numbers of individuals, with no control group, were of short time duration (months), and with a significant loss of participants due to lack of adherence to the diet. Only some studies randomized individuals, and most did not control for other medical conditions that could impact the course of MS (e.g. smoking, obesity, diabetes, hypertension).

5. Several studies reported some weight loss while on the diet, with subjective improvement of fatigue, better “quality of life,” and less depression. A decreased annualized relapse rate was noted in some studies, but this is difficult to interpret in the absence of a control group since a reduction in relapses occurs “naturally” in the course of relapsing MS (called a “regression to the mean”). Small decreases in inflammatory blood proteins were noted in some studies. Results from animal studies did show more robust effects of diet on the clinical course of experimental autoimmune encephalomyelitis (EAE) and on levels of inflammatory proteins.

6. The authors concluded there is no particular diet that is especially beneficial for persons with MS. Rather they suggested that a healthy, non-extreme, balanced diet is most desirable, along with elimination of other factors that affect the course of MS, such as smoking and lack of exercise.

7. Paper #2 is an example of a recent study assessing the effects of a ketogenic (high fat, low carbohydrate) diet on MS. This was a pilot study of twenty neurologically stable subjects with relapsing forms of multiple sclerosis who were recruited into an open-label, non-randomized, observational study lasting 6 months. Fifteen persons completed 6 months of the study. Compliance with the diet was monitored by obtaining daily levels of ketones in the urine.

8. After 6 months on the diet, participants who kept to the diet (15 of the 20) lost weight, felt better (had improved quality of life), had less depression, and had a small decrease in the inflammatory protein leptin in their blood. The study was too small and too short to determine clinical benefits in terms of disease activity.

9. The authors concluded that a ketogenic diet is safe, and well-tolerated over the short term, but that a larger study, involving persons with active MS, who were less overweight than their study population, and who were randomized to study and control groups, was needed to be run for a longer period of time. There are potential toxicities associated with a ketogenic diet (https://www.ncbi.nlm.nih.gov/pubmed/31990316) and persons should only undertake such diets under the supervision of a health care provider and a licensed dietitian.

10. Paper #3 is a most interesting study attempting to define how changes in the gut could influence central nervous system inflammation. The gut (small and large intestines) contains large numbers of immune cells in a system called the “gut associated lymphoid tissues” (GALT). Most of the immune cells are T cells, with lesser numbers of antibody-secreting B cells and a sub-population of more mature B cells called plasma cells.

11. The purpose of the GALT is to fight disease-causing bacteria and to prevent allergic reactions to ingested foods. When the system breaks down, persons can develop coeliac disease (gluten intolerance) and inflammatory bowel disease (ulcerative colitis and Crohn’s disease).

12. Clinical trials showed that removing younger B cells from the blood of persons with MS significantly reduced disease. Another study in which B cells and more mature plasma cells also were removed greatly worsened disease. The reasons for these differences are not known.

13. What is known is that the brains of persons with active MS contain increased numbers of plasma cells secreting a class of antibody called IgA. The researchers of Paper #3 wished to study where these cells came from and whether they were able to reduce central nervous system inflammation.

14. The investigators studied a mouse model of MS called experimental autoimmune encephalomyelitis (EAE). In particular they studied plasma cells secreting IgA. Increased numbers of IgA-secreting plasma cells are found in EAE brains but not control brains.

15. As a rule, IgA antibodies are produced in regions exposed to the environment, such as mucous surfaces of the gut and lungs. Numbers of such cells in the gut are increased on exposure to parasites and allergy-inducing substances. Mice with increased numbers of IgA secreting cells in the gut are resistant to EAE.

16. The researchers used sophisticated cell markers or identifiers to show that the cells in the brain producing IgA antibodies originated in the gut, then traveled to the lungs and from there into the central nervous system. They also were able to show that it wasn’t the IgA antibodies that reduced inflammation. Rather, once the cells entered the brain they produced an anti-inflammatory soluble protein or cytokine called “IL-10”. It was the actions of this cytokine, not the IgA antibodies that reduced brain inflammation. At the same time that numbers of IgA producing cells increased in the brains of mice with EAE, numbers of IgA producing cells in the gut were reduced.

17. The scientists wished to see whether a similar phenomenon could be occurring in persons with MS. They studied gut bacteria from persons with active relapsing forms of multiple sclerosis, stable relapsing forms of multiple sclerosis, and normal controls. MS. In particular they measured numbers of bacteria that had IgA antibodies on their surfaces. These numbers were used as an indirect measure of numbers of IgA producing cells in the gut.

18. They found that numbers of gut bacteria coated with IgA antibodies were significantly reduced in persons with active MS compared to gut bacteria from persons with stable MS and controls. The scientists interpreted these data to suggest, albeit indirectly, that numbers of IgA producing cells in persons with active MS are reduced in the GALT, possibly as a result of migration of cells into the central nervous system. The mystery that remains to be solved is what triggers the recruitment of these plasma cells to the brain, and how can their numbers be increased to possibly act as a treatment of disease.

Discussion: There are more bacteria in your body than there are your own cells.

They are found in all organs exposed to the environment (mouth, throat, lungs, intestine, skin). Each organ has its own unique population of bacteria, called that organ’s microbiome. They differ from person to person and are affected by many factors (air quality, diet, metabolic diseases such as diabetes, exposure to antibiotics, infections). The intestinal or gut microbiome is of particular interest regarding its role in autoimmune diseases. The gut, both small and large intestines, contain large numbers of immune cells, mainly T cells, but also large numbers of antibody producing cells such as plasma cells. This accumulation of gut-localized immune cells is called the gut associated lymphoid tissue or GALT. While not all aspects of the GALT’s functions are known, it is known to make immune responses to gut bacteria as well as the metabolic the products of gut bacteria such as bile acids. The patterns of such responses can significantly affect inflammation in the rest of the body.

The GALT’s major roles are to fight infections, prevent development of cancers, and prevent allergic reactions to ingested substances. The composition of the GALT changes with age, with immune cells having the capacity to suppress inflammation (regulatory T cells or Tregs) most numerous early in life. A disruption of these functions can result in allergic diseases such as coeliac disease (an allergy to gluten) or inflammatory bowel disease such as ulcerative colitis and Crohn’s disease. The pattern of immune responses, either inducing inflammation or suppressing inflammation varies with different bacteria.

Gut bacteria have been studied in diseases such as type 2 diabetes and rheumatoid arthritis. Studies of gut bacteria in persons with MS have shown a “dysbiosis” or alteration of the gut microbiome compared to normal controls. Such changes could alter the pattern of immune responses in the GALT, resulting either in more brain inflammation or less.

Multiple studies in animal models of MS, especially experimental autoimmune encephalomyelitis (EAE), showed that diet can either lessen or worsen disease. While great caution must be used in relating results in EAE to the human disease, these and similar studies resulted in multiple diets being suggested as a means of modifying MS-related disease activity. The range of diets is extensive, with most based on poorly supported hypotheses.

Data in support of the beneficial effects of diet on MS are well summarized in Paper #1. Most of the supportive evidence is weak, with many trials involving small numbers of persons studied for short periods of time with no objective proof that subjects kept to the diet or well-supported objective data(central nervous system MRIs or neurologic exams) that the diet altered the course of disease. As a result, the authors of Paper #1 could not recommend any particular diet as being of proven benefit. Rather they advised eating a healthy, well balanced diet, minimizing factors that worsen disease (smoking, being overweight, not getting enough sleep), and maximizing beneficial activities such as exercise, avoiding too much alcohol and OTC supplements, and reducing stress.

Paper #2 describes a pilot study evaluating the tolerance and safety of a diet high in fat and low in carbohydrates, the “ketogenic diet.” The authors felt the diet was well tolerated, though 25% of the original 20 participants dropped out or did not adhere to the diet. The study was short (only six months), but participants felt better, lost weight, and had a slight decrease in their blood of the inflammatory protein, leptin. A positive aspect of the study was the authors’ use of daily urine monitoring for ketones to assure compliance with the diet. A potential caveat regarding possible toxicity is that a study of high fat diet in EAE resulted in worsening of disease. In view of possible human toxicity of a ketogenic diet persons wishing to try such an approach should only do so under the supervision of a health care provider and a licensed dietitian.

Paper #3 is a very elegant study possibly explaining for the first time why two different treatments targeting human B cells resulted in radically different effects on the course of MS. Ocrelizumab is an antibody that leads to the removal from blood of a younger population of circulating B cells. Administration of ocrelizumab greatly reduces disease in relapsing forms of multiple sclerosis and to a much lesser degree in active inflammatory primary progressive multiple sclerosis. Atacicept is another antibody that removes circulating B cells, but it affects a much larger population, including more mature B cells such as plasma cells. When atacicept was given to persons with relapsing forms of multiple sclerosis it resulted in major worsening of disease. The reasons for these major differences are not known.

The authors of Paper #3 noted that there were increased numbers of plasma cells in the brains of mice with acute EAE, and that many of these cells secreted a class of antibody called IgA. A major site for IgA secreting plasma cells is in the GALT. In a very persuasive fashion they showed that these cells originated in the gut, were recruited from the gut to the lungs and eventually to the brains of mice with EAE. Infiltration of the brain with these IgA-secreting plasma cells significantly reduced the severity of disease. They also discovered that it was not the IgA antibodies that were responsible for the treatment effect, but a product secreted by the plasma cells, a cytokine called IL-10. This observation is most important since it indicates that the IgA secreting plasma cells were not recruited to the brain as a result of their response to a particular brain protein, but rather to a relatively “non-specific” stimulus. The nature of this recruitment trigger remains a mystery. The authors do suggest some possible mechanisms. They note that the intestinal barrier is impaired in both EAE and MS, with gaps present in the lining of the gut. They also suggest that IgA positive plasma cells may be affected by the inflammation in the central nervous system, resulting in the expression of receptors on their surfaces that attracts them to inflamed brain.

Of particular interest, the researchers related their experimental data to the human disease by studying gut bacteria from three groups of individuals, persons with active relapsing forms of multiple sclerosis, persons with stable relapsing forms of multiple sclerosis, and normal individuals. They counted numbers of gut bacteria that were coated with IgA antibodies and used this as an indicator of the number of IgA-secreting plasma cells in the gut. Numbers of IgA-coated bacteria were significantly lower in the gut of persons with active relapsing forms of multiple sclerosis compared to gut bacteria in persons with stable MS and controls. While this is very indirect evidence, it does suggest that in persons with active relapsing forms of multiple sclerosis there may be a recruitment of IgA secreting plasma cells from the gut to the brain. Maximizing numbers of such cells and maximizing migration of such cells to the brain could result in therapeutic benefit. An interesting observation in that regard is that gut exposure to the parasite Tritrichomonas musculis (T.mu) greatly increases numbers of IgA producing plasma cells in the gut and results in mice being resistant to EAE.Similar observations have been made in persons with MS, to the extent that one paper raised the possibility of treating MS by initiating a benign parasitic infection.

As is often the case, more questions are raised by this research than are answered. Nevertheless, there is great promise in developing a better understanding of the role of the gut microbiome in autoimmune disease, its effect on body immunity, and its potential to serve as a therapeutic modality in persons with MS.

Abstracts of the above papers are available.


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