Diets high in guar gum, a common food additive and dietary fibre, limited inflammation and delayed the onset of multiple sclerosis (MS) symptoms in mice, according to new research by members of the University of British Columbia (UBC) Microbiology and Immunology department.

“The rapid increase of autoimmune and inflammatory disorders in industrialized countries in the last few decades indicates dietary choices are one environmental factor contributing to incidence,” said Dr. Lisa Osborne, senior researcher on the study and an assistant professor with UBC Microbiology and Immunology.

“Dietary fibres are potent modulators of immune responses and can control inflammation in multiple diseases, but they’re a very biochemically diverse family. Our study gives us a clearer window into the potential of several sources of fibre in maintaining immune health.”

Dr. Osborne and colleagues exposed groups of mice to a variety of diets—a control five percent cellulose fibre diet, a diet entirely lacking in dietary fibre, or diets enriched (30%) with fibre in either resistant starch, inulin, pectin, or guar gum. Quar gum was the only fibre type that significantly limited the MS-like symptoms. 

Guar gum—guaran—is extracted from guar beans, and is often used as an additive to thicken and stabilize food and animal feed, and in industrial applications. India and Pakistan are major growers of the bean.

“Guar beans aren’t that common in western diets, and the gum isn’t used at these high levels as an additive in the west,” says Naomi Fettig, first author on the study and a PhD student with the Department of Microbiology and Immunology at UBC.

“Experts have consistently been saying fibre is good for you—and a variety of fibre sources is important to immune health—but there hasn’t been very much critical work into identifying how the body responds to different fibre types. It’s fascinating that this particular source has such an impact.”

In the US and Canada, the average daily intake of fibre is 15 grams—current recommendations are double that at 30 grams. The recommended values don’t take into account any specific fibre type. “Incorporating guar beans might be challenging to achieve at the doses we gave to mice,” says Dr. Osborne. “But a guar gum derivative, partially hydrolyzed guar gum, is commercially available as a prebiotic.”

After the gum is broken down by the microbiota of mice, the resulting molecules appeared to reduce the activity and proliferation of a type of CD4+ T cells, Th1 cells, that play a key part in activating the autoimmune response. It’s that response that leads to MS-like symptoms in mice. The effects of fibre on Th1 cells remained largely unknown prior to this study, and these findings suggest that the biochemical differences in fibre structures can influence diverse immune pathways.   

Dr. Osborne and her lab now want to explore the potential benefits in humans—including developing a more detailed understanding of the molecular picture, which might help design therapeutics that offer the benefits of such high guar gum diets in a more practical form. 

Zebrafish and humans both have a GPR17 receptor. In the study, the fish receptor was replaced by its human counterpart. This makes it more likely to find pharmacologically active substances. CREDIT © AG Kostenis-Gomeza / University of Bonn

The zebrafish should be known to many aquarium enthusiasts mainly because of its striking pigmentation. However, the characteristic black-blue stripes, to which the animal owes its name, only form over time. Its eyelash-sized larvae, on the other hand, are still more or less transparent. Many developmental processes in their bodies can therefore be observed under the light microscope. For this reason, they now serve as a model organism for research groups around the globe.

“At the University of Bonn, for example, we are investigating how zebrafish repair defective nerve tissue,” explains Prof. Dr. Benjamin Odermatt from the Institute of Anatomy at the University Hospital Bonn. “We are also interested in this because many genes involved in this process also exist in a similar form in humans.” In principle, agents that boost these repair genes in fish could thus also work in humans. However, the differences between the genetic makeup of fish and humans are often significant. The larvae are therefore sometimes of limited use in the search for new drugs.

Fish gene replaced by human gene

“We therefore took a different approach,” explains Prof. Dr. Evi Kostenis from the Institute of Pharmaceutical Biology at the University of Bonn. ” For a human gene known to play a role in the repair of nerve cells we looked for its counterpart in zebrafish. Then we excised this counterpart in the fish and replaced it with the human version.” The new genetic material took over the function of the original zebrafish gene. “If we now find a substance that boosts the repair processes in the fish with the human gene, there is a good chance that this will also be the case in humans,” says the scientist, who is also a member of the Transdisciplinary Research Area “Life and Health” at the University of Bonn.

The researchers demonstrated that this replacement works in their pilot study on the so-called GPR17 receptor. In humans, its overactivation can lead to diseases such as multiple sclerosis (MS). Nerve cells communicate by means of electrical signals. Their extensions are surrounded by a kind of insulating layer, a lipid-like substance called myelin. It prevents short circuits and also significantly speeds up the transmission of stimuli. This protective sheath is produced by specialized cells named oligodendrocytes. These resemble a microscopic octopus: many long arms extend from their cell body, most of which consist of myelin. Like an insulating tape, these wrap themselves around the nerve cell processes during brain development. Normally, the protective layer lasts a lifetime.

Insulating tape dispenser remain in immature state

In multiple sclerosis, however, the body’s own immune system destroys the myelin layer. This results in neurological disorders, for example in speech, vision or walking. But normally there is a supply of immature oligodendrocytes in the brain for repair work. When damage occurs, they mature and patch up the hole. In multiple sclerosis, this mechanism is disrupted – many of the cellular insulating tape donor cells remain in their immature state. The GPR17 receptor seems to bear the main blame for this: if it is activated by a molecular signal, it slows down the maturation of the oligodendrocytes.

“Zebrafish also have a GPR17 receptor,” explains Dr. Jesus Gomeza, who led the study with Kostenis and Odermatt. “And there it also regulates how many oligodendrocytes mature.” The researchers now replaced part of the receptor gene with its human counterpart – namely, the very structure responsible for receiving molecular signals. “We were able to show that this new mosaic gene functions normally in the fish larvae,” says Gomeza. A molecule that inhibits the human GPR17 receptor in the test tube also cranked up the formation of mature oligodendrocytes in the modified fish.

In the search for new active ingredients, substances are first tested in cell cultures. Only individual, very promising candidates are then tested in mice or other animal models. But even if they work there, tests in humans still often end soberingly. “Humanized zebrafish larvae allow many substances to be screened quickly, and with a high chance of success, since the target genes originate from humans,” explains Benjamin Odermatt. “From our point of view, this is a very promising avenue for drug development.”

Thalamic atrophy needs to be considered in clinical studies of the functional abilities of individuals with multiple sclerosis, according to findings reported by a team of experts.

The authors are Brian Sandroff, PhD, Cristina A.F. Román, PhD, Glenn R. Wylie, DPhil, and John DeLuca, PhD, of Kessler Foundation, Robert W. Motl, PhD, of the University of Illinois Chicago, Gary R. Cutter, MS, PhD, of the University of Alabama at Birmingham, and Ralph H.B. Benedict, PhD, Michael G. Dwyer III, PhD, and Robert Zivadinov, MD, PhD, of the University of Buffalo.

MS-related thalamic atrophy is a major biomarker for neurodegeneration and associated physical and cognitive decline, highlighting the importance of exploring ways to restore and maintain function in individuals who present with this consequence of the disease. Aerobic exercise training is one promising approach, but little is known about its potential effects in individuals who present with thalamic atrophy.

The team conducted a cross-sectional study to examine the associations among aerobic fitness, cognitive processing speed, and walking endurance in individuals with and without thalamic atrophy. Subjects comprised 44 fully ambulatory individuals with MS from three randomized controlled trials. Outcomes included aerobic fitness (peak oxygen consumption during graded treadmill exercise), processing speed (Symbol Digit Modalities Test), walking endurance (6-min walk test), and thalamic neuroimaging.

Results provided initial evidence for strong and selective associations among aerobic fitness, cognitive processing speed, and walking endurance in individuals with thalamic atrophy, according to lead author Dr. Sandroff. “This study suggests that aerobic exercise training has the potential to restore function in individuals with thalamic atrophy, who are clearly at risk for progressive physical and cognitive decline,” he stated. “To explore the impact on outcomes, we need to develop randomized controlled trials of aerobic exercise training in the subgroup presenting with thalamic atrophy.”   

An international research consortium led by UC San Francisco scientists has shown significant differences between the gut bacteria profiles of multiple sclerosis (MS) patients and healthy individuals, as well as between MS patients receiving different drug treatments. While some of these changes had been reported before, most are reported for the first time. The group also uncovered novel mechanisms by which these bacteria may potentially influence disease development and treatment response. 

In recent years, scientists have increasingly made connections between intestinal bacteria and a number of diseases—not just diseases of the gut—including diabetes and arthritis. The field of microbiome studies really opened up with advances in DNA sequencing in the early 2010s that allowed scientists to get a detailed picture of what bacteria are present in samples of stool, blood, mucosal tissue, and skin.

Until recently, most of the experimental evidence suggesting a link between gut bacteria and MS had come from research in mice. Studies in humans had offered inconsistent results—in part because of smaller numbers of participants, and a failure to screen out the effects of the environment on an individual’s microbiome. Where one lives—rural or urban, on a mountain top or next to an oil refinery—plays a big role in the bacteria our bodies harbor. 

To get around these limitations, the consortium of scientists participating in the International Multiple Sclerosis Microbiome Study (IMSMS) recruited a large number of MS patients from three continents and selected genetically unrelated controls from the same households as the patients. It was the first time this methodology had been used in such a large study. The study, which was published in Cell on September 15, 2022, describes differences between the gut microbiome profiles of 576 patients and an equal number of household controls in the United States, the United Kingdom, Spain and Argentina. The findings could lead to new therapeutics that involve either manipulating the microbiome or dietary interventions.

“This is the reference study that will be used by the field for years to come,” said Sergio Baranzini, PhD, the Heidrich Family and Friends Endowed Chair in Neurology and member of the UCSF Weill Institute for Neurosciences, who is the lead author on the new study. 

With their innovative protocol, Baranzini and his colleagues were able to identify dozens of new bacteria species associated with MS and confirm other species that had previously only been associated with the disease. “We were surprised by the number of species that were differentially present in MS when compared to controls,” said Baranzini. They also found that the largest source of variation in bacteria species was linked to the geographical location of the participants, which confirmed the importance of location and local variations in diet to the gut microbiome. The second largest source of variation was a participant’s disease status, which is what the researchers had expected. 

The study was the second in a series being conducted by iMSMS, an international consortium established in 2015 for the purpose of determining the role of gut bacteria in MS disease susceptibility, progression, and response to therapy. The first study validated the household control protocol, showing that it increases statistical power in population-based microbiome studies. 

The findings of the study are primarily descriptive, acknowledges Baranzini. “When looking at the microbiome, there are two questions that usually are asked,” he said. “The first one is ‘Who’s there?’ This is what we’re trying to answer in this paper. The second is, ‘What are they doing?’” 

Answering the second question requires mechanistic studies with individual bacteria to understand their metabolic profiles. Still, the researchers got some hints at what the bacteria they found are doing by studying the potential pathways that these bacteria encode. 

“Knowing which genes from which species we are able to identify in cases and controls, we can now start to reconstruct which potential pathways are active in patients and controls,” said Baranzini. 

For example, some of the bacteria the team found to be associated with MS seem to play a role in helping humans process fiber from plants, the byproducts of which tend to be found in increased concentrations in MS patients. Other species seem to have an influence on inflammation and the energy production machinery of the cell.  

The researchers also found that patients treated with an immunomodulator known as interferon beta-1a, the oldest therapy for MS, have lower concentrations of short-chain fatty acids in their feces and higher concentrations in their blood. Short-chain fatty acids are known for their anti-inflammatory properties, so this suggests that interferon works by increasing the transportation of these molecules from the gut to the blood stream, which Baranzini said could be one of the mechanisms of action of interferon. 

The iMSMS group will continue to recruit patients, expanding to Germany and Canada, until the total number of participants in the cohort reaches 2000. Starting this fall, they will also follow a subset of patients over two years to see how their gut microbiota change in response to treatment, lifestyle changes and disease progression. All of the data from these studies will be publicly available. 

“This is an example of how big science can only be achieved collaboratively,” he added. “In the iMSMS, we really brought together the best and the brightest researchers in the microbiome research field and in multiple sclerosis, and they’re all pulling towards the same objective.” 

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