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Dietary restriction can lessen the severity of multiple sclerosis (MS) by modulating levels of fat-related hormones, new research suggests.
The findings were shared at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2021, in the presentation “Weight, Obesity and Adipokines,” given by Laura Piccio, MD, PhD, a professor at Washington University School of Medicine in St. Louis, Missouri, and at the University of Sydney, Australia.
Although a link between obesity early in life and the risk of MS has been demonstrated in several epidemiological studies, “the mechanisms underlying these associations are not exactly known,” Piccio said.
“However,” she added, “one potential link between obesity and MS is the role of the adipose [fat] tissue in the production of adipokines.”
Adipokines are hormones and other signaling molecules produced by fat tissue.
“Adipokines have a primary function on metabolic responses, but they also have effects on immune cells,” Piccio said. “They represent a link between metabolic and immune inflammatory responses.”
“Obesity is characterized by the release by the adipose tissue of adipokines shifting the balance to a more pro-inflammatory milieu,” she added, noting that such chronic low-grade inflammatory state “may promote autoimmunity.”
For example, an adipokine called leptin has been shown to have pro-inflammatory properties and has been implicated in MS.
According to Piccio, other biological mechanisms — such as alterations in gut bacteria and abnormal levels of certain vitamins (namely vitamin D) — also may link obesity and MS.
Piccio and her colleagues have been studying the effects of dietary restriction in MS, as calorie restriction may potentially have anti-inflammatory effects.
“Dietary restriction … represents the other end of the spectrum compared to obesity,” Piccio said. She defined dietary restriction as “chronic or intermittent reduction of food intake without malnutrition.”
Piccio’s group have shown that in mice with experimental autoimmune encephalomyelitis (EAE), a mouse disease commonly used as a model of MS, dietary restriction substantially lessened the severity of disease.
Similar results were found for two dietary restriction strategies: chronic calorie restriction, in which mice ate 40% less food every day, and intermittent fasting, where mice did not eat every other day (24-hour cycles fasting/feeding). Piccio noted that the latter may be an easier option to implement in humans.
Blood analyses showed that intermittent fasting led to reduced levels of the pro-inflammatory adipokine leptin, whereas it increased levels of an anti-inflammatory adipokine called adiponectin. Levels of corticosterone, an anti-inflammatory steroid hormone, also increased following intermittent fasting.
“Intermittent fasting induced changes in corticosterone, leptin, and adiponectin, all favoring a reduction of inflammation,” Piccio said.
Consistently, intermittent fasting decreased levels of pro-inflammatory immune cells (Th17 cells) in the intestine, while it increased levels of anti-inflammatory immune cells (regulatory T-cells).
Intermittent fasting also changed the makeup of the bacteria in the mice’s guts. Generally, mice that underwent intermittent fasting had a more diverse makeup of gut bacteria, as well as higher levels of bacteria known to have anti-inflammatory effects, namely bacteria of the Lactobacillaceae, Bacteroidaceae, and Prevotellaceae families.
The researchers also found statistical evidence of links between several gut bacteria species and bodily leptin levels.
Taken together, these findings are indicative of “the strong interaction between the gut microbiome [gut bacteria] and host metabolism,” Piccio said.
The research team then sought to translate the animal model data to human disease. They conducted a pilot clinical trial (NCT02411838) that enrolled 16 people with relapsing-remitting MS (RRMS) receiving treatment with steroids.
Participants were divided into two groups. Those in the fasting group underwent intermittent energy restriction (IER) — rather than fasting every other day, they ate a very small amount (total 400–500 calories/day, about one or two salads with non-starchy vegetables and a light dressing) every other day. Participants in the control group ate a normal diet.
After 15 days, participants in the fasting group experienced a slight, but significant, decrease in body mass index (BMI, a ratio of weight to height), compared to the control group. Levels of leptin also decreased significantly in the fasting group.
Levels of adiponectin did not significantly change in the fasting group, and neither did gut bacterial makeup. Picco said this is, “probably because the study included only a small number of patients, and there is high variability in humans.”
She noted a trend toward increased levels of a type of gut bacteria with anti-inflammatory properties, called Faecalibacterium, in the fasting group. There also was some evidence that fasting increased the activity of regulatory T-cells.
Piccio said that the diet was well-tolerated in this small study, and that no safety concerns were raised. Nonetheless, she noted that the results of this pilot study are limited by its small size and short duration.
Piccio concluded by saying that “dietary restriction is very powerful in ameliorating EAE through multiple mechanisms,” including “reduction of the pro-inflammatory leptin, and increase of the anti-inflammatory adiponectin and endogenous corticosterone,” plus “effects also on the gut microbiome.”
Of note, Piccio is the principal investigator of an ongoing clinical trial (NCT03539094) comparing the effect of IER to a standard western diet in people with RRMS. According to her, the trial is still recruiting participants at Washington University in St Louis; more information is available here.
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