Specific dietary interventions to tackle obesity should be a routine part of recommended MS care – Yes

Multiple sclerosis (MS) pathogenesis is regulated by a number of genetic and environmental influences. Of these, some modifiable factors affecting MS risk and clinical course, as vitamin D deficiency, smoking, and obesity, attract interest. Increased prevalence of autoimmune disorders observed in the last decades in developed countries has been related to changes in lifestyle and diet, and, particularly, to increased prevalence of obesity.

Obesity is currently considered a low-grade inflammatory state and has been identified as a risk factor for several autoimmune conditions. Obesity in childhood and adolescence has been consistently shown to be a risk factor for MS. ¹ Studies in pediatric MS evidenced that obesity was associated with twofold risk of developing the disease and reduced response to first line therapies. ² Obesity, together with elevated serum cholesterol and increased total cholesterol/high density lipoprotein (HDL) ratio, has been associated with increased disability and worse disease course.^3,4 Accordingly, enhanced expanded disability status scale (EDSS) score progression and reduced response to interferon-β therapy have been reported in MS patients with higher body mass index (BMI) and altered serum lipid profile.^4,5

Experimental studies recently contributed to defining the link between metabolism and inflammation, showing that adipocytes release soluble mediators (i.e. adipokines) involved in the regulation of different physiological functions, including the innate and adaptive immune responses. Particularly, leptin is released by adipocytes in proportion to the fat mass and acts as a fasting hormone, reducing food intake and promoting energetic expenditure. ⁶ Leptin also plays important proinflammatory activities, regulating the function of immune cells, stimulating the differentiation of Th-17 lymphocytes, inhibiting regulatory T cells, and enhancing the secretion of proinflammatory cytokines, as interleukin (IL)-6 and tumor necrosis factor (TNF). Studies in animal models of MS (i.e. experimental autoimmune encephalomyelitis (EAE)) have demonstrated that leptin critically participates in the disease pathogenesis. Accordingly, leptin-deficient mice are resistant to the induction of EAE, and leptin administration restored EAE susceptibility in these mice. ⁶ The role of leptin has been clearly documented also in human MS. Leptin signaling has been identified in active MS lesions and has been associated with enhanced prospective disease activity. Moreover, increased expression of this molecule has been reported in the cerebrospinal fluid (CSF) and in the serum of MS patients naive to therapy, and has been associated with reduced expression of regulatory T cells. ⁶

It has been proposed that enhanced inflammatory responses in obese MS could promote worse disease course. Notably, increased CSF inflammation has been reported in obese relapsing remitting (RR)-MS compared with patients with normal BMI. Obesity has been associated to higher CSF levels of different proinflammatory molecules, including leptin and IL-6, and reduced expression of the anti-inflammatory cytokine IL-13. ⁵ Moreover, serum triglycerides and total cholesterol/HDL-cholesterol positively correlated with CSF IL-6 concentrations. Previous studies have shown that a proinflammatory CSF milieu negatively influences MS prognosis. Accordingly, elevated CSF levels of specific inflammatory cytokines at the time of diagnosis have been associated to a higher number of relapses, increased prospective disability, and enhanced neurodegeneration. ⁵

Taken together, these studies suggest that contrasting adiposity and altered lipid metabolism could reduce neuroinflammation and promote a stable disease course, representing a possible disease modifying intervention in MS.

As an increased prevalence of obesity is largely associated to the diffusion of westernized diets, rich in saturated animal fats, several preclinical and clinical studies explored the impact of diet on EAE and MS clinical course. Administration of long-chain fatty acids, commonly found in processed food, has been associated to enhanced EAE severity and increased expression of Th1 and Th17 cells in the small intestine. ⁷ Moreover, high-fat diet has been associated with a worse disease course in EAE mice. In particular, it has been observed that elevated fat consumption promoted immune cell infiltration and production of inflammatory mediator in the central nervous system. ⁸ Conversely, it has been reported that caloric restriction before EAE induction reduced the inflammatory response, improving clinical manifestations. Caloric restriction has been associated with an anti-inflammatory effect, with reduced expression of the proinflammatory molecules, IL-6 and leptin. These results suggest that dietary modifications could be useful to reduce demyelination and axonal damage, contrasting oxidative stress and promoting neuroprotection. ⁶ Finally, fasting-mimicking diet could positively influence the course of EAE, being associated to increased regulatory T cells and reduced expression of proinflammatory cytokines. ⁹

Several studies explored the possibility that dietary modifications may improve MS clinical course. In particular, it has been hypothesized that different dietary components could modulate specific pathogenetic mechanisms, promoting mitochondrial function, reducing oxidative stress and lessening neuroinflammation. Although a number of specific diets have been proposed, including low fat/vegan, ketogenic, Mediterranean, and intermittent fasting, most studies have been conducted in small groups of patients, with a limited follow-up. Therefore, further investigations are needed to clarify the role of dietary interventions in MS. ¹⁰

On the whole, current literature shows that overweight and obesity, as well as altered lipid metabolism are associated to increased MS risk and poorer prognosis. These data suggest that weight control should be strongly recommended in patients with MS, as it appears to be associated to reduced disability, better response to therapies and increased neuroprotection. Although numerous studies explored specific dietary interventions, it is still unclear whether specific diets should be adopted in MS.