Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the CNS. Bile acids are cholesterol metabolites that can signal through receptors on cells throughout the body, including in the CNS and the immune system. Whether bile acid metabolism is abnormal in MS is unknown. Using global and targeted metabolomic profiling, we identified lower levels of circulating bile acid metabolites in multiple cohorts of adult and pediatric patients with MS compared with controls. In white matter lesions from MS brain tissue, we noted the presence of bile acid receptors on immune and glial cells. To mechanistically examine the implications of lower levels of bile acids in MS, we studied the in vitro effects of an endogenous bile acid, tauroursodeoxycholic acid (TUDCA), on astrocyte and microglial polarization. TUDCA prevented neurotoxic (A1) polarization of astrocytes and proinflammatory polarization of microglia in a dose-dependent manner. TUDCA supplementation in experimental autoimmune encephalomyelitis reduced the severity of disease through its effects on G protein–coupled bile acid receptor 1 (GPBAR1). We demonstrate that bile acid metabolism was altered in MS and that bile acid supplementation prevented polarization of astrocytes and microglia to neurotoxic phenotypes and ameliorated neuropathology in an animal model of MS. These findings identify dysregulated bile acid metabolism as a potential therapeutic target in MS.

Objective To assess the association between diet quality and intake of specific foods with disability and symptom severity in people with multiple sclerosis (MS). Methods In 2015, participants in the North American Research Committee on MS (NARCOMS) Registry completed a dietary screener questionnaire that estimates intake of fruits, vegetables and legumes, whole grains, added sugars, and red/processed meats. We constructed an overall diet quality score for each individual based on these food groups; higher scores denoted a healthier diet. We assessed the association between diet quality and disability status as measured using Patient-Determined Disease Steps (PDDS) and symptom severity using proportional odds models, adjusting for age, sex, income, body mass index, smoking status, and disease duration. We assessed whether a composite healthy lifestyle measure, a healthier diet, healthy weight (body mass index <25), routine physical activity, and abstinence from smoking was associated with symptom severity. Results Of the 7,639 (68%) responders, 6,989 reported physician-diagnosed MS and provided dietary information. Participants with diet quality scores in the highest quintile had lower levels of disability (PDDS; proportional odds ratio [OR] for Q5 vs Q1 0.80; 95% confidence interval [CI] 0.69–0.93) and lower depression scores (proportional OR for Q5 vs Q1 0.82; 95% CI 0.70–0.97). Individuals reporting a composite healthy lifestyle had lower odds of reporting severe fatigue (0.69; 95% CI 0.59–0.81), depression (0.53; 95% CI 0.43–0.66), pain (0.56; 95% CI 0.48–0.67), or cognitive impairment (0.67; 95% CI 0.55–0.79). Conclusions Our large cross-sectional survey suggests a healthy diet and a composite healthy lifestyle are associated with lesser disability and symptom burden in MS.

Our objective was to determine if amyotrophic lateral sclerosis (ALS) risk varies according to body mass index (BMI) captured up to three decades earlier. At baseline 537,968 females and 562,942 males in five ongoing cohorts reported height, current weight and weight at age 18/21 years. During 14–28 years of follow-up, 1153 participants developed ALS. Cohort-specific Cox proportional hazards models were used to estimate rates that were then pooled with random-effects models. Results showed that lower BMI at baseline was associated with ALS; for each 5-unit increase in BMI, ALS rates were 21% lower (95% CI 14% 27%). Compared to individuals with healthy BMI, ALS rates were significantly lower among the overweight (RR = 0.76 (95% CI 0.62–0.93)) and obese (RR = 0.73 (95% CI 0.55–0.96)). Among never smokers the association persisted: RR = 0.75 (95% CI 0.65–0.85) for each 5-unit increase. Excluding the first seven years of follow-up, the associations were materially unchanged suggesting that weight loss from undiagnosed disease does not fully explain the findings. Overall, 75% of males and females had a healthy BMI at age 18/21 years, 15% of males and 8% of females were overweight or obese; there was no association with ALS although numbers with an unhealthy weight were small. In conclusion, these findings support an association between lower premorbid BMI and ALS.

Multiple sclerosis (MS) is a debilitating disease of the central nervous system characterized by episodic periods of inflammatory demyelination and progressive neurologic deficits.^1,2 The higher MS risk among individuals with low vitamin D intake³ or low circulating 25-hydroxyvitamin D (25[OH]D)^4-6 levels and the worse prognosis among patients with MS who have low 25(OH)D levels^7-12 suggest that these low levels may contribute to the disease process. Most recently, a previous study indicated that individuals with average serum 25(OH)D levels less than <50.0 nmol/L (to convert to nanograms per milliliter, divide by 2.496) in the 12 months following a first demyelinating event had worse clinical and imaging outcomes after 5 years than did those with higher levels.⁷ However, since average 25(OH)D levels in that study were low and there was no clear ceiling effect, the optimal serum level of 25(OH)D could not be identified. In addition, it is important to determine whether this association between 25(OH)D and MS outcomes differs among subgroups of patients and particularly whether it applies to patients with high disease activity who may benefit from other potential therapeutic alternatives.¹³ To address these issues, we conducted a prospective study among a large group of patients with relapsing-remitting MS treated with interferon beta-1b with a wide distribution of serum 25(OH)D levels and disease severity.