Evidence for a causal relationship between low vitamin D, high BMI, and pediatric-onset MS

Gianfrancesco, Milena; Stridh, Pernilla; Rhead, Brooke; Shao, Xiaorong; Xu, Edison; Graves, Jennifer; Chitnis, Tanuja; Waldman, Amy; Lotze, Timothy; Schreiner, Teri; Belman, Anita; Greenberg, Benjamin; Weinstock‐Guttman, Bianca; Aaen, Gregory; Tillema, Jan Mendelt; Hart, Janace; Caillier, Stacy J.; Ness, Jayne; Harris, Yolanda; Rubin, Jennifer; Candee, Meghan; Krupp, Lauren; Gorman, Mark; Benson, Lina; Rodriguez, Moses; Mar, Soe; Kahn, Ilana; Rose, John; Roalstad, Shelly; Casper, T. Charles; Shen, Lei; Quach, Hong; Quach, Diana; Hillert, J.; Bäärnhielm, Maria; Hedström, Anna Karin; Olsson, Tomas; Kockum, Ingrid; Alfredsson, Lars; Metayer, Catherine; Schaefer, Catherine; Barcellos, Lisa F.; Waubant, Emmanuelle

doi:10.1212/wnl.0000000000003849

Cited by 141 publications

(136 citation statements)

References 39 publications

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“…25OHD levels were used to adjust analyses because they are associated with risk of MS onset and MS outcomes, such as relapse and possibly disability 26, 27…”

Section: Methodsmentioning

confidence: 99%

Altered tryptophan metabolism is associated with pediatric multiple sclerosis risk and course

Nourbakhsh

Bhargava

Tremlett

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo determine if altered tryptophan (Trp) metabolism is associated with MS risk or disease severity in children.MethodsParticipants with pediatric‐onset MS and clinically isolated syndrome (CIS) within 4 years of disease onset and healthy controls underwent collection of serum. Longitudinal disability and processing speed measures and relapse data were collected in cases. Global metabolomics were conducted in 69/67 cases/controls. Targeted Trp measurement was performed in a discovery group (82 cases, 50 controls) and a validation group (92 cases, 50 controls), while functional gut microbiome analysis was done in 17 cases. Adjusted logistic, linear and negative binomial regression and Cox‐proportional hazard models were used.ResultsUsing global metabolomics data, higher relative abundances of Trp and indole lactate, a known gut microbiota‐derived Trp metabolite, were associated with lower risk of MS. In cases, higher relative abundances of gut microbiota‐derived Trp metabolites were associated with lower disability and higher processing speed scores and higher relative abundance of kynurenine was associated with higher relapse rate. Using targeted tryptophan measures, in the discovery and validation groups, each 1 mcg/mL increase in serum Trp level was associated with 20% (95% CI: 4–34%) and 32% (95% CI: 16–44%) decrease in adjusted odds of having MS, respectively. A lower relative abundance of gut microbial genes involved in Trp catabolism was associated with higher relapse risk.InterpretationTrp metabolism by the gut microbiota and the kynurenine pathway may be relevant to the risk of MS in children as well as MS activity and severity.

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“…25OHD levels were used to adjust analyses because they are associated with risk of MS onset and MS outcomes, such as relapse and possibly disability 26, 27…”

Section: Methodsmentioning

confidence: 99%

Altered tryptophan metabolism is associated with pediatric multiple sclerosis risk and course

Nourbakhsh

Bhargava

Tremlett

et al. 2018

Ann Clin Transl Neurol

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“…Although there has been a lot of research on vitamin D status and MS risk in adult-onset cases, there is lack of data on association with pediatric-onset MS (64)(65)(66). A recent meta-analysis based on Mendelian randomization has used instrumental variable analysis to provide evidence for causal and independent association between low vitamin D levels and increased body mass index (BMI) with the risk of developing pediatric MS (64).…”

Section: Ms Risk and Vitamin Dmentioning

confidence: 99%

“…A recent meta-analysis based on Mendelian randomization has used instrumental variable analysis to provide evidence for causal and independent association between low vitamin D levels and increased body mass index (BMI) with the risk of developing pediatric MS (64). In addition, there is evidence suggesting vitamin D-based regulation of klotho and nuclear factor-erythroid-2-related factor 2 (Nrf2) signaling pathways to be responsible for MS development as they are believed to maintain calcium and redox homeostasis within the body (67) and as a result klotho and Nrf2 in conjunction with vitamin D (vitamin D-klothoNrf2) act as keepers of several cell signaling pathways including myelin synthesis pathway (68).…”

Section: Ms Risk and Vitamin Dmentioning

confidence: 99%

Vitamin D and Multiple Sclerosis: An Update

Zahoor

Haq

2017

Multiple Sclerosis: Perspectives in Treatment and Pathogenesis

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Multiple sclerosis (MS) is a long-lasting inflammatory neurodegenerative disease of the central nervous system caused by an inappropriate attack of the body' s immune system on its own cells. To date, its etiology remains highly enigmatic, with insufficient evidence on the exact cause triggering the disease. Many studies have highlighted the role of different environmental and genetic factors in its etiopathogenesis, each adding a new wedge to MS conundrum and therefore making it a multifactorial and polygenic disease. One of the entrants in the risk factor category for MS is vitamin D, and there is sufficient evidence to suggest its role in increasing the risk of MS development. MS patients have lower levels of vitamin D, and in conjunction with other factors like low sunlight intensity and genetic variations in vitamin D metabolic pathway genes, vitamin D has been adjudged as a potent risk factor for MS. The biological effects of vitamin D in the body are mediated by the vitamin D receptor that acts as a transcription factor after activation by vitamin D and subsequent heterodimerization with the retinoid-X receptor. This allows regulation of protein expression of target genes involved in diverse cellular processes including immune response and vitamin D metabolism. It clearly suggests use of vitamin D supplementation as an unconventional option for MS treatment; however, much work needs to be done to precisely determine the level and/or dosage of vitamin D required for achieving optimum therapeutic response in patients without causing adverse effects.

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“…Besides genetic factors, the etiopathogenesis of MS may be also associated with an altered immunological response during the Epstein-Barr virus infection, decreased vitamin D levels, and smoking (11)(12)(13). Although, some authors reported a link between childhood obesity and MS, this correlation has not been fully clarified; however, the authors believe that this is due to the low levels of vitamin D, since most of the vitamin D is deposited in the adipose tissue (14). Childhood obesity can also increase the risk of MS, independently of vitamin D levels.…”

Section: Introductionmentioning

confidence: 99%

“…Childhood obesity can also increase the risk of MS, independently of vitamin D levels. Low levels of serum vitamin D in mothers, during early stages of pregnancy, can also lead to an increased risk of MS in progeny (14). The consequential production of proinflammatory cytokines during the altered immunological response damages oligodendrocytes and myelin, causing plaques of inflammatory demyelination (15).…”

Section: Introductionmentioning

confidence: 99%

Multiple Sclerosis Therapies in Pediatric Patients: Challenges and Opportunities

Jančić

Nikolić

Ivančević

et al. 2017

Multiple Sclerosis: Perspectives in Treatment and Pathogenesis

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Multiple sclerosis (MS) is an autoimmune, chronic, inflammatory, and demyelinating disease of the central nervous system (CNS). The etiology of MS is most likely multifactorial; it is dependent on genetic, autoimmune, and environmental factors, with a variable course among patients. The two main clinical events that characterize MS are relapses and progression. In recent years, diagnosis and treatment of pediatric MS has drawn attention of the scientific community. Management of pediatric MS focuses on reducing relapses and symptoms via administration of disease-modifying drugs (DMDs) and specific symptomatic treatment. A multidisciplinary approach to pediatric MS treatment is preferred, which aims at alleviating and preventing the accumulation of neurological deficits. MS therapy should be based on DMDs, that is, immunomodulatory drugs. These drugs, which sequester immune system activity, are further subdivided into two categories: first-line and second-line immunomodulatory therapy. First-line immunomodulatory therapy (interferon beta-1a, interferon beta-1b, Multiple Sclerosis in Pediatric Patients 40and glatiramer acetate) is ineffective (either no response or partial response) in roughly 30% of patients. Patients with a poor response to first-line therapy require second-line immunomodulatory therapy (natalizumab, mitoxantrone, fingolimod, teriflunomide, azathioprine, rituximab, dimethyl fumarate, daclizumab, alemtuzumab, and ocrelizumab). In addition to immunomodulatory drugs, treatment of relapses also involves the use of high intravenous doses of corticosteroids, administration of intravenous immunoglobulins, and plasmapheresis.

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Evidence for a causal relationship between low vitamin D, high BMI, and pediatric-onset MS

Abstract: We provide evidence supporting independent and causal effects of decreased vitamin D levels and increased BMI on susceptibility to pediatric-onset MS.

Cited by 141 publications

References 39 publications

Altered tryptophan metabolism is associated with pediatric multiple sclerosis risk and course

Altered tryptophan metabolism is associated with pediatric multiple sclerosis risk and course

Vitamin D and Multiple Sclerosis: An Update

Multiple Sclerosis Therapies in Pediatric Patients: Challenges and Opportunities

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