S. Baranzini
University of California San Francisco NeurologyAuthor Of 2 Presentations
FC04.05 - Understanding the relative contributions of obesity, vitamin D, leptin and adiponectin to MS risk: a Mendelian randomization mediation analysis
Abstract
Background
Obesity is increasingly recognized as a risk for multiple sclerosis (MS). While the underlying mechanisms remain undetermined, reduced vitamin D bioavailability and altered levels of the immunomodulatory cytokines adiponectin and leptin have been proposed.
Objectives
To determine the roles of vitamin D, adiponectin and leptin levels in explaining the effect of obesity on MS, using a Mendelian randomization (MR) mediation framework.
Methods
Independent genetic estimates for body mass index (BMI), 25-hydroxyvitamin D (25OHD), adiponectin and leptin levels were obtained from from large-scale genome-wide association studies and the UK Biobank, totalling over 800,000 participants. The effect on MS was measured using summary genetic data on 14,802 MS cases and 26,703 controls from the International MS Genetics Consortium (IMSGC). To avoid bias from population stratification, all participants were of European ancestry. We estimated the odds of MS for each of the exposures, and the proportion of the effect of BMI explained by potential mediators significantly associated with MS, using the product of coefficients method in a two-step MR framework.
Results
Each standard deviation (SD) increase in BMI was associated with a 40% increase in the odds of MS (95% CI 1.16 to 1.67, P=3.1x10-4). Similarly, a SD increase in standardized log transformed 25OHD levels reduced the odds of MS by 28% (95% CI 0.60-0.87, P=6.2x10-4). In contrast, we observed no notable effect of adiponectin (OR=1.05, 95% CI 0.74-1.49, P=0.78) or leptin (OR=1.18, 95% CI 0.59-2.36, P=0.64) on the odds of MS. In MR mediation analysis, we estimate that the reduction in 25OHD levels only explains 5.4% of the effect of increased BMI on the risk of MS (95% CI 0.4% to 30.5%). Sensitivity analyses showed that these estimates were robust to potential bias from pleiotropy.
Conclusions
This study found that only a minority of the increased risk of MS conferred by obesity is mediated by lowered vitamin D levels, while leptin and adiponectin had no measurable effect. This suggests that vitamin D supplementation would only modestly reverse the effect of obesity on MS, the majority of which remains unexplained.
PS10.05 - Gut dysbiosis in neuromyelitis optica promotes CNS autoimmunity
Abstract
Background
Neuromyelitis optica (NMO) is a severe demyelinating disease of the central nervous system (CNS) causing irreversible neurological damage. Initial analyses of gut microbiota in NMO, multiple sclerosis and healthy controls (HHC) revealed dysbiosis in the NMO group, suggesting that the gut microbiome may regulate inflammatory responses
Objectives
We hypothesized that gut microbiota from NMO patients may participate and promote inflammatory responses in NMO pathogenesis.
Methods
Wild-type (WT) C57BL/6 germ-free mice were colonized with fecal samples from one untreated NMO patient (n = 10), one household HC (HHC) (n = 9) or vehicle (n = 13) for five weeks and then examined for susceptibility to MOG p35-55-induced experimental autoimmune encephalomyelitis (EAE) for 30 days post immunization. Upon termination of the study, lymphocytes from spleen, lamina propria of small (LP-SI) and large (LP-LI) intestine, mesenteric lymph nodes (MLN), Peyer’s patches (PP), brain, and spinal cord were examined for the expression of IL-17, IFN-γ, Foxp3, CD25, RORγt and Helios.
Results
In comparison to the mean EAE score of the vehicle group (1.9 ± 0.3), severity was greater (p ≤ 0.01) in mice colonized with fecal microbiota from NMO (3.1 ± 0.8) and HHC (2.7 ± 0.7). The mean clinical score of mice colonized with NMO gut microbiota was significantly greater than mice colonized with gut microbiota from HHC or vehicle (p ≤ 0.001). The frequency of CD4+Foxp3+CD25+ cells was decreased in LP-SI, LP-LI, PP and MLN compartments in NMO and HHC compared with vehicle group (p ≤ 0.01). CD4+Foxp3+Helios+ (another regulatory T cell subpopulation) was significantly decreased in MLN and LP-SI of NMO and HHC compared to vehicle group (P ≤ 0.01).
Conclusions
Our data suggest that NMO fecal microbiota increases EAE susceptibility. Reduction in frequency of Tregs in the gut of mice colonized with NMO fecal material may contribute to EAE exacerbation. Further analysis of microbiota and lymphocyte populations in mice colonized with fecal material from NMO and HHC samples are needed. Results from our ongoing study should provide valuable insight regarding the potential role of gut microbiota in NMO.