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Untangling the most probable role for vitamin D3 in autism.

ABSTRACT: Recent studies indicate an important role for vitamin D3 in autism spectrum disorder (ASD), although its mechanism is not completely understood. The most puzzling aspect of ASD is that identical twins, who share identical DNA, do not have 100% concordance rates (?88% for identical and ?31% for fraternal twins). These findings provide major clues into the etiology: ASD must involve an environmental factor present in the prenatal milieu that both identical twins are not always exposed to because they do not always share it (i.e., placentas). Combined with the exponential increasing rates of ASD around the world, these observations suggest a contagious disease is probably transferred to the fetus via the placenta becoming infected by a cervical virus. Vitamin D3 boosts immune responses clearing viral infections and increases serotonin and estrogen brain levels. Here we review the different roles and untangle the most probable one vitamin D3 plays in ASD.

SUBMITTER: Godar DE

PROVIDER: S-EPMC5821151 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Untangling the most probable role for vitamin D<sub>3</sub> in autism.

Godar Dianne E DE Merrill Stephen J SJ

Dermato-endocrinology 20171023 1

Recent studies indicate an important role for vitamin D<sub>3</sub> in autism spectrum disorder (ASD), although its mechanism is not completely understood. The most puzzling aspect of ASD is that identical twins, who share identical DNA, do not have 100% concordance rates (∼88% for identical and ∼31% for fraternal twins). These findings provide major clues into the etiology: ASD must involve an environmental factor present in the prenatal milieu that both identical twins are not always exposed t ...[more]

PMID: 29484101

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Project description:BACKGROUNDAdverse drug reactions are unpredictable immunologic events presenting frequent challenges to clinical management. Systemically administered cholecalciferol (vitamin D3) has immunomodulatory properties. In this randomized, double-blinded, placebo-controlled interventional trial of healthy human adults, we investigated the clinical and molecular immunomodulatory effects of a single high dose of oral vitamin D3 on an experimentally induced chemical rash.METHODSSkin inflammation was induced with topical nitrogen mustard (NM) in 28 participants. Participant-specific inflammatory responses to NM alone were characterized using clinical measures, serum studies, and skin tissue analysis over the next week. All participants underwent repeat NM exposure to the opposite arm and then received placebo or 200,000 IU cholecalciferol intervention. The complete rash reaction was followed by multi-omic analysis, clinical measures, and serum studies over 6 weeks.RESULTSCholecalciferol mitigated acute inflammation in all participants and achieved 6 weeks of durable responses. Integrative analysis of skin and blood identified an unexpected divergence in response severity to NM, corroborated by systemic neutrophilia and significant histopathologic and clinical differences. Multi-omic and pathway analyses revealed a 3-biomarker signature (CCL20, CCL2, CXCL8) unique to exaggerated responders that is suppressed by cholecalciferol and implicates IL-17 signaling involvement.CONCLUSIONHigh-dose systemic cholecalciferol may be an effective treatment for severe reactions to topical chemotherapy. Our findings have broad implications for cholecalciferol as an antiinflammatory intervention against the development of exaggerated immune responses.TRIAL REGISTRATIONclinicaltrials.gov (NCT02968446).FUNDINGNIH and National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS; grants U01AR064144, U01AR071168, P30 AR075049, U54 AR079795, and P30 AR039750 (CWRU)).

Project description:Multiple sclerosis (MS) is a common disease of the central nervous system and a major cause of disability amongst young adults. Genome-wide association studies have identified many novel susceptibility loci including rs2248359. We hypothesized that genotypes of this locus could increase the risk of MS by regulating expression of neighboring gene, CYP24A1 which encodes the enzyme responsible for initiating degradation of 1,25-dihydroxyvitamin D3.We investigated this hypothesis using paired gene expression and genotyping data from three independent datasets of neurologically healthy adults of European descent. The UK Brain Expression Consortium (UKBEC) consists of post-mortem samples across 10 brain regions originating from 134 individuals (1231 samples total). The North American Brain Expression Consortium (NABEC) consists of cerebellum and frontal cortex samples from 304 individuals (605 samples total). The brain dataset from Heinzen and colleagues consists of prefrontal cortex samples from 93 individuals. Additionally, we used gene network analysis to analyze UKBEC expression data to understand CYP24A1 function in human brain.The risk allele, rs2248359-C, is strongly associated with increased expression of CYP24A1 in frontal cortex (p-value=1.45×10-13), but not white matter. This association was replicated using data from NABEC (p-value=7.2×10-6) and Heinzen and colleagues (p-value=1.2×10-4). Network analysis shows a significant enrichment of terms related to immune response in eight out of the 10 brain regions.The known MS risk allele rs2248359-C increases CYP24A1 expression in human brain providing a genetic link between MS and vitamin D metabolism, and predicting that the physiologically active form of vitamin D3 is protective. Vitamin D3's involvement in MS may relate to its immunomodulatory functions in human brain.Medical Research Council UK; King Faisal Specialist Hospital and Research Centre, Saudi Arabia; Intramural Research Program of the National Institute on Aging, National Institutes of Health, USA.

Project description:RationalePatients with chronic rhinosinusitis with nasal polyps (CRSwNP) have been shown to be vitamin D3 (VD3) deficient, which is associated with more severe disease and increased polyp size. To gain mechanistic insights into these observational studies, we examined the impact of VD3 deficiency on inflammation and VD3 metabolism in an Aspergillus fumigatus (Af) mouse model of chronic rhinosinusitis (Af-CRS).MethodsBalb/c mice were fed control or VD3 deficient diet for 4 weeks. Mice were then sensitized with intraperitoneal Af, and one week later given Af intranasally every three days for four weeks while being maintained on control or VD3 deficient diet. Airway function, sinonasal immune cell infiltrate and sinonasal VD3 metabolism profiles were then examined.ResultsMice with VD3 deficiency had increased Penh and sRaw values as compared to controls as well as exacerbated changes in sRaw when coupled with Af-CRS. As compared to controls, VD3 deficient and Af-CRS mice had reduced sinonasal 1α-hydroxylase and the active VD3 metabolite, 1,25(OH)2D3. Differential analysis of nasal lavage samples showed that VD3 deficiency alone and in combination with Af-CRS profoundly upregulated eosinophil, neutrophil and lymphocyte numbers. VD3 deficiency exacerbated increases in monocyte-derived dendritic cell (DC) associated with Af-CRS. Conversely, T-regulatory cells were decreased in both Af-CRS mice and VD3 deficient mice, though coupling VD3 deficiency with Af-CRS did not exacerbate CD4 or T-regulatory cells numbers. Lastly, VD3 deficiency had a modifying or exacerbating impact on nasal lavage levels of IFN-γ, IL-6, IL-10 and TNF-α, but had no impact on IL-17A.ConclusionsVD3 deficiency causes changes in sinonasal immunity, which in many ways mirrors the changes observed in Af-CRS mice, while selectively exacerbating inflammation. Furthermore, both VD3 deficiency and Af-CRS were associated with altered sinonasal VD3 metabolism causing reductions in local levels of the active VD3 metabolite, 1,25(OH)2D3, even with adequate circulating levels.

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Untangling the most probable role for vitamin D3 in autism.

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Untangling the most probable role for vitamin D<sub>3</sub> in autism.

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