Metabolic alterations in multiple sclerosis and the impact of vitamin D supplementation

Bhargava, Pavan; Fitzgerald, Kathryn C.; Calabresi, Peter A.; Mowry, Ellen M.

doi:10.1172/jci.insight.95302

Cited by 96 publications

(90 citation statements)

References 44 publications

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“…Numerous studies had shown increased free radical activity, and/or deficiencies in important antioxidant enzymes in patients with MS compared with healthy controls [36]. From the metabolomics point of view, several study demonstrate the key role of metabolites linked to the presence of oxidative stress in MS [37,38]. Interestedly, Koch et al analyzed the serum and peripheral blood leukocytes from patients with benign relapsing remitting MS, secondary progressive MS, primary progressive MS and healthy controls found increased ROS formation occurs in all subgroups of MS, but the highest production of ROS was found in patients with PPMS [39].…”

Section: Discussionmentioning

confidence: 99%

Multi-Platform Characterization of Cerebrospinal Fluid and Serum Metabolome of Patients Affected by Relapsing–Remitting and Primary Progressive Multiple Sclerosis

Murgia

Lorefice

Poddighe

et al. 2020

JCM

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Background: Multiple sclerosis (MS) is a chronic immunemediated disease of the central nervous system with a highly variable clinical presentation and disease progression. In this study, we investigate the metabolomics profile of patients affected by relapsing–remitting MS (RRMS)and primary progressive MS (PPMS), in order to find potential biomarkers to distinguish between the two forms. Methods: Cerebrospinal Fluid CSF and blood samples of 34 patients (RRMS n = 22, PPMS n = 12) were collected. Nuclear magnetic resonance (1H-NMR) and mass spectrometry (coupled with a gas chromatography and liquid chromatography) were used as analytical techniques. Subsequently, a multivariate statistical analysis was performed; the resulting significant variables underwent U-Mann–Whitney test and correction for multiple comparisons. Receiver Operating Characteristic ROC curves were built and the pathways analysis was conducted. Results: The analysis of the serum and the CSF of the two classes, allowed the identification of several altered metabolites (lipids, biogenic amines, and amino acids). The pathways analysis indicated the following pathways were affected: Glutathione metabolism, nitrogen metabolism, glutamine–glutamate metabolism, arginine–ornithine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis etc. Conclusion: The analysis allowed the identification of a set of metabolites able to classify RRMS and PPMS patients, each of whom express different patterns of metabolites in the two biofluids.

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Section: Discussionmentioning

confidence: 99%

Multi-Platform Characterization of Cerebrospinal Fluid and Serum Metabolome of Patients Affected by Relapsing–Remitting and Primary Progressive Multiple Sclerosis

Murgia

Lorefice

Poddighe

et al. 2020

JCM

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“…The circulating metabolome can be substantially affected by environmental exposures and gut microbiota and hence provides insight into these important factors that influence MS risk and pathogenesis (6). Several studies have demonstrated abnormalities in the metabolome in MS (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Bile acid metabolism is altered in multiple sclerosis and supplementation ameliorates neuroinflammation

Bhargava

Smith

Mische

et al. 2020

Journal of Clinical Investigation

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109

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“…Global metabolomics analyses were performed at Metabolon Inc (Durham, NC) as previously described 33 . In brief, recovery standards were added prior to the extraction process for quality control.…”

Section: Global Metabolomics Analysesmentioning

confidence: 99%

Bile acid metabolism is altered in multiple sclerosis and supplementation ameliorates neuroinflammation

Bhargava¹,

Mische²,

Smith³

et al. 2019

Preprint

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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 the CNS and 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 MS patients compared to 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 pro-inflammatory polarization of microglia in a dose-dependent manner. TUDCA supplementation in experimental autoimmune encephalomyelitis reduced severity of disease, based on behavioral and pathological measures. We demonstrate that bile acid metabolism is altered in MS; bile acid supplementation prevents polarization of astrocytes and microglia to neurotoxic phenotypes and ameliorates neuropathology in an animal model of MS. These findings identify dysregulated bile acid metabolism as a potential therapeutic target in MS. An endogenous bile acid blocks neurotoxic polarization of astrocytes and proinflammatory polarization of microgliaSince bile acid receptors are present on astrocytes and inflammatory cells in MS tissue, we investigated the effects of a bile acid -TUDCA on these cell populations in vitro. We chose TUDCA since it is currently being tested in multiple human trials in various neurological disorders including MS 20 . We treated murine astrocytes with IL-1α, TNF-α, and C1q to polarize them to a neurotoxic (A1) phenotype 21 . We tested the effect of two doses of TUDCA and an agonist of GPBAR-1 (INT-777) in these polarizing conditions. TUDCA treatment blocked the upregulation of A1-specific gene transcripts in a dose dependent manner (Figure 4a).Interestingly, INT-777 partially recapitulated the effects of TUDCA on astrocyte polarization.

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Metabolic alterations in multiple sclerosis and the impact of vitamin D supplementation

Cited by 96 publications

References 44 publications

Multi-Platform Characterization of Cerebrospinal Fluid and Serum Metabolome of Patients Affected by Relapsing–Remitting and Primary Progressive Multiple Sclerosis

Multi-Platform Characterization of Cerebrospinal Fluid and Serum Metabolome of Patients Affected by Relapsing–Remitting and Primary Progressive Multiple Sclerosis

Bile acid metabolism is altered in multiple sclerosis and supplementation ameliorates neuroinflammation

Bile acid metabolism is altered in multiple sclerosis and supplementation ameliorates neuroinflammation

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