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

Bhargava, Pavan; Smith, Matthew D.; Mische, Leah; Harrington, Emily P.; Fitzgerald, Kathryn C.; Martin, Kenneth E.; Kim, Sol; Reyes, Arthur Anthony; Cardona, Jaime Gonzalez; Volsko, Christina; Tripathi, Ajai K.; Singh, Sonal; Varanasi, Kesava; Lord, Hannah Noelle; Meyers, Keya; Taylor, Michelle; Gharagozloo, Marjan; Sotirchos, Elias S.; Nourbakhsh, Bardia; Dutta, Ranjan; Mowry, Ellen M.; Waubant, Emmanuelle; Calabresi, Peter A.

doi:10.1172/jci129401

Cited by 119 publications

(111 citation statements)

References 52 publications

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“…We recently identified lower levels of multiple primary and secondary bile acids in patients with MS compared to controls. 36 The alterations in bile acid metabolism were most pronounced in the progressive MS group using both untargeted and targeted metabolomics approaches. Interestingly, we also noted abnormalities in primary bile acid metabolism in pediatric MS patients.…”

Section: Specific Pathways Identified Using Metabolomics Could Be Trementioning

confidence: 97%

Metabolomics in multiple sclerosis disease course and progression

Bhargava

Anthony

2020

Mult Scler

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Multiple sclerosis (MS) is associated with changes in the metabolome. Numerous studies employing varying metabolomics platforms have examined a range of biological material ranging from brain tissue to urine and demonstrated consistently alterations in multiple metabolic pathways in MS. We review not only the studies that describe the ability of metabolomics to differentiate MS patients from healthy controls and other neurological disease but also discuss the potential of metabolomics-based methods to build predictive models that are able to stage disease, monitor progression, and select the most appropriate therapy. The increasing number of impressive claims for the capacity of metabolomics to distinguish between different types of demyelinating disease suggests that the provision of such tests may be close at hand. Besides the ability to provide potential diagnostic and prognostic biomarkers, metabolomics also provides us with unique insights into the pathophysiology of the disease and helps identify metabolic pathways that may be potential therapeutic targets. Future studies will integrate metabolomics data with other omics techniques to provide further insight into the source of these metabolic abnormalities and help with identification of the most promising targets for therapeutic intervention.

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Section: Specific Pathways Identified Using Metabolomics Could Be Trementioning

confidence: 97%

Metabolomics in multiple sclerosis disease course and progression

Bhargava

Anthony

2020

Mult Scler

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“…Hence, lower BCAA levels could potentially impair Treg number and function and predispose to increased inflammatory T cell activity (43). We recently linked observations of reduced bile acids in people with MS to key underlying mechanisms and found that bile acid supplementation prevented the polarization of astrocytes and microglia to neurotoxic phenotypes in EAE models (44). Here, we also noted changes in xenobiotic metabolism – including xanthine/caffeine metabolism in MS. Caffeine metabolism is altered in other neurodegenerative disorders, and intake of caffeine has been linked to the risk of developing MS as well as disease severity; our results may suggest that altered caffeine metabolism may underlie the observed associations.…”

Section: Discussionmentioning

confidence: 99%

Multi-omic Evaluation of Metabolic Alterations in Multiple Sclerosis Identifies Shifts in Aromatic Amino Acid Metabolism

Fitzgerald

Smith

Sotirchos

et al. 2021

Preprint

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The circulating metabolome is a product of interactions between the genome, epigenome, exposome and microbiome. The metabolome may be altered in people with multiple sclerosis (MS); however, existing metabolomics studies were relatively small or characterized a limited number of metabolites. Herein, we performed a multi-site study profiling the circulating metabolome to obtain relative abundances for 269 metabolites in a large cohort of MS patients and healthy controls. After adjusting for batch effects and extensive quality control, we created an overall metabolic dysfunction score, defined apriori sets of metabolites using known metabolic pathways, and derived novel networks of correlated metabolites using a weighted correlation network analysis (WGCNA). We assessed whether metabolic dysfunction, individual metabolites, metabolic pathways or WGCNA-identified module scores differed between people with MS versus healthy controls (HC) after adjusting for age, sex and race using generalized estimating equations (participants could provide multiple samples). In a subset of patients, information on disability status was also available. Similar models assessed the association between metabolites and metabolite sets with measures of disability. In people with MS, we identified striking abnormalities in a WGCNA-defined module enriched in aromatic amino acid (AAA) metabolites (FDR-adjusted p-value=2.77E-18) that are also strongly associated with disability (FDR-adjusted p-value for AAA module=1.01E-4). Consistent results were obtained using apriori-defined metabolite sets or in analyses of individual metabolites. The identified abnormalities likely relate to imbalances in gut microbial metabolism of AAAs resulting in reduced production of immunomodulatory metabolites and increased production of metabotoxins (indole acetate, phenylacetylglutamine, p-cresol sulfate, p-cresol glucuronide). Single cell RNA sequencing data analysis demonstrated altered AAA metabolism in CSF and blood derived monocyte cell populations, while treatment of human peripheral blood mononuclear cells with AAA-derived metabotoxins resulted in increased production of tumor necrosis factor-α. We identify novel metabolic alterations in people with MS potentially contributing to disease pathophysiology.

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“…In addition, there are reports of abnormalities in bile acids in the blood of MS patients, with altered cholesterol metabolism in astrocytes, associated with neuroinflammation in EAE [93,132]. Based on these findings, bile acid metabolism may provide new targets for therapeutic intervention in MS. To identify alterations in bile acid metabolism, a recent study by Bhargava et al applied a global untargeted and targeted metabolomics approach using UPLC-MS-MS and LC-MS/MS on plasma samples from multiple cohorts of adult (discovery cohort: 56 RRMS, 51 PMS, and 52 controls; validation cohort: 50 RRMS, 125 PMS, and 75 controls) and pediatric (31 MS and 31 controls) patients [133]. They reported significantly reduced levels of several bile acid metabolites in patients compared to controls, with a more pronounced effect in samples from patients with progressive form of the disease.…”

Section: Application Of Metabolomics In Ms Therapeuticsmentioning

confidence: 99%

An emerging potential of metabolomics in multiple sclerosis: a comprehensive overview

Zahoor

Rui

Khan

et al. 2021

Cell. Mol. Life Sci.

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Multiple sclerosis (MS) is an inflammatory demyelinating disease of the nervous system that primarily affects young adults. Although the exact etiology of the disease remains obscure, it is clear that alterations in the metabolome contribute to this process. As such, defining a reliable and disease-specific metabolome has tremendous potential as a diagnostic and therapeutic strategy for MS. Here, we provide an overview of studies aimed at identifying the role of metabolomics in MS. These offer new insights into disease pathophysiology and the contributions of metabolic pathways to this process, identify unique markers indicative of treatment responses, and demonstrate the therapeutic effects of drug-like metabolites in cellular and animal models of MS. By and large, the commonly perturbed pathways in MS and its preclinical model include lipid metabolism involving alpha-linoleic acid pathway, nucleotide metabolism, amino acid metabolism, tricarboxylic acid cycle, d-ornithine and d-arginine pathways with collective role in signaling and energy supply. The metabolomics studies suggest that metabolic profiling of MS patient samples may uncover biomarkers that will advance our understanding of disease pathogenesis and progression, reduce delays and mistakes in diagnosis, monitor the course of disease, and detect better drug targets, all of which will improve early therapeutic interventions and improve evaluation of response to these treatments.

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

Cited by 119 publications

References 52 publications

Metabolomics in multiple sclerosis disease course and progression

Metabolomics in multiple sclerosis disease course and progression

Multi-omic Evaluation of Metabolic Alterations in Multiple Sclerosis Identifies Shifts in Aromatic Amino Acid Metabolism

An emerging potential of metabolomics in multiple sclerosis: a comprehensive overview

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