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

Publication date: Mar 17, 2020

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 through its effects on GPBAR1, 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.

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Bhargava, P., Smith, M.D., Mische, L., Harrington, E.P., Fitzgerald, K.C., Martin, K.A., Kim, S., Reyes, A.A.A., Gonzalez-Cardona, J., Volsko, C., Tripathi, A., Singh, S., Varanasi, K., Lord, H.N., Meyers, K.R., Taylor, M., Gharagozloo, M., Sotirchos, E.S., Nourbakhsh, B., Dutta, R., Mowry, E., Waubant, E., and Calabresi, P.A. Bile acid metabolism is altered in multiple sclerosis and supplementation ameliorates neuroinflammation. 20475. 2020 J Clin Invest.

Concepts Keywords
Astrocyte Ursodeoxycholic acid
Astrocytes Microglia
Bile Glial cells
Bile Acid Bile acid
Brain Medicine
Cholesterol Hepatology
Endogenous Branches of biology
Glial Cells Medical specialties
Immune System MS
Metabolism Experimental autoimmune encephalomyelitis
Metabolomic Altered multiple sclerosis
Microglia Neuroinflammation
Multiple Sclerosis Neuroscience
Neuropathology
Neurotoxic
Pediatric
Phenotypes
Polarization
Receptors
White Matter

Semantics

Type Source Name
disease MESH multiple sclerosis
disease MESH demyelinating disorder
drug DRUGBANK Cholesterol
pathway REACTOME Immune System
drug DRUGBANK Tauroursodeoxycholic acid
disease MESH experimental autoimmune encephalomyelitis
disease MESH bile
disease MESH Pathology
drug DRUGBANK Antithymocyte immunoglobulin (rabbit)
disease MESH inflammation
disease MESH abnormalities
pathway KEGG Cholesterol metabolism
drug DRUGBANK Glycine
drug DRUGBANK Taurine
drug DRUGBANK Ursodeoxycholic acid
disease MESH metabolic diseases
disease MESH dysbiosis
drug DRUGBANK Deoxycholic Acid
drug DRUGBANK Dichloroacetic Acid
drug DRUGBANK Cholic Acid
drug DRUGBANK Chenodeoxycholic acid
disease MESH neurological disorders
disease MESH death
disease MESH neurodegenerative disorders
disease MESH astrocytosis
drug DRUGBANK Isoxaflutole
disease MESH mild cognitive impairment
drug DRUGBANK Obeticholic acid
disease MESH aging
disease MESH fasting
pathway KEGG Metabolic pathways
drug DRUGBANK Phosphate ion
drug DRUGBANK Human Serum Albumin
drug DRUGBANK Nitrogen
drug DRUGBANK Methionine
drug DRUGBANK Pyridoxal Phosphate
drug DRUGBANK Citric Acid
drug DRUGBANK Biotin
disease MESH dissociation
drug DRUGBANK Papain
drug DRUGBANK L-Lysine
drug DRUGBANK Streptomycin
drug DRUGBANK L-Cysteine
drug DRUGBANK Edetic Acid
drug DRUGBANK Dextrose unspecified form
drug DRUGBANK L-Glutamine
drug DRUGBANK Colforsin
disease MESH pertussis
pathway KEGG Pertussis
disease MESH paralysis
drug DRUGBANK Isoflurane
drug DRUGBANK Collagenase clostridium histolyticum
disease MESH separated
drug DRUGBANK Pentaerythritol tetranitrate
drug DRUGBANK Sucrose
drug DRUGBANK Gold
drug DRUGBANK Aspartame
disease MESH Mult
disease MESH secondary progressive multiple sclerosis
drug DRUGBANK Guanosine
disease MESH autoimmunity
disease MESH autoimmune encephalitis
disease MESH amyotrophic lateral sclerosis
disease MESH Relapsing remitting Multiple Sclerosis
disease MESH X linked adrenoleukodystrophy
pathway KEGG Tryptophan metabolism
disease MESH cancer

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