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June 3, 2024

Treatment for multiple sclerosis: bile acid supplementation prevents polarization of astrocytes and microglia to neurotoxic phenotypes

Multiple sclerosis (MS) is a non-contagious autoimmune neurological disease of the central nervous system. MS is a degenerative disease affecting the psychological and physical conditions of the patients, as well as both patients’ and caregivers’ quality of life with a relevant economic burden.[1]

The estimated number of people with MS worldwide has increased to 2.8 million.

In general, MS is more common in areas farthest from the equator. In the last decade, MS’ prevalence has risen worldwide. However, prevalence rates may differ significantly among groups living in the same geographic area regardless of distance from the equator.

countries with most multiple sclerosis

Prevalence (per 100,000 persons) of new diagnosis of MS[2]

Correlation between multiple sclerosis and bile acid metabolism

Many scientific research studies on multiple sclerosis reveal a direct connection between eating habits, human intestinal microbiota, and the development of chronic-degenerative diseases[AG1] [CR2] . In several studies, multiple sclerosis patients have shown an altered gut-microbiome which increases intestinal permeability and changes the bile acid metabolism.

Bile acid metabolism is abnormal in MS. In general, bile acids have important effects on key inflammatory pathways and are neuroprotective. Theseconjectures  have driven scientists to investigate the role of bile acids in modulating neuroinflammation in multiple sclerosis.[3]

Another important aspect is that the farnesoid X receptor (FXR), also known as the bile acid receptor, is detected in demyelinating lesions in MS brains as well as the cell-surface bile acid receptor GPBAR1. The presence of both BAs receptors on immune and glial cells in chronic MS lesions confirmed the possibility that BAs and their metabolites could play a role in modulating the disease.

TUDCA, Tauroursodeoxycholic acid (TUDCA), an endogenous bile acid, blocked the polarization of astrocytes to a neurotoxic phenotype and the polarization of microglia to a proinflammatory phenotype in vitro and in animal models.

The role of TUDCA supplement in progressive Multiple Sclerosis

An observational cohort study, conducted at Johns Hopkins University from June 2018 to April 2022, evaluated the safety and efficacy of TUDCA supplementation in progressive multiple sclerosis. This randomised, double-blind, placebo-controlled and single-centre phase 1/2a study found that TUDCA supplementation in progressive multiple sclerosis was safe and tolerable[4].

TUDCA supplements effects in MS patients

Image4

Didascalia dell’immagine: Patients on TUDCA supplements experienced significant reductions in levels of several types of inflammatory T-cells such as multiple T cell populations which, in several studies, decreased compared to placebo.

Preclinical studies indicate that TUDCA is a potent inhibitor of apoptosis, the process of programmed cell death, but also of H2O2-induced oxidative stress.

TUDCA has a protective effect on mitochondria, by producing an anti-neuroinflammatory action, and acting as a chemical chaperone to maintain the stability and correct folding of the quaternal stage of proteins. 

Microglia can be found polarized in two forms, M1 and M2: M1 are the pro-inflammatory isoform whereas M2 are anti-inflammatory. Mitochondrial health can influence this polarisation. In multiple sclerosis states, these polarizations are dysregulated.

Macrophages effects in multiple sclerosis

Image[5]

M1 form attacks the myelin sheath or the cells, while M2 microglia release anti-inflammatory mediators. The first isoform (M1) causes inflammation and injury to the nerve and to the nerve fibers, whereas M2 microglial cells can promote cell tissue repair and regeneration, enhance phagocytic activity, and play a neuroprotective role. The process can result in multiple areas of scarring (sclerosis). Targeting the polarization of microgliais a functional treatment option to restore remyelination.

Astrocytes (astroglia), the most abundant cell type in the central nervous system (CNS), support neuronal activity. Astrocytes are key components for the functionality of the blood brain barrier (BBB). Neural functionality and survival depend on the delivery of supplements such as oxygen, ions, and glucose through the blood supply, and their adjustment according to the neural activity. Abnormal astrocytes are present since the early stage of MS and have a role in disease progression.

Recently, the importance of astrocyte polarization in the pathogenesis of MS has been described. Astrocytes are classified as “A1” astrocytes when are characterized by their neurotoxic, proinflammatory action and as “A2” when they improve the formation of synapses with a neuroprotective effect.

TUDCA supplementation can increase the number of A2 astrocytes and block their polarization to an A1 phenotype.3

Conclusion

The Multiple Sclerosis (MS) treatment scenario is deeply changing. This disease can’t be treated exclusively with disease modify drugs, something more must be investigated, like the role of biological molecules that can reduce adverse effects of the therapies and ameliorate MS patients’ quality of life.

Keyword utilizzate:

  • multiple sclerosis treatment
  • treatment for multiple sclerosis
  • research on multiple sclerosis
  • bile acid metabolism
  • bile acid multiple sclerosis
  • tudca multiple sclerosis
  • TUDCA supplement
  • bile acid supplements
  • bile acid supplement
  • bile acid supplementation

[1] Battaglia MA, Bezzini D, Cecchini I, Cordioli C, Fiorentino F, Manacorda T, Nica M, Ponzio M, Ritrovato D, Vassallo C, Patti F. Patients with multiple sclerosis: a burden and cost of illness study. J Neurol. 2022 Sep;269(9):5127-5135.

[2] Illustration by Bailey Mariner, from “Multiple Sclerosis: Facts, Statistics, and You” Medically reviewed by Hammond N and Koskie B, 2022

[3] Bhargava P, Smith MD, Mische L, Harrington E, Fitzgerald KC, Martin K, Kim S, Reyes AA, Gonzalez-Cardona J, Volsko C, Tripathi A, Singh S, Varanasi K, Lord HN, Meyers K, Taylor M, Gharagozloo M, Sotirchos ES, Nourbakhsh B, Dutta R, Mowry EM, Waubant E, Calabresi PA. Bile acid metabolism is altered in multiple sclerosis and supplementation ameliorates neuroinflammation. J Clin Invest. 2020 Jul 1;130(7):3467-3482. 

[4] Ladakis DC, Harrison KL, Smith MD, Solem K, Gadani S, Jank L, Hwang S, Farhadi F, Dewey BE, Fitzgerald KC, Sotirchos ES, Saidha S, Calabresi PA, Bhargava P. Bile acid metabolites predict multiple sclerosis progression and supplementation is safe in progressive disease. medRxiv [Preprint]. 2024 Jan 23:2024.01.17.24301393. 

[5] Kuntzel T, Bagnard D. Manipulating Macrophage/Microglia Polarization to Treat Glioblastoma or Multiple Sclerosis. Pharmaceutics. 2022; 14(2):344. https://doi.org/10.3390/pharmaceutics14020344


 [AG1]Quando pubblicate l’articolo, aggiungete a queste parole il link all’articolo 3 “How diet affects the gut microbiome and its implications for diseases”

 [CR2]Translation: when you publish the article, add to these words the link to article of the website “How diet affects the gut microbiome and its implications for diseases”