Investigation of probiotics in multiple sclerosis

Abstract

None of the disease-modifying therapies (DMTs) currently being used for the management of multiple sclerosis (MS) are 100% effective. In addition, side effects associated with the use of these DMTs have limited the practice of combination therapy. Hence, there is a need for safe immunomodulatory agents to fine-tune the management of MS. The gut microbiome plays an important role in autoimmunity, and several studies have reported alterations in the gut microbiome of MS patients. Studies in animal model of MS have identified members of the gut commensal microflora that exacerbate or ameliorate neuroinflammation. Probiotics represent an oral, non-toxic immunomodulatory agent that could be used in combination with current MS therapy. We designed a pilot study to investigate the effect of VSL3 on the gut microbiome and peripheral immune system function in healthy controls and MS patients. VSL3 administration was associated with increased abundance of many taxa with enriched taxa predominated by Lactobacillus, Streptococcus, and Bifidobacterium species. At the immune level, VSL3 administration induced an anti-inflammatory peripheral immune response characterized by decreased frequency of intermediate monocytes (CD14^highCD16^low), decreased mean fluorescence intensity (MFI) of CD80 on classical monocytes as well as decreased human leukocyte antigen–antigen D related (HLA-DR) MFI on dendritic cells.

Keywords

Probiotic gut microbiome MS peripheral immune response

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References

Caporaso

Lauber

Walters

et al . Ultra-high-throughput microbial community analysis on the Illumina Hiseq and Miseq platforms. ISME J 2012; 6: 1621–1624.

Caporaso

Kuczynski

Stombaugh

et al . QIIME allows analysis of high-throughput community sequencing data. Nat Methods 2010; 7: 335–336.

Kopylova

Noé

Touzet

SortMeRNA: Fast and accurate filtering of ribosomal RNAs in metatranscriptomic data. Bioinformatics 2012; 28: 3211–3217.

Anderson

. A new method for non-parametric multivariate analysis of variance. Austral Ecology 2001; 26: 32–46.

Oksanen

Blanchet

Kindt

et al . vegan: Com-munity Ecology Package. R package version 20–29.

Jangi

Gandhi

Cox

et al . Alterations of the human gut microbiome in multiple sclerosis. Nat Commun 2016; 7: 12015.

Zhang

Jia

et al . The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat Med 2015; 21: 895–905.

Miyake

Kim

Suda

et al . Dysbiosis in the gut microbiota of patients with multiple sclerosis, with a striking depletion of species belonging to clostridia XIVa and IV clusters. PLoS One 2015; 10: e0137429.

Chen

Chia

Kalari

et al . Multiple sclerosis patients have a distinct gut microbiota compared to healthy controls. Sci Rep 2016; 6: 28484.

10.

Ochoa-Reparaz

Mielcarz

Ditrio

et al . Role of gut commensal microflora in the development of experimental autoimmune encephalomyelitis. J Immunol 2009; 183: 6041–6050.

11.

Berer

Mues

Koutrolos

et al . Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 2011; 479: 538–541.

12.

Ochoa-Reparaz

Mielcarz

Ditrio

et al . Central nervous system demyelinating disease protection by the human commensal Bacteroides fragilis depends on polysaccharide A expression. J Immunol 2010; 185: 4101–4108.

13.

Lee

Menezes

Umesaki

et al . Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 2011; 108: 4615–4622.

14.

Rothhammer

Mascanfroni

Bunse

et al . Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med 2016; 22: 586–597.

15.

Mangalam

Shahi

Luckey

et al . Human gut-derived commensal bacteria suppress CNS inflammatory and demyelinating disease. Cell Rep 2017; 20: 1269–1277.

16.

Cosorich

Dalla-Costa

Sorini

et al . High frequency of intestinal TH17 cells correlates with microbiota alterations and disease activity in multiple sclerosis. Sci Adv 2017; 3: 1–9.

17.

Di Giacinto

Marinaro

Sanchez

et al . Probiotics ameliorate recurrent Th1-mediated murine colitis by inducing IL-10 and Il-10-dependent TGF: Bearing regulatory cells. J Immunol 2005; 174: 3237–3246.

18.

Barletta

Rossi

Schiavi

et al . Probiotic Vsl#3-induced TGF-β ameliorates food allergy inflammation in a mouse model of peanut sensitization through the induction of regulatory T cells in the gut mucosa. Mol Nutr Food Res 2013; 57: 2233–2244.

19.

Dolpady

Sorini

Di Pietro

et al . Oral probiotic VSL#3 prevents autoimmune diabetes by modulating microbiota and promoting indoleamine 2,3-dioxygenase-enriched tolerogenic intestinal environment. J Diabetes Res 2016; 2016: 7569431.

20.

d’Ettorre

Rossi

Scagnolari

et al . Probiotic supplementation promotes a reduction in T-cell activation, an increase in Th17 frequencies, and a recovery of intestinal epithelium integrity and mitochondrial morphology in ART-treated HIV-1-positive patients. Immun Inflamm Dis 2017; 5: 244–260.

21.

Kigerl

Hall

Wang

et al . Gut dysbiosis impairs recovery after spinal cord injury. J Exp Med 2016; 213: 2603–2620.

22.

D’Mello

Ronaghan

Zaheer

et al . Probiotics improve inflammation-associated sickness behavior by altering communication between the peripheral immune system and the brain. J Neurosci 2015; 35: 10821–10830.

23.

Bibiloni

Fedorak

Tannock

et al . VSL#3 probiotic-mixture induces remission in patients with active ulcerative colitis. Am J Gastroenterol 2005; 100: 1539–1546.

24.

Gionchetti

Rizzello

Helwig

et al . Prophylaxis of pouchitis onset with probiotic therapy: A double-blind, placebo-controlled trial. Gastroenterology 2003; 124: 1202–1209.

25.

Jafarnejad

Saremi

Jafarnejad

et al . Effects of a multispecies probiotic mixture on glycemic control and inflammatory status in women with gestational diabetes: A randomized controlled clinical trial. J Nutr Metab 2016; 2016: 5190846.

26.

Nettenstrom

Alderson

Raschke

et al . An optimized multi-parameter flow cytometry protocol for human T regulatory cell analysis on fresh and viably frozen cells, correlation with epigenetic analysis, and comparison of cord and adult blood. J Immunol Methods 2013; 387: 81–88.