Abstract
Beneficial effects of probiotics on gut microbiota homeostasis and inflammatory immune responses suggested the investigation of their potential clinical efficacy in experimental models of autoimmune diseases. Indeed, administration of two bifidobacteria and lactobacilli probiotic strains prevented disease manifestations in the Lewis rat model of Myasthenia Gravis (EAMG). Here, we demonstrate the clinical efficacy of therapeutic administration of vital bifidobacteria (i.e., from EAMG onset). The mechanisms involved in immunomodulation were investigated with ex vivo and in vitro experiments. Improvement of EAMG symptoms was associated to decreased anti-rat AChR antibody levels, and differential expression of TGFβ and FoxP3 immunoregulatory transcripts in draining lymph nodes and spleen of treated-EAMG rats. Exposure of rat bone marrow-derived dendritic cells to bifidobacteria or lactobacilli strains upregulated toll-like receptor 2 mRNA expression, a key molecule involved in bacterium recognition via lipotheicoic acid. Live imaging experiments of AChR-specific effector T cells, co-cultured with BMDCs pre-exposed to bifidobacteria, demonstrated increased percentages of motile effector T cells, suggesting a hindered formation of TCR-peptide-MHC complex. Composition of gut microbiota was studied by 16S rRNA gene sequencing, and α and β diversity were determined in probiotic treated EAMG rats, with altered ratios between Tenericutes and Verrucomicrobia (phylum level), and Ruminococcaceae and Lachnospiraceae (family level). Moreover, the relative abundance of Akkermansia genus was found increased compared to healthy and probiotic treated EAMG rats. In conclusion, our findings confirms that the administration of vital bifidobacteria at EAMG onset has beneficial effects on disease progression; this study further supports preclinical research in human MG to evaluate probiotic efficacy as supplementary therapy in MG.
Highlights
Myasthenia Gravis (MG) is a chronic autoimmune disease characterized by the presence of serum autoantibodies against the nicotinic acetylcholine receptor (AChR) at the neuromuscular junction (NMJ) in a large proportion of patients; AChR-specific antibodies lead to the alteration and destruction of NMJ causing muscle weakness and fatigability, major clinical symptoms in MG [1]
We investigated whether the beneficial effect of BBmix could be associated to vital or heat exposed probiotics; administration of vital bacteria was significantly associated with a decreased clinical score, whereas heat exposed bifidobacteria did not modify the disease course (Figure 1B; vehicle-Experimental autoimmune myasthenia gravis (EAMG), mean score 2.2 ± 1.25, BBmix vital- EAMG, mean score 0.86 ± 1.34, corrected p < 0.001; BBmix heat exposed- EAMG, mean score 1.54 ± 1.19, corrected p-value = 0.26 vs. vehicle-EAMG)
We evaluated the probiotic efficacy in the Lewis rat EAMG model, given to animals according to a therapeutic protocol
Summary
Myasthenia Gravis (MG) is a chronic autoimmune disease characterized by the presence of serum autoantibodies against the nicotinic acetylcholine receptor (AChR) at the neuromuscular junction (NMJ) in a large proportion of patients; AChR-specific antibodies lead to the alteration and destruction of NMJ causing muscle weakness and fatigability, major clinical symptoms in MG [1]. Experimental autoimmune myasthenia gravis (EAMG), induced in susceptible strains as the Lewis rat or the C57Bl/6 mouse, is a well-characterized model to study the mechanisms involved in MG and novel therapeutic treatments [2]. Effects of probiotic administration on clinical symptoms and on immune mechanisms of EAMG has been investigated by us and other groups, according to a preventive or prophylactic/preventive protocol [6, 7]. We previously demonstrated the effects of the preventive administration of two bifidobacteria strains or two lactobacilli strains in the Lewis rats EAMG model. We observed that probiotics significantly attenuated EAMG symptoms, decreased serum anti-rat AChR antibody levels and increased muscle AChR content. Pro-inflammatory and immunoregulatory transcripts were found differentially expressed in primary and secondary immune organs, and increased levels of Transforming Growth Factor-β (TGFβ) were measured in EAMG rat serum [6]
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