Therapeutic Effect of Bifidobacterium Administration on Experimental Autoimmune Myasthenia Gravis in Lewis Rats

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.

Intestinal Microbes in Autoimmune and Inflammatory Disease

“…In this review, we provided examples of mechanistic ways microbes can alter disease pathology in IBD, SLE, RA, MS, and T1D models with microbes playing a role in pathology of additional autoimmune diseases (121)(122)(123)(124). While we focused on bacteria, emerging data suggests potential roles for yeast and enteric viruses in modulating immune responses and autoimmune and inflammatory disease (125)(126)(127)(128).…”

Gut Microbiota as Regulators of Th17/Treg Balance in Patients With Myasthenia Gravis

“…A study with applications of two bifidobacteria or lactobacilli strains in a Lewis rat model also resulted in promising results ( 30 ). A subsequent study ( 134 ) reported the clinical efficacy of bifidobacterium on the course of EAMG and found that the immunomodulatory properties of viable bifidobacteria relied on the maintenance of the integrity of bacterial proteins and DNA sequences, which is denatured when exposed to high temperatures ( 135 ). Together, these studies support the effectiveness of probiotics in different immune-mediated inflammatory conditions and their possible use as a treatment in patients with MG to modulate the immune system and contribute to the restoration of the immunological tolerance to AChR.…”

Characteristics of an In Vitro Mesenteric Lymph Node Cell Suspension Model and Its Possible Association with In Vivo Functional Evaluation

“…Traditionally, various in vitro and in vivo models have been used to compare the immune regulatory roles of different bacterial strains. In vitro models include the macrophage RAW 264.7, human peripheral blood mononuclear cells (PBMCs), and bone-marrow-derived dendritic cells (BMDCs) [13][14][15]. Although these models are classically for primary immune evaluation, they have limitations.…”