How oral probiotics affect the severity of an experimental model of progressive multiple sclerosis? Bringing commensal bacteria into the neurodegenerative process

Abstract

A growing number of studies support that the bidirectional interactions between the gut microbiota, the immune system and the CNS are relevant for the pathophysiology of MS. Several studies have reported alterations in the gut microbiome of MS patients. In addition, a variety of studies in animal models of MS have suggested that specific members of the gut commensal microbiota can exacerbate or ameliorate neuroinflammation. Probiotics represent oral nontoxic immunomodulatory agents that would exert benefits when using in combination with current MS therapy. Here we investigate the effect of Vivomixx on the gut microbiome and central and peripheral immune responses in a murine model of primary progressive MS. Vivomixx administration was associated with increased abundance of many taxa such as Bacteroidetes, Actinobacteria, Tenericutes and TM7. This was accompanied by a clear improvement of the motor disability of Theiler's virus infected mice; in the CNS Vivomixx reduced microgliosis, astrogliosis and leukocyte infiltration. Notably, the presence of Breg cells (CD19 + CD5 + CD1d high) in the CNS was enhanced by Vivomixx, and while spinal cord gene expression of IL-1β and IL-6 was diminished, the probiotic promoted IL-10 gene expression. One of the most significant findings was the increased plasma levels of butyrate and acetate levels in TMEV-mice that received Vivomixx. Peripheral immunological changes were subtle but interestingly, the probiotic restricted IL-17 production by Th17-polarized CD4 + T-cells purified from the mesenteric lymph nodes of Theiler's virus infected mice. Our data reinforce the beneficial effects of oral probiotics that would be coadjuvant treatments to current MS therapies.

Associations of serum short-chain fatty acids with circulating immune cells and serum biomarkers in patients with multiple sclerosis

“…To conclude, the measurement of SCFAs in the serum of patients with CIS/MS provided a window to dissect potential mechanisms of gut-brain communication that may be associated with MS development, and to pinpoint the immune cells and mediators that may be intermediates in that pathway. Although only associative, this study adds supportive data to emerging proposals that changes in diets for MS patients could increase the production of beneficial SCFAs via changes to the microbiome, or MS patients be supplemented with particular SCFAs or pre/probiotics to improve clinical outcomes 11 , 52 , 53 . In our study, SCFA levels were associated principally with processes reflecting the function of germinal centres and IL-10-producing B-cells, rather than Treg cells.…”

Probiotic and commensal gut microbial therapies in multiple sclerosis and its animal models: a comprehensive review

“…More studies investigated the effects of Lactobacillus spp. [48][49][50]52,53,59,67,68,[71][72][73][74][75][76] and probiotic combinations [43][44][45]48,50,53,69 rather than Bifidobacterium spp. [51][52][53]68 and E. coli Nissle 1917, 54,55 and just a single study utilized E. faecium.…”

“…66 L. casei Shirota, 68,72,73 and B. animalis [50][51][52][53] were the least clinically successful therapies among the studies investigated, while L. paracasei, 48,49 L. plantarum, 48,50 and E. coli Nissle 1917 54,55 appeared the most successful. Notably, despite disparate outcomes, VSL#3 45 and Vivomixx 43,44 contain the same probiotic formulation, although importantly each study used a different model: cuprizone-induced demyelination/remyelination vs. TMEV-IDD vs. EAE, respectively, with the former (cuprizone) lacking a strong immune-mediated component. Furthermore, L. paracasei 49 and the combinations of L. crispatus and L. rhamnosus 53 and B. animalis subsp.…”

“…Five studies demonstrated a doseresponse relationship, 44,48,50,53,54 and three studies provided evidence for the combinatorial effects of probiotics. 43,45,69 Only ~32% of the animal studies (n = 22) reported primarily no effect or exacerbation of clinical disease. 51,59,68,[72][73][74][75] It should also be noted that only four of the studies were classified as high quality, all of which reported positive results with probiotics.…”

“…51,59,68,[72][73][74][75] It should also be noted that only four of the studies were classified as high quality, all of which reported positive results with probiotics. 44,45,50,53 The majority of studies reported favorable secondary immunological findings, with elevated levels of anti-inflammatory cytokines (IL-10, IL-4, TGFβ) 43,48,50,53,55,59,69,71,74 and CD4+ CD25+ FoxP3 + Tregs 44,50,54,55,69,74 and reduced levels of proinflammatory cytokines (IL-17, IL-1, IL-6, TNF-α, IFN-γ), 43,48,50,53,55,67,69,71,75 chemokines (CCL3, CCL4, CXCL5, CXCL13), 49 and T H 1 and T H 17 cells. 43,54,55,67,69,74,75 Multiple Lactobacillus spp.…”