Molecular patterns from a human gut-derived Lactobacillus strain suppress pathogenic infiltration of leukocytes into the central nervous system

Abstract

Background Multiple sclerosis (MS) is an inflammatory demyelinating disease that affects 2.5 million people worldwide. Growing evidence suggests that perturbation of the gut microbiota, the dense collection of microorganisms that colonize the gastrointestinal tract, plays a functional role in MS. Indeed, specific gut-resident bacteria are altered in patients with MS compared to healthy individuals, and colonization of gnotobiotic mice with MS-associated microbiota exacerbates preclinical models of MS. However, defining the molecular mechanisms by which gut commensals can remotely affect the neuroinflammatory process remains a critical gap in the field. Methods We utilized monophasic experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice and relapse-remitting EAE in SJL/J mice to test the effects of the products from a human gut-derived commensal strain of Lactobacillus paracasei (Lb). Results We report that Lb can ameliorate preclinical murine models of MS with both prophylactic and therapeutic administrations. Lb ameliorates disease through a Toll-like receptor 2-dependent mechanism via its microbe-associated molecular patterns that can be detected in the systemic circulation, are sufficient to downregulate chemokine production, and can reduce immune cell infiltration into the central nervous system (CNS). In addition, alterations in the gut microbiota mediated by Lb-associated molecular patterns are sufficient to provide partial protection against neuroinflammatory diseases. Conclusions Local Lb modulation of the gut microbiota and the shedding of Lb-associated molecular patterns into the circulation may be important physiological signals to prevent aberrant peripheral immune cell infiltration into the CNS and have relevance to the development of new therapeutic strategies for MS.

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.…”

“…studies (n = 4), 100% of E. coli Nissle 1917 studies (n = 2), and about 81% of probiotic combination studies (n= 11), while E. faecium was shown to be at least as effective as the standard MS DMT glatiramer acetate. 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.…”

“…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.…”

“…[86][87][88] Only five studies tested the effects of live versus heat-killed organisms or their products. 48,49,53,56,62 This distinction is important, since equivalent efficacy with heat-killed organisms would help to reduce any associated risks of therapy posed by live microbiota and likely improve treatment uptake and adherence in patients. Furthermore, this effect likely differs across organisms.…”

“…(Continued). DR3.DQ8 transgenic56,57,58 and IL-10-,48 TLR-2-,49 and TLR-9-49 deficient strains. L. paracasei DSM 24734, L. plantarum DSM 24730, L. acidophilus DSM 24735, L. delbrueckii subsp.…”