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Published on: May 2, 2018
Molecular patterns from a human gut-derived Lactobacillus strain suppress pathogenic infiltration of leukocytes into
John Michael S Sanchez1, Daniel J Doty1, Ana Beatriz DePaula-Silva1
1Department of Pathology, University of Utah School of Medicine, 15 North Medical Drive East, 2600 EEJMRB, Salt Lake City, UT, 84112, USA.
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.
Insights
Lactobacillus paracasei (Lb) ameliorates multiple sclerosis (MS) models by reducing neuroinflammation. Its microbe-associated molecular patterns modulate the gut microbiota and immune cell infiltration into the central nervous system (CNS).
Area of Science:
- Microbiology
- Immunology
- Neuroscience
Background:
- Multiple sclerosis (MS) is a global inflammatory demyelinating disease affecting 2.5 million people.
- Gut microbiota alterations are implicated in MS pathogenesis, with specific bacteria differing between patients and healthy individuals.
- Colonizing mice with MS-associated microbiota worsens preclinical MS models, highlighting the gut-brain axis in disease.
Purpose of the Study:
- To investigate the therapeutic potential of Lactobacillus paracasei (Lb), a human gut commensal, in preclinical models of MS.
- To elucidate the molecular mechanisms by which Lb influences neuroinflammation and gut microbiota composition.
Main Methods:
- Utilized monophasic and relapse-remitting experimental autoimmune encephalomyelitis (EAE) mouse models.
- Administered products from Lactobacillus paracasei (Lb) prophylactically and therapeutically.
- Investigated Toll-like receptor 2 (TLR2) dependency and the role of microbe-associated molecular patterns (MAMPs).
Main Results:
- Lactobacillus paracasei (Lb) demonstrated both prophylactic and therapeutic efficacy in ameliorating MS preclinical models.
- Lb-MAMPs act via a Toll-like receptor 2-dependent pathway, downregulating chemokine production and reducing immune cell infiltration into the CNS.
- Lb-induced alterations in gut microbiota composition provided partial protection against neuroinflammatory disease.
Conclusions:
- Local modulation of the gut microbiota by Lb and systemic circulation of Lb-MAMPs are key mechanisms in preventing CNS immune cell infiltration.
- These findings suggest Lb and its products may represent novel therapeutic strategies for multiple sclerosis.
- The gut-brain axis, influenced by commensal bacteria like Lb, plays a significant role in managing neuroinflammatory conditions.
