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The microbiota regulates murine inflammatory responses to toxin-induced CNS demyelination but has minimal impact on remyelination.

ABSTRACT: The microbiota is now recognized as a key influence on the host immune response in the central nervous system (CNS). As such, there has been some progress toward therapies that modulate the microbiota with the aim of limiting immune-mediated demyelination, as occurs in multiple sclerosis. However, remyelination-the regeneration of myelin sheaths-also depends upon an immune response, and the effects that such interventions might have on remyelination have not yet been explored. Here, we show that the inflammatory response during CNS remyelination in mice is modulated by antibiotic or probiotic treatment, as well as in germ-free mice. We also explore the effect of these changes on oligodendrocyte progenitor cell differentiation, which is inhibited by antibiotics but unaffected by our other interventions. These results reveal that high combined doses of oral antibiotics impair oligodendrocyte progenitor cell responses during remyelination and further our understanding of how mammalian regeneration relates to the microbiota.

SUBMITTER: McMurran CE

PROVIDER: S-EPMC6911206 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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The microbiota regulates murine inflammatory responses to toxin-induced CNS demyelination but has minimal impact on remyelination.

McMurran Christopher E CE Guzman de la Fuente Alerie A Penalva Rosana R Ben Menachem-Zidon Ofra O Dombrowski Yvonne Y Falconer John J Gonzalez Ginez A GA Zhao Chao C Krause Fynn N FN Young Adam M H AMH Griffin Julian L JL Jones Clare A CA Hollins Claire C Heimesaat Markus M MM Fitzgerald Denise C DC Franklin Robin J M RJM

Proceedings of the National Academy of Sciences of the United States of America 20191118 50

The microbiota is now recognized as a key influence on the host immune response in the central nervous system (CNS). As such, there has been some progress toward therapies that modulate the microbiota with the aim of limiting immune-mediated demyelination, as occurs in multiple sclerosis. However, remyelination-the regeneration of myelin sheaths-also depends upon an immune response, and the effects that such interventions might have on remyelination have not yet been explored. Here, we show that ...[more]

PMID: 31740610

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Project description:Virus infections have been associated with acute and chronic inflammatory central nervous system (CNS) diseases, e.g., acute flaccid myelitis (AFM) and multiple sclerosis (MS), where animal models support the pathogenic roles of viruses. In the spinal cord, Theiler's murine encephalomyelitis virus (TMEV) induces an AFM-like disease with gray matter inflammation during the acute phase, 1 week post infection (p.i.), and an MS-like disease with white matter inflammation during the chronic phase, 1 month p.i. Although gut microbiota has been proposed to affect immune responses contributing to pathological conditions in remote organs, including the brain pathophysiology, its precise role in neuroinflammatory diseases is unclear. We infected SJL/J mice with TMEV; harvested feces and spinal cords on days 4 (before onset), 7 (acute phase), and 35 (chronic phase) p.i.; and examined fecal microbiota by 16S rRNA sequencing and CNS transcriptome by RNA sequencing. Although TMEV infection neither decreased microbial diversity nor changed overall microbiome patterns, it increased abundance of individual bacterial genera Marvinbryantia on days 7 and 35 p.i. and Coprococcus on day 35 p.i., whose pattern-matching with CNS transcriptome showed strong correlations: Marvinbryantia with eight T-cell receptor (TCR) genes on day 7 and with seven immunoglobulin (Ig) genes on day 35 p.i.; and Coprococcus with gene expressions of not only TCRs and IgG/IgA, but also major histocompatibility complex (MHC) and complements. The high gene expression of IgA, a component of mucosal immunity, in the CNS was unexpected. However, we observed substantial IgA positive cells and deposition in the CNS, as well as a strong correlation between CNS IgA gene expression and serum anti-TMEV IgA titers. Here, changes in a small number of distinct gut bacteria, but not overall gut microbiota, could affect acute and chronic immune responses, causing AFM- and MS-like lesions in the CNS. Alternatively, activated immune responses would alter the composition of gut microbiota.

Project description:The presence of inflammation and demyelination in a central nervous system (CNS) biopsy points towards a limited, yet heterogeneous group of pathologies, of which multiple sclerosis (MS) represents one of the principal considerations. Inflammatory demyelination has also been reported in patients with clinically suspected primary central nervous system lymphoma (PCNSL), especially when steroids had been administered prior to biopsy acquisition. The histopathological changes induced by corticosteroid treatment can range from mild reduction to complete disappearance of lymphoma cells. It has been proposed that in the absence of neoplastic B cells, these biopsies are indistinguishable from MS, yet despite the clinical relevance, no histological studies have specifically compared the two entities. In this work, we analyzed CNS biopsies from eight patients with inflammatory demyelination in whom PCNSL was later histologically confirmed, and compared them with nine well defined early active multiple sclerosis lesions. In the patients with steroid-treated PCNSL (ST-PCNSL) the interval between first and second biopsy ranged from 3 to 32 weeks; all of the patients had received corticosteroids before the first, but not the second biopsy. ST-PCNSL patients were older than MS patients (mean age: ST-PCNSL: 62 ± 4 years, MS: 30 ± 2 years), and histological analysis revealed numerous apoptoses, patchy and incomplete rather than confluent and complete demyelination and a fuzzy lesion edge. The loss of Luxol fast blue histochemistry was more profound than that of myelin proteins in immunohistochemistry, and T cell infiltration in ST-PCNSL exceeded that in MS by around fivefold (P = 0.005). Our data indicate that in the presence of extensive inflammation and incomplete, inhomogeneous demyelination, the neuropathologist should refrain from primarily considering autoimmune inflammatory demyelination and, even in the absence of lymphoma cells, instigate close clinical follow-up of the patient to detect recurrent lymphoma.

Project description:Introduction: Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis, a serious neurological autoimmune disorder caused by autoantibodies with diverse clinical manifestations, may simultaneously onset with antimyelin oligodendrocyte glycoprotein (MOG) demyelination after recurrent central nervous system (CNS) demyelination. Case Report: We present a case of anti-NMDAR encephalitis combining with anti-MOG CNS demyelination following recurrent CNS demyelination. A 38-year-old man admitted to hospital developed epileptic seizures following recurrent episodes of cross-sensory disturbance and dizziness. Magnetic resonance imaging (MRI) showed a demyelinating lesion in the right brainstem initially. Despite a good response to methylprednisolone pulse therapy at the beginning, the patient still had relapses and progression after corticosteroid reduction or withdrawal. Then brain MRI discovered new serpentine lesions involving extensive cerebral cortex on his second relapse. Repeat autoantibodies test indicated cerebrospinal fluid (CSF) NMDAR antibodies coexisted with MOG-Abs simultaneously, suggesting the diagnosis of anti-NMDAR encephalitis with anti-MOG CNS demyelination. Results: After a definite diagnosis, the patient was treated with mycophenolate mofetil (MMF) and corticosteroid. He was discharged after his symptoms ameliorated. No neurological sequels remained, and there were no effects on his activities of daily living after 6 months of immunoregulatory therapy of MMF and corticosteroid. Conclusion: For individuals with recurrent CNS demyelination, especially combining with cortical encephalitis, repeated detection of autoantibodies against AE, and demyelination in CSF/serum can be helpful to enable a definite early diagnosis. For patients who suffer from anti-NMDAR encephalitis combining with anti-MOG CNS demyelination, second-line immunotherapy is recommended when first-line treatment such as steroids, intravenous immunoglobulin G (IVIG) and plasma exchange has been proven ineffective to prevent the relapse of disease.

Dataset Information

The microbiota regulates murine inflammatory responses to toxin-induced CNS demyelination but has minimal impact on remyelination.

Publications

The microbiota regulates murine inflammatory responses to toxin-induced CNS demyelination but has minimal impact on remyelination.

Similar Datasets

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