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Epsilon Toxin-Producing Clostridium perfringens within the MS Gut Microbiome and Epsilon Toxin Function on Immune Privilege

ABSTRACT: Multiple Sclerosis (MS) is a complex disease of the CNS believed to require one or more environmental triggers and is characterized by episodic formation of inflammatory demyelinating lesions in the brain and spinal cord. Gut dysbiosis is a common feature in MS and here, using enhanced and quantitative PCR detection, we show that people with MS are more likely to harbor and have higher abundance of epsilon toxin (ETX)-producing strains of Clostridium perfringens within their gut microbiome compared to healthy controls (HC). MS patient-derived isolates produce functional ETX and have a genetic architecture typical of highly conjugative plasmids. In the active immunization model of experimental autoimmune encephalomyelitis (EAE), where pertussis toxin (PTX) is used to overcome CNS immune privilege, we find that ETX can substitute for PTX in disease induction. In contrast to PTX-induced EAE, where inflammatory demyelination is largely restricted to the spinal cord, ETX-induced EAE results in multifocal demyelination in the corpus callosum, thalamus, cerebellum, brainstem, and spinal cord, more akin to the lesion distribution observed in MS. Transcriptional profiles from CNS endothelial cells reveal ETX-induced genes that are known to play a role in overcoming CNS immune privilege. Together, these findings support ETX-producing strains of C. perfringens as biologically plausible pathogens in MS to trigger inflammatory demyelination in the context of circulating myelin autoreactive lymphocytes.

ORGANISM(S): Mus musculus

PROVIDER: GSE223137 | GEO | 2023/03/31

REPOSITORIES: GEO

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Project description:Multiple sclerosis (MS) is a chronic, inflammatory, and demyelinating disease of the central nervous system (CNS). Ursolic acid (UA) can be used in the MS treatment with anti-inflammatory and neuroprotective activities. However, UA is insoluble in water, which may affect its medication effectiveness. In this study, we evaluated the pharmacological effects of UAOS-Na, a water-soluble UA derivative, on experimental autoimmune encephalomyelitis (EAE) mouse, explored its underlying mechanism, and verified the mechanism by in vitro and in vivo experiments. As we expected, UAOS-Na (30 mg/kg/d) delayed the onset time of EAE from 11.78 days post immunization (dpi) to 14.33 dpi, reduced the incidence from 90.0% to 42.9%, and was more effective than UA. UAOS-Na (60 mg/kg/d) significantly decreased the serum levels of IFN-γ, IL-17A, TNF-α and IL-6, reduced the mononuclear cell infiltration of spinal cord, and inhibited the overexpression of key transcription factors T-bet and ROR-γt of EAE mouse spinal cord and spleen. In addition, UAOS-Na attenuated demyelination and astrogliosis in the CNS of EAE and Cuprizone-induced mice. Mechanically, proteomics showed that 217 differential expression proteins (DEPs) were enriched and 215 were upregulated in EAE mice. After UAOS-Na treatment, 52 DEPs were enriched and 49 were downregulated, and these DEPs were markedly enriched in inositol phosphate metabolism, calcium, sphingolipid, cAMP, and antigen processing and presentation (APP) signaling pathways. Among them, there were few studies on APP signaling pathway related with MS. Therefore, we further investigated the effect of UAOS-Na on APP signaling pathway and found that UAOS-Na downregulated the protein levels of Tapbp and H2-T23 in MHC-I antigen presentation pathway and decreased the proliferation of splenic CD8 T cells, thereby inhibiting the CNS infiltration of CD8 T cells. Together, our findings demonstrated that UAOS-Na have both direct anti-demyelination and anti-inflammation effects. And it could reduce the inflammation of MS by downregulating the expression of Tapbp and H2-T23 in the MHC-I antigen presentation pathway.

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Epsilon Toxin-Producing Clostridium perfringens within the MS Gut Microbiome and Epsilon Toxin Function on Immune Privilege

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