Epsilon toxin-producing Clostridium perfringens colonize the MS gut and epsilon toxin overcomes immune privilege.

TitleEpsilon toxin-producing Clostridium perfringens colonize the MS gut and epsilon toxin overcomes immune privilege.
Publication TypeJournal Article
Year of Publication2023
AuthorsMa Y, Sannino D, Linden JR, Haigh S, Zhao B, Grigg JB, Zumbo P, D√ľndar F, Butler DJ, Profaci CP, Telesford KM, Winokur PN, Rumah KR, Gauthier SA, Fischetti VA, McClane BA, Uzal FA, Zexter L, Mazzucco M, Rudick R, Danko D, Balmuth E, Nealon N, Perumal J, Kaunzner UW, Brito IL, Chen Z, Xiang JZ, Betel D, Daneman R, Sonnenberg GF, Mason CE, Vartanian T
JournalJ Clin Invest
Date Published2023 Feb 28
ISSN1558-8238
Abstract

Multiple Sclerosis (MS) is a complex disease of the CNS thought to require an environmental trigger. Gut dysbiosis is common in MS, but specifically causative species are unknown. To address this knowledge gap, we used sensitive and quantitative PCR detection to show that people with MS were more likely to harbor and show a greater abundance of epsilon toxin (ETX)-producing strains of C. perfringens within their gut microbiomes compared to healthy controls (HC). MS patient-derived isolates produced functional ETX and had 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, ETX can substitute for PTX. In contrast to PTX-induced EAE, where inflammatory demyelination is largely restricted to the spinal cord, ETX-induced EAE caused demyelination in the corpus callosum, thalamus, cerebellum, brainstem, and spinal cord, more akin to the neuroanatomical lesion distribution in MS. CNS endothelial cell transcriptional profiles revealed ETX-induced genes that are known to play a role in overcoming CNS immune privilege. Together, these findings suggest that ETX-producing C. perfringens strains are biologically plausible pathogens in MS that trigger inflammatory demyelination in the context of circulating myelin autoreactive lymphocytes.

DOI10.1172/JCI163239
Alternate JournalJ Clin Invest
PubMed ID36853799