Epsilon toxin-producing Clostridium perfringens colonize the multiple sclerosis gut microbiome overcoming CNS immune privilege.

TitleEpsilon toxin-producing Clostridium perfringens colonize the multiple sclerosis gut microbiome overcoming CNS 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 D, Profaci CP, Telesford K, 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 U, Brito IL, Chen Z, Xiang JZ, Betel D, Daneman R, Sonnenberg GF, Mason CE, Vartanian T
JournalJ Clin Invest
Volume133
Issue9
Date Published2023 May 01
ISSN1558-8238
KeywordsAnimals, Clostridium perfringens, Encephalomyelitis, Autoimmune, Experimental, Gastrointestinal Microbiome, Humans, Immune Privilege, Lymphocytes, Multiple Sclerosis
Abstract

Multiple sclerosis (MS) is a complex disease of the CNS thought to require an environmental trigger. Gut dysbiosis is common in MS, but specific 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-producing (ETX-producing) strains of C. perfringens within their gut microbiomes compared with individuals who are healthy controls (HCs). Isolates derived from patients with MS 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 seen 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
PubMed Central IDPMC10145940

Weill Cornell Medicine Neurology 525 E. 68th St.
PO Box 117
New York, NY 10065 Phone: (212) 746-6575