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

被引：26

作者：

Ma, Yinghua ^{[1
]}

Sannino, David ^{[1
]}

Linden, Jennifer R. ^{[1
]}

Haigh, Sylvia ^{[1
]}

Zhao, Baohua ^{[1
]}

Grigg, John B. ^{[2
,3
,4
,5
]}

Zumbo, Paul ^{[6
,7
]}

Duendar, Friederike ^{[6
,7
]}

Butler, Daniel ^{[7
]}

Profaci, Caterina P. ^{[8
]}

Telesford, Kiel ^{[1
]}

Winokur, Paige N. ^{[9
]}

Rumah, Kareem R. ^{[10
]}

Gauthier, Susan A. ^{[11
]}

Fischetti, Vincent A. ^{[10
]}

McClane, Bruce A. ^{[12
]}

Uzal, Francisco A. ^{[13
]}

Zexter, Lily ^{[11
]}

Mazzucco, Michael ^{[1
]}

Rudick, Richard ^{[14
]}

Danko, David ^{[7
]}

Balmuth, Evan ^{[1
]}

Nealon, Nancy ^{[11
]}

Perumal, Jai ^{[11
]}

Kaunzner, Ulrike ^{[11
]}

Brito, Ilana L. ^{[15
]}

Chen, Zhengming ^{[16
]}

Xiang, Jenny Z. ^{[17
]}

Betel, Doron ^{[6
,7
]}

Daneman, Richard ^{[8
]}

Sonnenberg, Gregory F. ^{[2
,3
,4
,5
]}

Mason, Christopher E. ^{[1
,7
]}

Vartanian, Timothy ^{[1
,5
,11
]}

机构：

[1] Cornell Univ, Feil Family Brain & Mind Res Inst, New York, NY USA

[2] Cornell Univ, Jill Roberts Inst Res Inflammatory Bowel Dis, New York, NY USA

[3] Cornell Univ, Joan & Sanford I Weill Dept Med, New York, NY USA

[4] Cornell Univ, Weill Cornell Med Coll, Dept Microbiol & Immunol, New York, NY USA

[5] Weill Cornell Med, Immunol & Microbial Pathogenesis Program, New York, NY USA

[6] Weill Cornell Med, Dept Med, Div Hematol Oncol, Appl Bioinformat Core,Inst Computat Biomed, New York, NY USA

[7] Cornell Univ, Inst Computat Biomed, Weill Cornell Med Coll, Physiol & Biophys, New York, NY USA

[8] Univ Calif San Diego, Dept Pharmacol & Neurosci, San Diego, CA USA

[9] Rockefeller Univ, Harold & Margaret Milliken Hatch Lab Neuroendocri, New York, NY USA

[10] Rockefeller Univ, Lab Bacterial Pathogenesis & Immunol, New York, NY USA

[11] Cornell Univ, Weill Cornell Med Coll, Dept Neurol, New York, NY USA

[12] Univ Pittsburgh, Dept Microbiol & Mol Genet, Sch Med, Pittsburgh, PA USA

[13] UCD, Sch Vet Med, Calif Anim Hlth & Food Safety Lab, Davis, CA USA

[14] Astoria Biol Inc, Norwalk, CT USA

[15] Cornell Univ, Meinig Sch Biomed Engn, Ithaca, NY USA

[16] Weill Cornell Med, Dept Populat Hlth Sci, Div Biostat, New York, NY USA

[17] Weill Cornell Med, Core Labs Ctr, Genom Resources Core Facil, New York, NY USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2023年 / 133卷 / 09期

基金：

美国国家卫生研究院;

关键词：

T-CELLS; ENDOTHELIAL BARRIER; GENE-EXPRESSION; PLASMIDS; PORE; MARINE; BRAIN; IMMUNOREACTIVITY; ENTEROTOXIN; DIVERSITY;

D O I：

10.1172/JCI163239

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页数：17

共 2 条

[1] Is Clostridium perfringens epsilon toxin associated with multiple sclerosis?
Titball, Richard W.
Lewis, Nicholas
Nicholas, Richard
MULTIPLE SCLEROSIS JOURNAL, 2023, 29 (09) : 1057 - 1063
[2] Identification of epsilon toxin-producing Clostridium perfringens strains in American retail food
Regan, Samantha B.
Anwar, Zuha
Miraflor, Patricia
Williams, Libra B.
Shetty, Sarah
Sepulveda, Juan
Moreh, Jake
Bogdanov, Sam
Haigh, Sylvia
Lustig, Abigail
Gaehde, Steffi
Vartanian, Anthony
Rubin, Noah
Linden, Jennifer R.
ANAEROBE, 2018, 54 : 124 - 127

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