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Gut dysbiosis is a feature of MS and it is characterized by bacteria able to regulate lymphocyte differentiation in vitro
Author(s): ,
E Cekanaviciute
Affiliations:
Neurology, UCSF, San Francisco
,
J.W Debelius
Affiliations:
UCSD, San Diego, CA, United States
,
S Singh
Affiliations:
Neurology, UCSF, San Francisco
,
T Runia
Affiliations:
Neurology, Erasmus MC, Rotterdam, The Netherlands
,
C Nelson
Affiliations:
Graduate Program in Bioinformatics, UCSF, San Francisco
,
B Yoo
Affiliations:
Immunology, Caltech, Pasadena
,
R Kanner
Affiliations:
Neurology, UCSF, San Francisco
,
E Crabtree-Hartman
Affiliations:
Neurology, UCSF, San Francisco
,
S Mazmanian
Affiliations:
Immunology, Caltech, Pasadena
,
R Knight
Affiliations:
Pediatrics;Computer Science, UCSD, San Diego, CA
,
I Katz Sand
Affiliations:
Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
,
P Casaccia
Affiliations:
Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
,
B.C.A Cree
Affiliations:
Neurology, UCSF, San Francisco
,
S.E Baranzini
Affiliations:
Neurology, UCSF, San Francisco
for the MS Microbiome Consortium
for the MS Microbiome Consortium
Affiliations:
ECTRIMS Online Library. Baranzini S. Sep 16, 2016; 147026
Sergio E. Baranzini
Sergio E. Baranzini
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Abstract: 179

Type: Oral

Abstract Category: Pathology and pathogenesis of MS - Immunology

An essential function of the gut microbiota is to regulate immune responses, including T lymphocyte functions in health and disease. We hypothesized that gut microbiota contribute to the pathogenesis of MS. We found that MS patients exhibited impaired in-vitro Treg differentiation in response to their own microbiota. We thus analyzed the microbiome of stool samples from 64 treatment-naïve MS patients and 68 healthy controls using amplicon sequencing of the 16S V4 region of the rRNA gene. No major shifts in microbial community structure were observed. However, we were able to identify individual microbial taxa that were significantly associated with MS and studied their ability to regulate primary human T lymphocyte differentiation in vitro.

A statistical classifier was then created by mapping identified operational taxonomic units (OTU) to known biological pathways and a machine learning approach was implemented to discriminate patients from controls based on their gut bacterial profiles. This approach was able to classify samples from patients and controls with more than 90% sensitivity and specificity.

We next conducted in-vitro assays to characterize the functional properties of the MS gut microbiota. We found that MS-associated Acinetobacter calcoaceticus was sufficient to reduce Treg differentiation and increase both Th1 and Th2 differentiation. The expansion of Th1 lymphocytes was recapitulated by Akkermansia muciniphila, which was also more abundant in MS patients. In contrast, Parabacteroides distasonis, which was significantly reduced in MS microbiomes, stimulated CD4+ T lymphocyte differentiation into a CD25+ IL-10+ regulatory phenotype. Our results suggest that MS-associated changes in microbiota alter T lymphocyte differentiation in a complex fashion and likely through multiple mechanisms. This study is the first to demonstrate the functional effects of gut dysbiosis in MS on host immunity and forms a basis for future research on microbial functions in regulating the adaptive autoimmune responses.

Disclosure:

Egle Cekanaviciute: nothing to disclose

Tessel F. Runia: nothing to disclose

Charlotte Nelson: nothing to disclose

Justine W. Debelius: nothing to disclose

Sneha Singh: nothing to disclose

Rachel Kanner: nothing to disclose

Bruce A. C. Cree: Research support from Hoffman La Roche, Receptos, MedImmune and Teva.

Ilana Katz Sand: research support from the National MS Society, the US Department of Defense, and the Guthy Jackson Charitable Foundation

Sarkis K. Mazmanian: Received funding from NIH, NMSS, Burroughs Wellcome Fund

Patrizia Casaccia: Received funding from Biogen Inc.

Rob Knight: Received funding from NIH, NSF, Bill and Melinda Gates Foundation,

Sergio E. Baranzini: Received funding from NMSS, Department of Defense, NIH and the Valhalla Charitable Foundation.

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