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Cited by 338Multiple Sclerosis Research StudiesPsoriasis: Treatment and PathogenesisInflammatory Bowel Disease

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High frequency of intestinal T H 17 cells correlates with microbiota alterations and disease activity in multiple sclerosis

Open access
Cosorich, Ilaria, Dalla-Costa, Gloria, Sorini, Chiara, Ferrarese, Roberto, Messina, Maria Josè, Dolpady, Jayashree, Radice, Elisa, Mariani, Alberto, Testoni, Pier Alberto, Canducci, Filippo, Comi, Giancarlo, Martinelli, Vittorio, Falcone, Marika·2017·Science Advances
DOI 10.1126/sciadv.1700492PMC PMC5507635
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Abstract

The headquarter of our immune system resides in the gut and modulates autoimmune disease activation in multiple sclerosis.

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Fig. 1 Study design. Tissue samples from the duodenal mucosa were collected during EGD from RRMS patients (n = 19) and HCs (n = 17). Simultaneously, we collected 6 to 7 ml of peripheral blood from the same individuals. Total lymphocytes were isolated from one to two fragments of intestinal tissue by collagenase digestion and from peripheral blood by Ficoll gradient. Mucosal immune cells and peripheral blood mononuclear cells (PBMCs) were FACS-analyzed for immunological profiling of the following TH cell subsets: IL-17A+CD4+ TH17 cells, IFN-γ+CD4+ TH1 cells, and IL-22+ TH22 cells. Microbial DNA was extracted from frozen intestinal tissue samples (seven RRMS and seven HC samples), and 16S rRNA sequencing was performed on the Roche 454 platform. At the 2-year end point, we stratified RRMS patients in two cohorts on the basis of evidence of disease activity by clinical and MRI criteria. RRMS patients with no evidence of disease activity in the 2-year follow-up were classified as RRMS/NEDA (n = 9), whereas RRMS patients with evidence of disease activity were classified as RRMS/EDA (n = 10). SSCA, side scatter FACS parameter.
Fig. 1 Study design. Tissue samples from the duodenal mucosa were collected during EGD from RRMS patients (n = 19) and HCs (n = 17). Simultaneously, we collected 6 to 7 ml of peripheral blood from the same individuals. Total lymphocytes were isolated from one to two fragments of intestinal tissue by collagenase digestion and from peripheral blood by Ficoll gradient. Mucosal immune cells and peripheral blood mononuclear cells (PBMCs) were FACS-analyzed for immunological profiling of the following TH cell subsets: IL-17A+CD4+ TH17 cells, IFN-γ+CD4+ TH1 cells, and IL-22+ TH22 cells. Microbial DNA was extracted from frozen intestinal tissue samples (seven RRMS and seven HC samples), and 16S rRNA sequencing was performed on the Roche 454 platform. At the 2-year end point, we stratified RRMS patients in two cohorts on the basis of evidence of disease activity by clinical and MRI criteria. RRMS patients with no evidence of disease activity in the 2-year follow-up were classified as RRMS/NEDA (n = 9), whereas RRMS patients with evidence of disease activity were classified as RRMS/EDA (n = 10). SSCA, side scatter FACS parameter.CC BY-NC · PubMed Central
Fig. 2 Intestinal T cell subsets in RRMS patients and HCs. (A) Relative percentages of CD3+, CD4+, and CD8+ cells out of total lymphocytes isolated from the small intestinal mucosa of individuals with RRMS and of HCs. (B) Frequencies of different TH cell subsets (TH17, TH1, and TH22) in the intestinal mucosa (GUT) and PBMCs of HCs and RRMS patients. Blood samples were collected from the same individuals at the time of intestinal tissue sample collection. Data are means ± SEM. (C) RRMS patients were divided into two cohorts on the basis of disease activity. RRMS patients with evidence of disease activity at 2-year follow-up were classified as EDA, whereas patients with no disease activity were classified as NEDA. Percentages of intestinal TH17 cells out of total CD4+ T cells in HCs and RRMS/NEDA and RRMS/EDA patients are shown. (A to C) **P < 0.01 and *P < 0.05 by unpaired t test. (D) Logistic regression analysis showing correlation between TH17 cell percentages in the gut mucosa and predicted probability of showing disease activity at 2-year follow-up (NEDA score: RRMS/NEDA, 1; RRMS/EDA, 0). Odds ratio, 0.96; 95% CI, 0.02 to 0.98; P = 0.01.
Fig. 2 Intestinal T cell subsets in RRMS patients and HCs. (A) Relative percentages of CD3+, CD4+, and CD8+ cells out of total lymphocytes isolated from the small intestinal mucosa of individuals with RRMS and of HCs. (B) Frequencies of different TH cell subsets (TH17, TH1, and TH22) in the intestinal mucosa (GUT) and PBMCs of HCs and RRMS patients. Blood samples were collected from the same individuals at the time of intestinal tissue sample collection. Data are means ± SEM. (C) RRMS patients were divided into two cohorts on the basis of disease activity. RRMS patients with evidence of disease activity at 2-year follow-up were classified as EDA, whereas patients with no disease activity were classified as NEDA. Percentages of intestinal TH17 cells out of total CD4+ T cells in HCs and RRMS/NEDA and RRMS/EDA patients are shown. (A to C) **P < 0.01 and *P < 0.05 by unpaired t test. (D) Logistic regression analysis showing correlation between TH17 cell percentages in the gut mucosa and predicted probability of showing disease activity at 2-year follow-up (NEDA score: RRMS/NEDA, 1; RRMS/EDA, 0). Odds ratio, 0.96; 95% CI, 0.02 to 0.98; P = 0.01.CC BY-NC · PubMed Central
Fig. 3 Differences of gut mucosa-associated microbiota composition between RRMS patients and HCs. (A) α-Diversity of gut microbiota profiles assessed by 16S amplicon sequencing of DNA purified from human small intestinal tissue of HCs and RRMS patients with active (RRMS/EDA) and nonactive (RRMS/NEDA) disease. (B) Average phylum-level composition of microbiota isolated from small intestinal samples of HC and total RRMS, RRMS/NEDA, and RRMS/EDA patients. (C) Means ± SEM of the relative abundance of different phyla. *P < 0.05 by unpaired t test. (D) Average genus-level composition in four cohorts of individuals. (E) Left: Means ± SEM of the relative abundance of Prevotella and Streptococcus strains. *P < 0.05 by unpaired t test. Right: Regression linear plot in all individuals (RRMS + HC) showing inverse relation between percentages of intestinal TH17 cells and relative abundance of Prevotella strains.
Fig. 3 Differences of gut mucosa-associated microbiota composition between RRMS patients and HCs. (A) α-Diversity of gut microbiota profiles assessed by 16S amplicon sequencing of DNA purified from human small intestinal tissue of HCs and RRMS patients with active (RRMS/EDA) and nonactive (RRMS/NEDA) disease. (B) Average phylum-level composition of microbiota isolated from small intestinal samples of HC and total RRMS, RRMS/NEDA, and RRMS/EDA patients. (C) Means ± SEM of the relative abundance of different phyla. *P < 0.05 by unpaired t test. (D) Average genus-level composition in four cohorts of individuals. (E) Left: Means ± SEM of the relative abundance of Prevotella and Streptococcus strains. *P < 0.05 by unpaired t test. Right: Regression linear plot in all individuals (RRMS + HC) showing inverse relation between percentages of intestinal TH17 cells and relative abundance of Prevotella strains.CC BY-NC · PubMed Central

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Metadata

Authors
Cosorich, I., Dalla-Costa, G., Sorini, C., Ferrarese, R., Messina, M. J., Dolpady, J., Radice, E., Mariani, A., Testoni, P. A., Canducci, F., Comi, G., Martinelli, V., & Falcone, M.
Affiliations
  • Vita-Salute San Raffaele University (IT)
  • Clinical Neurology Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • IRCCS Ospedale San Raffaele (IT)
  • University of Insubria (IT)
Corresponding author
  • Cosorich, Ilaria
  • Martinelli, Vittorio
  • Falcone, Marika
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2017-07-07
Volume
3
Issue
7
Pages
e1700492-e1700492
ISSN
2375-2548 (ISSN-L)
DOI
10.1126/sciadv.1700492
PMC
PMC5507635
OpenAlex
W2734586792
Cited by
338
References
48
Citations by year
2026: 29 · 2025: 34 · 2024: 51 · 2023: 41 · 2022: 48 · 2021: 46 · 2020: 30 · 2019: 31 · 2018: 25 · 2017: 3
FWCI
19.11
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Science Advances (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
Funders
Fondazione Italiana Sclerosi Multipla (award330486)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
  • Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
Keywords
multiple sclerosis, Th17 cells, intestinal immune cells, gut microbiota, microbiota alterations, disease activity, autoimmune disease, gut-immune axis
MeSH terms
Gastrointestinal Microbiome, Adult, Biopsy, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Multiple Sclerosis, Peyer's Patches, Severity of Illness Index, Biomarkers, T-Lymphocyte Subsets, Lymphocyte Count, Immunity, Mucosal, Th17 Cells

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