Gut Microbiota and Associated Mucosal Immune Response in Eosinophilic Granulomatosis with Polyangiitis (EGPA)

Eosinophilic granulomatosis with polyangiitis (EGPA) is an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. A genome-wide association study showed a correlation between ANCA-negative EGPA and variants of genes encoding proteins with intestinal barrier functions, suggesting that modifications of the mucosal layer and consequent gut dysbiosis might be involved in EGPA pathogenesis. Here, we characterized the gut microbiota (GM) composition and the intestinal immune response in a cohort of EGPA patients. Faeces from 29 patients and 9 unrelated healthy cohabitants were collected, and GM and derived metabolites’ composition were compared. Seven intestinal biopsies from EGPA patients with gastrointestinal manifestations were analysed to assess the T-cell distribution and its correlation with GM and EGPA clinical and laboratory features. No significant differences in GM composition, nor in the total amount of faecal metabolites, emerged between patients and controls. Nevertheless, differences in bacterial taxa abundances and compositional GM-derived metabolites profile were observed. Notably, an enrichment of potential pathobionts (Enterobacteriacee and Streptococcaceae) was found in EGPA, particularly in patients with active disease, while lower levels were found in patients on immunosuppression, compared with non-immunosuppressed ones. Significantly lower amounts of hexanoic acid were found in patients, compared to controls. The analysis of the immune response in the gut mucosa revealed a high frequency of IFN-γ/IL-17-producing T lymphocytes, and a positive correlation between EGPA disease activity and intestinal T-cell levels. Our data suggest that an enrichment in potential intestinal pathobionts might drive an imbalanced inflammatory response in EGPA.

[1]  A. Amedei,et al.  The Gut Microbiota-Immunity Axis in ALS: A Role in Deciphering Disease Heterogeneity? , 2021, Biomedicines.

[2]  A. Vaglio,et al.  Occupational Exposures and Smoking in Eosinophilic Granulomatosis With Polyangiitis: A Case–Control Study , 2021, Arthritis & rheumatology.

[3]  K. Davies,et al.  Streptococcus-associated vasculitis: A role for antibiotic therapy? , 2021, IDCases.

[4]  Brendan J. Kelly,et al.  Dynamic Changes in the Nasal Microbiome Associated With Disease Activity in Patients With Granulomatosis With Polyangiitis , 2021, Arthritis & rheumatology.

[5]  G. Emmi,et al.  Eosinophilic Granulomatosis With Polyangiitis: Dissecting the Pathophysiology , 2021, Frontiers in Medicine.

[6]  A. Kronbichler,et al.  Nasal microbiome research in ANCA-associated vasculitis: Strengths, limitations, and future directions , 2020, Computational and structural biotechnology journal.

[7]  F. Locatelli,et al.  Significance of PR3-ANCA positivity in eosinophilic granulomatosis with polyangiitis (Churg-Strauss). , 2020, Rheumatology.

[8]  F. Sofi,et al.  Butyrate Rich Diets Improve Redox Status and Fibrin Lysis in Behçet's Syndrome. , 2020, Circulation research.

[9]  Alison H. Clifford,et al.  An update on the microbiome in vasculitis , 2020, Current opinion in rheumatology.

[10]  Y. Shoenfeld,et al.  International Consensus on ANCA Testing in Eosinophilic Granulomatosis with Polyangiitis. , 2020, American journal of respiratory and critical care medicine.

[11]  A. Vaglio,et al.  Eosinophilic granulomatosis with polyangiitis: understanding the disease and its management. , 2020, Rheumatology.

[12]  A. Amedei,et al.  The Link "Cancer and autoimmune diseases" in the light of microbiota: evidence of a potential culprit. , 2020, Immunology letters.

[13]  M. Gulisano,et al.  Faecal microbiota transplant from aged donor mice affects spatial learning and memory via modulating hippocampal synaptic plasticity- and neurotransmission-related proteins in young recipients , 2019, bioRxiv.

[14]  William J. Astle,et al.  Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status , 2019, Nature Communications.

[15]  J. Parkhill,et al.  The composition and functional protein subsystems of the human nasal microbiome in granulomatosis with polyangiitis: a pilot study , 2019, Microbiome.

[16]  F. Stingo,et al.  Evaluation and comparison of short chain fatty acids composition in gut diseases , 2019, World journal of gastroenterology.

[17]  L. Svensson,et al.  Microbiomes of Inflammatory Thoracic Aortic Aneurysms Due to Giant Cell Arteritis and Clinically Isolated Aortitis Differ From Those of Non-Inflammatory Aneurysms , 2019, Pathogens & immunity.

[18]  L. Burkhardt,et al.  Changes in the composition of the upper respiratory tract microbial community in granulomatosis with polyangiitis. , 2019, Journal of autoimmunity.

[19]  P. Pandiyan,et al.  Role of Short Chain Fatty Acids in Controlling Tregs and Immunopathology During Mucosal Infection , 2018, Front. Microbiol..

[20]  P. Merkel,et al.  Characterisation of the nasal microbiota in granulomatosis with polyangiitis , 2018, Annals of the rheumatic diseases.

[21]  Robert C. Edgar,et al.  Taxonomy annotation and guide tree errors in 16S rRNA databases , 2018, PeerJ.

[22]  F. Cianchi,et al.  The Different Functional Distribution of “Not Effector” T Cells (Treg/Tnull) in Colorectal Cancer , 2017, Front. Immunol..

[23]  S. Yancey,et al.  Mepolizumab or Placebo for Eosinophilic Granulomatosis with Polyangiitis , 2017, The New England journal of medicine.

[24]  F. Cianchi,et al.  Cytotoxic Th1 and Th17 cells infiltrate the intestinal mucosa of Behcet patients and exhibit high levels of TNF-α in early phases of the disease , 2016, Medicine.

[25]  K. Adachi,et al.  Th17 cells reflect colon submucosal pathologic changes in active eosinophilic granulomatosis with polyangiitis , 2015, BMC Immunology.

[26]  M. Kuroda,et al.  Characterization of the gut microbiota of Kawasaki disease patients by metagenomic analysis , 2015, Front. Microbiol..

[27]  S. Turroni,et al.  Dynamic efficiency of the human intestinal microbiota , 2015, Critical reviews in microbiology.

[28]  S. Rampelli,et al.  Behçet's syndrome patients exhibit specific microbiome signature. , 2015, Autoimmunity reviews.

[29]  W. Huber,et al.  Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 , 2014, Genome Biology.

[30]  Y. Belkaid,et al.  Role of the Microbiota in Immunity and Inflammation , 2014, Cell.

[31]  S. Rampelli,et al.  The Enterocyte-Associated Intestinal Microbiota of Breast-Fed Infants and Adults Responds Differently to a TNF-α-Mediated Pro-Inflammatory Stimulus , 2013, PloS one.

[32]  M. Hattori,et al.  Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota , 2013, Nature.

[33]  Yichun Hu,et al.  Patients with antineutrophil cytoplasmic antibody-associated vasculitis have defective Treg cell function exacerbated by the presence of a suppression-resistant effector cell population. , 2013, Arthritis and rheumatism.

[34]  Y. Belkaid,et al.  Effector and memory T cell responses to commensal bacteria. , 2013, Trends in immunology.

[35]  Susan Holmes,et al.  phyloseq: An R Package for Reproducible Interactive Analysis and Graphics of Microbiome Census Data , 2013, PloS one.

[36]  Richard Hansen,et al.  IBD—what role do Proteobacteria play? , 2012, Nature Reviews Gastroenterology &Hepatology.

[37]  S. Mazmanian,et al.  Pathobionts of the gastrointestinal microbiota and inflammatory disease. , 2011, Current opinion in immunology.

[38]  F. Moosig,et al.  CCL17/thymus and activation-related chemokine in Churg-Strauss syndrome. , 2010, Arthritis and rheumatism.

[39]  D A Bloch,et al.  The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). , 2010, Arthritis and rheumatism.

[40]  Hadley Wickham,et al.  ggplot2 - Elegant Graphics for Data Analysis (2nd Edition) , 2017 .

[41]  M. D’Elios,et al.  Moraxella Catarrhalis-Specific Th1 Cells in Bal Fluids of Chronic Obstructive Pulmonary Disease Patients , 2009, International journal of immunopathology and pharmacology.

[42]  David Steven Scott,et al.  Modification and validation of the Birmingham Vasculitis Activity Score (version 3) , 2008, Annals of the rheumatic diseases.

[43]  U. Maggiore,et al.  HLA-DRB4 as a genetic risk factor for Churg-Strauss syndrome. , 2007, Arthritis and rheumatism.

[44]  L. Cosmi,et al.  Phenotypic and functional features of human Th17 cells , 2007, The Journal of experimental medicine.

[45]  M. De Vos,et al.  Flow cytometric analysis of gut mucosal lymphocytes supports an impaired Th1 cytokine profile in spondyloarthropathy , 2001, Annals of the rheumatic diseases.

[46]  W. Gross,et al.  Elevated interleukin-4 and interleukin-13 production by T cell lines from patients with Churg-Strauss syndrome. , 2001, Arthritis and rheumatism.

[47]  N. Barnich,et al.  Presence of adherent Escherichia coli strains in ileal mucosa of patients with Crohn's disease. , 1998, Gastroenterology.

[48]  M. Sanak,et al.  Both Th2 and Th17 responses are involved in the pathogenesis of Churg-Strauss syndrome. , 2011, Clinical and experimental rheumatology.

[49]  B. Finlay,et al.  Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. , 2007, Cell host & microbe.

[50]  M. Sanak,et al.  Both Th 2 and Th 17 responses are involved in the pathogenesis of Churg-Strauss syndrome , 2006 .

[51]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .