scholarly journals Extracellular vesicles produced by the human commensal gut bacterium Bacteroides thetaiotaomicron affect host immune pathways in a cell-type specific manner that are altered in inflammatory bowel disease

2021 ◽  
Author(s):  
Lejla Gul ◽  
Dezso Modos ◽  
Sonia Fonseca ◽  
Matthew Madgwick ◽  
John P Thomas ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Extracellular Vesicles ◽  
Immune Cells ◽  
Bowel Disease ◽  
Immune Cell ◽  
Gut Health ◽  
Cell Type ◽  
Bacteroides Thetaiotaomicron ◽  
Cell Type Specific ◽  
Inflammatory Bowel

The gastrointestinal (GI) tract is inhabited by a complex microbial community, which contributes to its homeostasis. Disrupted microbiome can cause GI-related diseases, including inflammatory bowel disease, therefore identifying host-microbe interactions is crucial for better understanding gut health. Bacterial extracellular vesicles (BEVs), released into the gut lumen, can cross the mucus layer and access underlying immune cells. To study cross-kingdom communication between BEVs and host, we focused on the influence of BEVs, generated by Bacteroides thetaiotaomicron (VPI-5482), on host immune cells. Using single-cell RNA sequencing data and host-microbe protein-protein interaction networks, we examined the potential effect of BEVs on dendritic cells, macrophages and monocytes with particular focus on the Toll-like receptor (TLR) pathway. We identified biological processes affected in each immune cell type, and also cell-type specific processes (e.g myeloid cell differentiation). The TLR pathway analysis highlighted that BEV targets differ among cells and even between the same cells in healthy versus disease (ulcerative colitis) conditions. Our in silico findings were validated in BEV-monocyte co-cultures demonstrating the requirement for TLR4 in BEV-elicited NF-κB activation. This study demonstrates that both cell-type and health condition influence BEV-host communication. The results and the pipeline can facilitate BEV-based therapy development for the treatment of IBD.

Immune and nonimmune components orchestrate the pathogenesis of inflammatory bowel disease

2011 ◽  
Vol 300 (5) ◽  
pp. G716-G722 ◽  
Author(s):  
Silvio Danese
Keyword(s):  
Inflammatory Bowel Disease ◽  
Immune System ◽  
Immune Cells ◽  
Bowel Disease ◽  
Inflammatory Process ◽  
Adaptive Immune System ◽  
Cell Type ◽  
Current Role ◽  
Adaptive Immune ◽  
Inflammatory Bowel

Inflammatory bowel disease (IBD) pathogenesis is driven by the interactions between the innate and the adaptive immune system. Both systems are actually expressed not only by immune cells, but also by essentially all types of nonimmune cells. Nonimmune cells have classically been considered as simple targets of the aberrant inflammatory process occurring in IBD. However, the discovery that many of the functions traditionally attributed to immune cells are also performed by nonimmune cells has caused a shift to a multidirectional hypothesis in which nonimmune cells and even acellular elements are considered active players of IBD pathogenesis. The aim of this review is to summarize the current role played by each cell type in IBD pathogenesis.

scholarly journals Inferring intestinal mucosal immune cell associated microbiome species and microbiota-derived metabolites in inflammatory bowel disease

2020 ◽  
Author(s):  
Rajagopalan Lakshmi Narasimhan ◽  
Allison A. Throm ◽  
Jesvin Joy Koshy ◽  
Keith Metelo Raul Saldanha ◽  
Harikrishnan Chandranpillai ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
T Cells ◽  
B Cells ◽  
Immune Cells ◽  
Bowel Disease ◽  
Immune Cell ◽  
Bacterial Species ◽  
Secondary Bile Acid ◽  
New Findings ◽  
Inflammatory Bowel

AbstractInflammatory bowel disease (IBD) is a complex, chronic inflammatory disease of the gastrointestinal tract with subtypes Crohn’s disease (CD) and ulcerative colitis (UC). While evidence indicates IBD is characterized by alterations in the composition and abundance of the intestinal microbiome, the challenge remains to specify bacterial species and their metabolites associated with IBD pathogenesis. By the integration of microbiome multi-omics data and computational methods, we provide analyses and methods for the first time to identify microbiome species and their metabolites that are associated with the human intestine mucosal immune response in patients with CD and UC at a systems level. First, we identified seven gut bacterial species and seventeen metabolites that are significantly associated with Th17 cellular differentiation and immunity in patients with active CD by comparing with those obtained in inactive CD and non-IBD controls. The seven species are Ruminococcus gnavus, Escherichia coli, Lachnospiraceae bacterium, Clostridium hathewayi, Bacteroides faecis, Bacteroides vulgatus, and Akkermansia muciniphila, and a few associated metabolites include the secondary bile acid lithocholate and three short-chain fatty acids (SCFAs): propionate, butyrate, and caproate. We next systematically characterized potential mechanistic relationships between the Th17-involved metabolites and bacterial species and further performed differential abundance analysis for both microbiome species and their metabolites in CD and UC relative to non-IBD controls with their metagenomic and metabolomic data. Based on the deconvolution of immune cell compositions from host intestinal bulk RNA-seq, we investigated changes in immune cell composition and abundance in CD and UC in comparison to non-IBD controls. Finally, we further extended our species and metabolite associations with immune cells from Th17 and Th2 cells to B cells, plasma B cells, plasmablasts, CD4+ T cells, and CD8+ T cells. While a set of associations of immune cells with bacterial species and metabolites was supported by published evidence, the new findings in this work will help to furthering our understanding of immune responses and pathogenesis in IBD.

scholarly journals P085 Deep profiling of the circulating immune cell landscape in inflammatory bowel disease by mass cytometry

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S177-S177
Author(s):  
V Horn ◽  
Z Borek ◽  
E Mantzivi ◽  
M Urbicht ◽  
D Boesel ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Immune Cells ◽  
Bowel Disease ◽  
Immune Cell ◽  
Intestinal Inflammation ◽  
Therapy Monitoring ◽  
Mass Cytometry ◽  
Adaptive Immune Cells ◽  
Healthy Donors ◽  
Inflammatory Bowel

Abstract Background A complex interplay of innate and adaptive immune cells maintains intestinal homeostasis. In inflammatory bowel disease (IBD), the fragile balance between regulatory and inflammatory cell subsets breaks down. The latter are recruited to the gut where they sustain intestinal inflammation and lead to tissue destruction. Due to re-circulation and gut-homing processes, the circulating immune cell compartment experiences profound changes that reflect disease activity. Meanwhile, single-cell techniques like mass cytometry have become a powerful technology to shed a light on the heterogeneity and dynamics of immune cells. As obtaining intestinal biopsies from inflamed gut is invasive and poses patients at risk, diagnostics and therapy monitoring from ‘liquid biopsies’ would be a great advance. A deeper understanding of the circulating immune cell landscape in IBD pre- and post-treatment could significantly contribute to IBD patient management by early prediction of therapy response. Methods Whole blood from 24 IBD patients—including 16 ulcerative colitis (UC) and 6 Crohn’s disease (CD) patients before treatment—and 18 age- and sex-matched healthy donors (HDs) was incubated with proteomic stabiliser and frozen. Upon thawing, cell suspensions were Palladium barcoded, stained with a 37-marker panel and acquired on a Helios mass cytometer. The generated dataset was normalised, de-barcoded and subsequently analysed. Results Using dimensionality reduction and neural-network-based algorithms, we faithfully identified different circulating immune subsets in healthy donors and IBD patients. Our preliminary analysis revealed altered myeloid cell populations, like neutrophils and macrophages, in IBD patients. In line with an activation of the innate immune system, we observed a considerable increase in the neutrophil compartment compared with healthy donors. Moreover, patterns of marker expression within different subsets showed substantial differences between healthy donors, CD and UC patients. Conclusion Here, we show a mass cytometry panel that identifies the circulating immune cell landscape and shows major differences between healthy donors, CD and UC patients.

scholarly journals CCR8 Signaling via CCL1 Regulates Responses of Intestinal IFN-γ Producing Innate Lymphoid CelIs and Protects From Experimental Colitis

2021 ◽  
Vol 11 ◽  
Author(s):  
Le Kang ◽  
Angelika Schmalzl ◽  
Tamara Leupold ◽  
Miguel Gonzalez-Acera ◽  
Raja Atreya ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Immune Cells ◽  
Bowel Disease ◽  
Immune Cell ◽  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Lymphoid Cells ◽  
Protective Function ◽  
Inflammatory Bowel ◽  
Ifn Γ

A diverse spectrum of immune cells populates the intestinal mucosa reflecting the continuous stimulation by luminal antigens. In lesions of patients with inflammatory bowel disease, an aberrant inflammatory process is characterized by a very prominent infiltrate of activated immune cells producing cytokines and chemokines. These mediators perpetuate intestinal inflammation or may contribute to mucosal protection depending on the cellular context. In order to further characterize this complex immune cell network in intestinal inflammation, we investigated the contribution of the chemokine receptor CCR8 to development of colitis using a mouse model of experimental inflammation. We found that CCR8−/− mice compared to wildtype controls developed strong weight loss accompanied by increased histological and endoscopic signs of mucosal damage. Further experiments revealed that this gut protective function of CCR8 seems to be selectively mediated by the chemotactic ligand CCL1, which was particularly produced by intestinal macrophages during colitis. Moreover, we newly identified CCR8 expression on a subgroup of intestinal innate lymphoid cells producing IFN-γ and linked a functional CCL1/CCR8 axis with their abundance in the gut. Our data therefore suggest that this pathway supports tissue-specific ILC functions important for intestinal homeostasis. Modulation of this regulatory circuit may represent a new strategy to treat inflammatory bowel disease in humans.

scholarly journals Hyperactive chemotaxis contributes to anti-TNFα treatment resistance in inflammatory bowel disease

2021 ◽  
Author(s):  
Tung On Yau ◽  
Jayakumar Vadakekolathu ◽  
Gemma Ann Foulds ◽  
Guodong Du ◽  
Christos Polytarchou ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Immune Cell ◽  
Treatment Resistance ◽  
Enrichment Analysis ◽  
Cell Populations ◽  
Treated Animal ◽  
Necrosis Factor Alpha ◽  
Potential Biomarker ◽  
Inflammatory Bowel

Background & Aims Anti-tumour necrosis factor-alpha (anti-TNFα) agents have been used for inflammatory bowel disease (IBD), however, it has up to 30% non-response rate. Identifying molecular pathways and finding reliable diagnostic biomarkers for patient response to anti-TNFα treatment are clearly needed. Methods Publicly available transcriptomic data from IBD patients receiving anti-TNFα therapy was systemically collected and integrated. In silico flow cytometry approaches and MetaScape were applied to evaluate immune cell populations and to perform gene enrichment analysis, respectively. Genes identified within enrichment pathways validated in neutrophils were tracked in an anti TNFα-treated animal model (with lipopolysaccharide (LPS)-induced inflammation). The receiver operating characteristic (ROC) curve was applied to all genes to identify the best prediction biomarkers. Results A total of 449 samples were retrieved from control, baseline and after primary anti-TNFα therapy or placebo. No statistically significant differences were observed between anti-TNFα treatment responders and non-responders at baseline in immune microenvironment scores. Neutrophils, endothelial and B cell populations were higher in baseline non-responders and chemotaxis pathways may contribute to the treatment resistance. Genes related to chemotaxis pathways were significantly up-regulated in LPS-induced neutrophils but no statistically significant changes were observed in neutrophils treated with anti-TNFα. Interleukin 13 receptor subunit alpha 2 (IL13RA2) is the best predictor (ROC: 80.7%, 95% CI: 73.8% - 87.5%) with a sensitivity of 68.13% and specificity of 84.93%, and significantly higher in non-responders compared to responders (p < 0.0001). Conclusions Hyperactive chemotaxis influences responses to anti TNFα treatment and IL13RA2 is a potential biomarker to predict anti-TNFα treatment response.

scholarly journals OP33 Multi-omics analysis reveals specific bio-geographical and functional characteristics in inflammatory bowel disease intestinal mucosa

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S031-S034
Author(s):  
N Maimon ◽  
S Gerassy-Vainberg ◽  
H Bar-Yosef ◽  
A Alpert ◽  
E Starosvetsky ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Immune Cell ◽  
Response To Therapy ◽  
Anatomical Location ◽  
Specific Cell ◽  
Cell Composition ◽  
Dominant Feature ◽  
Inflammatory Bowel

Abstract Background Anatomical location and extent of disease are main factors that affect inflammatory bowel disease (IBD) course and prognosis. No explanation is available for segmental intestinal involvement in either Crohn’s disease (CD) or ulcerative colitis (UC), or for selective segmental response to therapy or disease complications. Therefore, studying the cellular composition of different intestinal segments may provide pathophysiological insights into these phenomena. Methods We compared location-specific cell composition and function by Cytometry Time-of-Flight (CyTOF), gene expression and single-cell (sc) RNAseq data obtained from 3 independent cohorts of healthy donors and IBD patients during remission and flare-ups. Using CyTOF data (n = 38 biopsies), we built a high-resolution screening of immune cell behaviour along the intestine. We validated the findings with gene expression data of 370 samples, and expanded screening resolution by computational methodologies. We then tested a specific pathway in scRNAseq data (n = 10 paired biopsies from 5 patients) and validated its significance by cell-specific Significance Analysis of Microarrays (csSAM). Results We found a location along the intestine to be a dominant feature determining immune and non-immune cell composition. We observed that inflammation reduced anatomic segregation beyond cell infiltration, and decreased the ability to cope with oxidative stress. An upregulated IL-6 pathway in T regulatory cells in UC patients was recognised as sigmoid-specific compared with known inflammatory IL-6 roles in macrophages, as seen in the right colon. This observation may be linked to colonic perforations associated with anti-IL-6R treatment. Suppressor of cytokine signalling 3 (SOCS3) may control IL-6 location-specific action. Conclusion Our study displays a unique and comprehensive cell map of IBD in a location-specific context, providing potential explanations to unexplained clinical phenomena. These observations may allow to tailor therapies to affected areas with improved therapeutic index and efficacy.

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