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 P111 Elucidation of inflammatory infiltration of myenteric plexus in IBD

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S191-S191
Author(s):  
J J Wiese ◽  
A Fascì ◽  
A A Kühl ◽  
B Siegmund ◽  
M S Prüß ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
T Cells ◽  
B Cells ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Bowel Disease ◽  
Myenteric Plexus ◽  
Pain Catastrophizing ◽  
Visual Analogue Scale Pain ◽  
Inflammatory Bowel

Abstract Background Since IBD is frequently associated with chronic abdominal pain and visceral hypersensitivity, affections to the sensory nerves within the ENS appear to be pivotal. In both inflammatory bowel diseases, i.e. the transmural inflammation of Crohn’s disease (CD) and the inflammation restricted to the colonic mucosa in ulcerative colitis (UC) infiltrations of the plexus by immune cells occur. However, the type of immune cells involved is so far unknown. Therefore, we characterised the immune cell infiltrations of myenteric plexus (MP) in CD and UC compared with controls. Methods We identified 12 IBD patients (four CD and eight UC) and four controls that had received surgery (ileocecal resections or colectomy). The severity of the disease was assessed by Mayo score, HBI score and questionnaires (Visual Analogue Scale, Pain Catastrophizing Scale, Inflammatory bowel disease quality of life and Irritable Bowel Symptom Severity Scale). Formalin-fixed, paraffin-embedded tissue was stained by classical immunohistochemistry. To identify myenteric plexus tissue was stained for CGRP and PGP9.5. Immunostainings for immune cells (T cells: CD3, CD4, CD8, Foxp3; B cells: CD20; monocytes/macrophages: CD68 and CD163) were analysed by quantifying within the plexus and within a defined area of 100 µm around the plexus. Results The mean size of myenteric ganglia in controls was found to be 0.100 ± 0.004 mm² and was significantly decreased in CD (0.055 ± 0.002 mm²) and UC (0.079 ± 0.004 mm²). The population of CD4+ T-cells, macrophages and monocytes within ganglia of the MP were unchanged in CD, UC. However, infiltrates within and around MP contained significantly more CD3+ T cells in CD (121 ± 63 intraganglionic cells/mm² and 1858 ± 1133 periganglionic cells/mm²) and UC (133 ± 80 intraganglionic cells/mm² and 1198 ± 693 periganglionic cells/mm²) compared with controls (28 ± 38 intraganglionic cells/mm² and 342 ± 93 periganglionic cells/mm²). This appeared to be secondary to a significant increase of periganglionic CD8+ T cells in UC (342 ± 293 cells/mm² compared with 164 ± 140 cells/mm² in controls) (see Figure 1) and secondary to a significant increase of periganglionic Foxp3+ T cells in CD (528 ± 193 cells/mm² compared with 0 ± 0 cells/mm² in controls). Moreover, CD20+ B cells were significantly increased in CD (528 ± 193 periganglionic cells/mm² compared with 0 ± 0 periganglionic cells/mm² in controls). Conclusion The intra- and periganglionic infiltrate of MP in inflammatory bowel disease contains CD3+CD8+ T cells in UC and CD3+Foxp3+ regulatory T cells as well as B cells in CD.

scholarly journals Store-Operated Calcium Entry Controls Innate and Adaptive Immune Cell Function in Inflammatory Bowel Disease

2021 ◽  
Author(s):  
Marilena Letizia ◽  
Ulrike Kaufmann ◽  
Yin-Hu Wang ◽  
Lorenz Gerbeth ◽  
Annegret Sand ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
T Cells ◽  
T Cell ◽  
Immune Cells ◽  
Bowel Disease ◽  
Clinical Course ◽  
Lymphoid Cells ◽  
Inflammatory Bowel ◽  
The Impact ◽  
Pharmacologic Inhibition

AbstractObjectiveInflammatory bowel disease (IBD) is characterized by dysregulated intestinal immune responses and constitutes a major clinical challenge in need of new treatment modalities to improve patient care. Store-operated Ca2+ entry (SOCE) is the predominant Ca2+ influx pathway in T cells and other immune cells, regulating many of their functional properties. It is currently unknown whether the pharmacologic blockade of SOCE represents a suitable drug-target for IBD treatment.DesignUsing mass and flow cytometry the effects of SOCE inhibition on lamina propria (LP) immune cells of patients with ulcerative colitis (UC) and Crohn’s disease (CD) were investigated. Primary organoid cultures served to study the impact of SOCE inhibition on the function, differentiation and survival of intestinal epithelial cells (IEC). T cell transfer models of colitis were applied to examine how the genetic or pharmacologic ablation of SOCE affects the clinical course of IBD in mice.ResultsWe observed that the LP of IBD patients is characterized by an enrichment of innate lymphoid cells (ILC), CD4+ and CD8+ effector- as well as T regulatory cells producing IL-17 and TNFα. The pharmacologic inhibition of SOCE attenuated the production of pathogenic cytokines including IL-2, IL-4, IL-6, IL-17, TNFα and IFNγ by human colonic T cells and ILC, reduced the production of IL-6 by B cells and the production of IFNγ by myeloid cells, without affecting the viability, differentiation and function of primary IEC. T cell-specific genetic deletion of the SOCE signaling components Orai1, Stim1 or Stim2 revealed that the magnitude of SOCE correlates with the function of T cells and intestinal inflammation in mice. Moreover, the pharmacologic inhibition of SOCE alleviated the clinical course of colitic mice.ConclusionOur data suggest that SOCE inhibition may serve as a new pharmacologic strategy for treating IBD.

scholarly journals Tryptophan Metabolism, Regulatory T Cells, and Inflammatory Bowel Disease: A Mini Review

2020 ◽  
Vol 2020 ◽  
pp. 1-10 ◽  
Author(s):  
Xueyan Ding ◽  
Peng Bin ◽  
Wenwen Wu ◽  
Yajie Chang ◽  
Guoqiang Zhu
Keyword(s):  
Inflammatory Bowel Disease ◽  
T Cells ◽  
Regulatory T Cells ◽  
Immune Cells ◽  
Bowel Disease ◽  
Kynurenine Pathway ◽  
Inflammatory Disorder ◽  
Chronic Inflammatory Disorder ◽  
Inflammatory Bowel ◽  
Treg Differentiation

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract resulting from the homeostasis imbalance of intestinal microenvironment, immune dysfunction, environmental and genetic factors, and so on. This disease is associated with multiple immune cells including regulatory T cells (Tregs). Tregs are a subset of T cells regulating the function of various immune cells to induce immune tolerance and maintain intestinal immune homeostasis. Tregs are correlated with the initiation and progression of IBD; therefore, strategies that affect the differentiation and function of Tregs may be promising for the prevention of IBD-associated pathology. It is worth noting that tryptophan (Trp) metabolism is effective in inducing the differentiation of Tregs through microbiota-mediated degradation and kynurenine pathway (KP), which is important for maintaining the function of Tregs. Interestingly, patients with IBD show Trp metabolism disorder in the pathological process, including changes in the concentrations of Trp and its metabolites and alteration in the activities of related catalytic enzymes. Thus, manipulation of Treg differentiation through Trp metabolism may provide a potential target for prevention of IBD. The purpose of this review is to highlight the relationship between Trp metabolism and Treg differentiation and the role of this interaction in the pathogenesis of 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 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.

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 Activation, Deficiency, and Reduced IFN-γ Production of Mucosal-Associated Invariant T Cells in Patients with Inflammatory Bowel Disease

2020 ◽  
Vol 12 (5) ◽  
pp. 422-434
Author(s):  
Jae Kyun Ju ◽  
Young-Nan Cho ◽  
Ki-Jeong Park ◽  
Han Deok Kwak ◽  
Hye-Mi Jin ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
T Cells ◽  
Bowel Disease ◽  
Inflammatory Bowel ◽  
Ifn Γ ◽  
Invariant T Cells

scholarly journals Alteration of Interleukin 4 Production Results in the Inhibition of T Helper Type 2 Cell–Dominated Inflammatory Bowel Disease in T Cell Receptor α Chain–Deficient Mice

1999 ◽  
Vol 190 (5) ◽  
pp. 607-616 ◽  
Author(s):  
Hideki Iijima ◽  
Ichiro Takahashi ◽  
Daisuke Kishi ◽  
Jin-Kyung Kim ◽  
Sunao Kawano ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Bowel Disease ◽  
Cell Receptor ◽  
Interleukin 4 ◽  
T Helper ◽  
Inflammatory Bowel ◽  
Α Chain

T cell receptor α chain–deficient (TCR-α−/−) mice are known to spontaneously develop inflammatory bowel disease (IBD). The colitis that develops in these mice is associated with increased numbers of T helper cell (Th)2-type CD4+TCR-ββ (CD4+ββ) T cells producing predominantly interleukin (IL)-4. To investigate the role of these Th2-type CD4+ββ T cells, we treated TCR-α−/− mice with anti–IL-4 monoclonal antibody (mAb). Approximately 60% of TCR-α−/− mice, including those treated with mock Ab and those left untreated, spontaneously developed IBD. However, anti–IL-4 mAb–treated mice exhibited no clinical or histological signs of IBD, and their levels of mucosal and systemic Ab responses were lower than those of mock Ab–treated mice. Although TCR-α−/− mice treated with either specific or mock Ab developed CD4+ββ T cells, only those treated with anti–IL-4 mAb showed a decrease in Th2-type cytokine production at the level of mRNA and protein and an increase in interferon γ–specific expression. These findings suggest that IL-4–producing Th2-type CD4+ββ T cells play a major immunopathological role in the induction of IBD in TCR-α−/− mice, a role that anti–IL-4 mAb inhibits by causing Th2-type CD4+ββ T cells to shift to the Th1 type.

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