Cytokine tuning of intestinal epithelial function

The intestine serves as both our largest single barrier to the external environment and the host of more immune cells than any other location in our bodies. Separating these potential combatants is a single layer of dynamic epithelium composed of heterogeneous epithelial subtypes, each uniquely adapted to carry out a subset of the intestine’s diverse functions. In addition to its obvious role in digestion, the intestinal epithelium is responsible for a wide array of critical tasks, including maintaining barrier integrity, preventing invasion by microbial commensals and pathogens, and modulating the intestinal immune system. Communication between these epithelial cells and resident immune cells is crucial for maintaining homeostasis and coordinating appropriate responses to disease and can occur through cell-to-cell contact or by the release or recognition of soluble mediators. The objective of this review is to highlight recent literature illuminating how cytokines and chemokines, both those made by and acting on the intestinal epithelium, orchestrate many of the diverse functions of the intestinal epithelium and its interactions with immune cells in health and disease. Areas of focus include cytokine control of intestinal epithelial proliferation, cell death, and barrier permeability. In addition, the modulation of epithelial-derived cytokines and chemokines by factors such as interactions with stromal and immune cells, pathogen and commensal exposure, and diet will be discussed

Hyposplenism and gastrointestinal diseases:significance and mechanisms

Open Access via the Karger Agreement This work was funded in part by Wellcome Trust Grant number 0934847/Z/10/Z.Peer reviewedPublisher PD

Novel biomarkers for risk stratification of Barrett's oesophagus associated neoplastic progression-epithelial HMGB1 expression and stromal lymphocytic phenotype

The preparation of this paper was funded in part by the Pathological Society of Great Britain and Ireland (intercalated degree educational studentship to R.J.P.). All data is published within this paper and within accompanying supporting files (indicated in text) and accessed via weblink on the journal site.Peer reviewedPublisher PD

Enterohepatic Helicobacter in ulcerative colitis:Potential pathogenic entities?

Background: Changes in bacterial populations termed "dysbiosis" are thought central to ulcerative colitis (UC) pathogenesis. In particular, the possibility that novel Helicobacter organisms play a role in human UC has been debated but not comprehensively investigated. The aim of this study was to develop a molecular approach to investigate the presence of Helicobacter organisms in adults with and without UC.Methodology/Principal Findings: A dual molecular approach to detect Helicobacter was developed. Oligonucleotide probes against the genus Helicobacter were designed and optimised alongside a validation of published H. pylori probes. A comprehensive evaluation of Helicobacter genus and H. pylori PCR primers was also undertaken. The combined approach was then assessed in a range of gastrointestinal samples prior to assessment of a UC cohort. Archival colonic samples were available from 106 individuals for FISH analysis (57 with UC and 49 non-IBD controls). A further 118 individuals were collected prospectively for dual FISH and PCR analysis (86 UC and 32 non-IBD controls). An additional 27 non-IBD controls were available for PCR analysis. All Helicobacter PCR-positive samples were sequenced. The association between Helicobacter and each study group was statistically analysed using the Pearson Chi Squared 2 tailed test. Helicobacter genus PCR positivity was significantly higher in UC than controls (32 of 77 versus 11 of 59, p = 0.004). Sequence analysis indicated enterohepatic Helicobacter species prevalence was significantly higher in the UC group compared to the control group (30 of 77 versus 2 of 59, p&lt;0.0001). PCR and FISH results were concordant in 74 (67.9%) of subjects. The majority of discordant results were attributable to a higher positivity rate with FISH than PCR.Conclusions/Significance: Helicobacter organisms warrant consideration as potential pathogenic entities in UC. Isolation of these organisms from colonic tissue is needed to enable interrogation of pathogenicity against established criteria.</p

Interleukin-27 regulates the function of the gastrointestinal epithelial barrier in a human tissue derived organoid model

Funding: This research was funded by CICRA (CICRA: better lives for children with crohns and colitis. Available online: https://www.cicra.org (last accessed on 23 January 2022); Ph.D. studentship to DBP) and an NHS Grampian Endowment project grant. Acknowledgments: We wish to acknowledge the Grampian Tissue Biorepository for assistance in tissue preparation. Organoids were stored at −80 ◦C at the University of Aberdeen. Graphical abstract was created using Biorender with a licence for use in publication (agreement number AD22YOD1N6). DBP now at Lydia Becker Institute of Immunology and Inflammation and Wellcome Centre for Cell-Matrix Research, University of Manchester, UKPeer reviewedPublisher PD

Subcellular Epithelial HMGB1 Expression Is Associated with Colorectal Neoplastic Progression, Male Sex, Mismatch Repair Protein Expression, Lymph Node Positivity, and an ‘Immune Cold’ Phenotype Associated with Poor Survival

Acknowledgments: The authors would like to thank NHS Grampian Biorepository, in particular Joan Wilson, Victoria Morrison, Kristine Nellany, and Nadine Hay, for their assistance in preparing tissue for this project. The authors also thank Tasneem O Atezia and Christina A Christopoulou for their contribution to this project during their time in the McLean laboratory. The laboratory work was instigated when M.H.M., R.J.P. and D.P.B. were based at the Institute of Medical Sciences, University of Aberdeen. Funding This work was funded by project grants from NHS Grampian Endowments and Friends of Anchor (https://www.friendsofanchor.org, charity no. SC025332). Within the McLean laboratory at the University of Aberdeen, SH received a Medical Research Scotland Summer Studentship, and AH received an Aberdeen Summer Research Studentship (University of Aberdeen).Peer reviewedPublisher PD

Colonic epithelial cathelicidin (LL-37) expression intensity is associated with progression of colorectal cancer and presence of CD8+ T cell infiltrate

Colorectal cancer (CRC) remains a leading cause of cancer mortality. Here, we define the colonic epithelial expression of cathelicidin (LL-37) in CRC. Cathelicidin exerts pleotropic effects including anti-microbial and immunoregulatory functions. Genetic knockout of cathelicidin led to increased size and number of colorectal tumours in the azoxymethane-induced murine model of CRC. We aimed to translate this to human disease. The expression of LL-37 in a large (n = 650) fully characterised cohort of treatment-naïve primary human colorectal tumours and 50 matched normal mucosa samples with associated clinical and pathological data (patient age, gender, tumour site, tumour stage [UICC], presence or absence of extra-mural vascular invasion, tumour differentiation, mismatch repair protein status, and survival to 18 years) was assessed by immunohistochemistry. The biological consequences of LL-37 expression on the epithelial barrier and immune cell phenotype were assessed using targeted quantitative PCR gene expression of epithelial permeability (CLDN2, CLDN4, OCLN, CDH1, and TJP1) and cytokine (IL-1β, IL-18, IL-33, IL-10, IL-22, and IL-27) genes in a human colon organoid model, and CD3+ , CD4+ , and CD8+ lymphocyte phenotyping by immunohistochemistry, respectively. Our data reveal that loss of cathelicidin is associated with human CRC progression, with a switch in expression intensity an early feature of CRC. LL-37 expression intensity is associated with CD8+ T cell infiltrate, influenced by tumour characteristics including mismatch repair protein status. There was no effect on epithelial barrier gene expression. These data offer novel insights into the contribution of LL-37 to the pathogenesis of CRC and as a therapeutic molecule

Oral delivery of il-27 recombinant bacteria attenuates immune colitis in mice

BACKGROUND & AIMS: Treatment of inflammatory bowel disease (IBD) would benefit from specific targeting of therapeutics to the intestine. We developed a strategy for localized delivery of the immunosuppressive cytokine IL27, which is actively synthesized in situ by the food-grade bacterium Lactococcuslactis (LL-IL-27), and tested its ability to reduce colitis in mice. METHODS: The 2 genes encoding mouse IL27 were synthesized with optimal codon usage for L lactis and joined with a linker; a signal sequence was added to allow for secretion of the product. The construct was introduced into L lactis. Colitis was induced via transfer of CD4(+)CD45RB(hi) T cells into Rag(−/−) mice to induce colitis; 7.5 weeks later, LL-IL-27 was administered to mice via gavage. Intestinal tissues were collected and analyzed. RESULTS: LL-IL-27 administration protected mice from T-cell transfer-induced enterocolitis and death. LL-IL-27 reduced disease activity scores, pathology features of large and small bowel, and levels of inflammatory cytokines in colonic tissue. LL-IL-27 also reduced numbers of CD4(+) and IL17(+) T cells in gut-associated lymphoid tissue. The effects of LL-IL-27 required production of IL10 by the transferred T cells. LL-IL-27 was more effective than either LL-IL-10 or systemic administration of recombinant IL27 in reducing colitis in mice. LL-IL-27 also reduced colitis in mice following administration of dextran sodium sulfate. CONCLUSIONS: L lactis engineered to express IL27 (LL-IL-27) reduces colitis in mice, by increasing production of IL10. Mucosal delivery of LL-IL-27 could be a more effective and safer therapy for IBD

The inflammatory microenvironment in colorectal neoplasia

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