Background Despite significant clinical improvements, there is evidence of persisting airway inflammation in people with cystic fibrosis (CF) established on elexacaftor/tezacaftor/ivacaftor (ETI) therapy. As CF is a multi-system disease, systemic immune profiles can reflect local inflammation within the lungs and other organs. Understanding systemic inflammation after ETI therapy may reveal important translational insights. This study aims to profile systemic inflammatory changes and relate these to the well-documented improvements observed with ETI therapy. Methods We conducted a single-centre longitudinal study with 57 CF subjects initiating ETI therapy. All participants were Phe508del homozygous or Phe508del/minimal function. Blood samples were collected pre-ETI and 3–12 months post-therapy initiation. Analyses included mass spectrometry-based proteomics, a multiplex immunoassay, and flow cytometry for peripheral immune cell counts and phenotype. Controls samples were provided by 29 age-matched healthy controls. Results Systemic inflammation reduced with ETI therapy; however, the immune profile remained distinct from healthy controls. ETI reduced neutrophil counts and was associated with a more mature, less inflammatory phenotype, as well as a shift towards an immune resolving state associated with increased CD206 expression. Cytokines known to influence neutrophil levels reduced with therapy. Despite ETI therapy, neutrophil and monocyte counts remained elevated compared with healthy controls. There was no obvious association between the ETI-related improvements in systemic inflammation and lung function. Conclusions Patients with CF showed evidence of persisting systemic inflammation despite ETI therapy, which may have long-term potentially adverse effects on respiratory and other organ systems.

New treatment targets are needed for colorectal cancer (CRC). We define expression of High Mobility Group Box 1 (HMGB1) protein throughout colorectal neoplastic progression and examine the biological consequences of aberrant expression. HMGB1 is a ubiquitously expressed nuclear protein that shuttles to the cytoplasm under cellular stress. HMGB1 impacts cellular responses, acting as a cytokine when secreted. A total of 846 human tissue samples were retrieved; 6242 immunohistochemically stained sections were reviewed. Subcellular epithelial HMGB1 expression was assessed in a CRC Tissue Microarray (n = 650), normal colonic epithelium (n = 75), adenomatous polyps (n = 52), and CRC polyps (CaP, n = 69). Stromal lymphocyte phenotype was assessed in the CRC microarray and a subgroup of CaP. Normal colonic epithelium has strong nuclear and absent cytoplasmic HMGB1. With progression to CRC, there is an emergence of strong cytoplasmic HMGB1 (p < 0.001), pronounced at the leading cancer edge within CaP (p < 0.001), and reduction in nuclear HMGB1 (p < 0.001). In CRC, absent nuclear HMGB1 is associated with mismatch repair proteins (p = 0.001). Stronger cytoplasmic HMGB1 is associated with lymph node positivity (p < 0.001) and male sex (p = 0.009). Stronger nuclear (p = 0.011) and cytoplasmic (p = 0.002) HMGB1 is associated with greater CD4⁺ T-cell density, stronger nuclear HMGB1 is associated with greater FOXP3⁺ (p < 0.001) and ICOS⁺ (p = 0.018) lymphocyte density, and stronger nuclear HMGB1 is associated with reduced CD8⁺ T-cell density (p = 0.022). HMGB1 does not directly impact survival but is associated with an ‘immune cold’ tumour microenvironment which is associated with poor survival (p < 0.001). HMGB1 may represent a new treatment target for CRC.

A treatment with direct healing effects on the gastrointestinal epithelial barrier is desirable for inflammatory bowel disease (IBD). Interleukin-27 (IL-27) is an immunoregulatory cytokine, and oral delivery is an effective treatment in murine models of IBD. We aimed to define IL-27 effects on the human gastrointestinal epithelial barrier. We characterised gene and protein expression of permeability mediators in a human colon-derived organoid model. Functional permeability was determined in an organoid-derived 2D monolayer by transepithelial electrical resistance. IL-27 effects on epithelial innate immune responses were assessed through expression of cytokines, anti-microbial peptides and MUC genes. IL-27 effects on wound healing and proliferation were determined in human colon epithelial cell lines. IL-27 led to restoration of permeability regulation following inflammatory cytokine insult (p = 0.001), associated with differential expression of tight junction mediators with decrease in claudin 2 (p = 0.024) and increase in claudin 4 (p < 0.001), E-cadherin (p < 0.001) and zona occludens (p = 0.0014). IL-27 evoked differential gene expression of epithelial-derived innate immune responses (reduced IL1B and IL18, and increased IL33, HBD1, MUC1 and MUC2; p < 0.012). IL-27 induced epithelial barrier wound healing through restitution (p < 0.001), and increased proliferation (p < 0.001) following injury. Overall, IL-27 provokes mucosal healing of the human gastrointestinal epithelial barrier.

Inflammatory bowel disease (IBD) describes chronic relapsing remitting inflammation of the gastrointestinal tract including ulcerative colitis and Crohn’s disease. The prevalence of IBD is rising across the globe. Despite a growing therapeutic arsenal, current medical treatments are not universally effective, do not induce lasting remission in all, or are accompanied by short- and long-term adverse effects. Therefore, there is a clinical need for novel therapeutic strategies for IBD. Current treatments for IBD mainly manipulate the immune system for therapeutic gain by inhibiting pro-inflammatory activity. There is a robust endogenous immunoregulatory capacity within the repertoire of both innate and adaptive immune responses. An alternative treatment strategy for IBD is to hijack and bolster this endogenous capability for therapeutic gain. This review explores this hypothesis and presents current evidence for this therapeutic direction in immune cell function, cytokine biology, and alternative mechanisms of immunoregulation such as microRNA, oligonucleotides, and the endocannabinoid system.

Aim: Controversy exists over whether surgical technique can reduce recurrence following Crohn's resection. This study compares the rate of endoscopic recurrence after different approaches to mesenteric excision (extended/close) and anastomosis (Kono‐S/standard of care) in adult patients undergoing ileocolic resection for primary or recurrent Crohn's disease. Method: MEErKAT is a UK multicentre, 2 × 2 factorial, randomised, controlled, open‐label superiority trial where participants (target sample size = 308) are blinded and centrally randomised (1:1:1:1) to one of four groups: (1) Kono‐S + extended mesenteric resection. (2) Kono‐S + close mesenteric resection. (3) Standard anastomosis + extended mesenteric resection. (4) Standard anastomosis + close mesenteric resection. The primary outcome is time to endoscopic recurrence of disease (up to 3 years follow‐up). Secondary outcomes include rates of severe and symptomatic recurrence, complications, and quality of life scores. The locality of recurrence will be investigated using endoscopic assessment of the mucosa relative to mucosal tattoos placed at the time of operation. The degree and anastomotic locality of different immune cells will be compared before and after each intervention to better understand the mechanistic processes driving disease recurrence. Conclusion: This study will robustly evaluate the efficacy of the Kono‐S anastomosis technique and extended mesenteric excision in reducing endoscopic recurrence rates. The additive effect of these techniques and local tissue immune response will be investigated. This will provide important evidence to guide the optimal surgical technique and improve our understanding of the processes leading to recurrent disease.

Background Despite significant clinical improvements, there is evidence of persisting airway inflammation in people with cystic fibrosis established on Elexacaftor/tezacaftor/ivacaftor (ETI) therapy. As CF is a multi-system disease, systemic immune profiles can reflect local inflammation within the lungs and other organs. Understanding systemic inflammation after ETI therapy may reveal important translational insights. This study aims to profile systemic inflammatory changes and relate these to the well-documented improvements observed with ETI therapy. Methods We conducted a single-centre longitudinal study with 57 CF subjects initiating ETI therapy. All participants were Phe508del homozygous or Phe508del/minimal function. Blood samples were collected pre-ETI and 3-12 months post-therapy initiation. Analyses included mass spectrometry-based proteomics, a multiplex immunoassay, and flow cytometry for peripheral immune cell counts and phenotype. Controls samples were provided by 29 age-matched healthy controls. Results Systemic inflammation reduced with ETI therapy; however, the immune profile remained distinct from healthy controls. ETI reduced neutrophil counts and was associated with a more mature, less inflammatory phenotype, as well as a shift toward an immune resolving state associated with increased CD206 expression. Cytokines known to influence neutrophil levels reduced with therapy. Despite ETI therapy, neutrophil and monocyte counts remained elevated compared to healthy controls. There was no obvious association between the ETI-related improvements in systemic inflammation and lung function. Conclusions Patients with CF show evidence of persisting systemic inflammation despite ETI therapy, this may have long term potentially adverse effects on respiratory and other organ systems.