Formylated Peptide Receptor-1-Mediated Gut Inflammation as a Therapeutic Target in Inflammatory Bowel Disease.

Background: Formylated peptide receptor (FPR)-1 is a G-coupled receptor that senses foreign bacterial and host-derived mitochondrial formylated peptides (FPs), leading to innate immune system activation. Aim: We sought to investigate the role of FPR1-mediated inflammation and its potential as a therapeutic target in inflammatory bowel disease (IBD). Methods: We characterized FPR1 gene and protein expression in 8 human IBD (~1000 patients) datasets with analysis on disease subtype, mucosal inflammation, and drug response. We performed in vivo dextran-sulfate sodium (DSS) colitis in C57/BL6 FPR1 knockout mice. In ex vivo studies, we studied the role of mitochondrial FPs and pharmacological blockade of FPR1 using cyclosporin H in human peripheral blood neutrophils. Finally, we assess mitochondrial FPs as a potential mechanistic biomarker in the blood and stools of patients with IBD. Results: Detailed in silico analysis in human intestinal biopsies showed that FPR1 is highly expressed in IBD (n = 207 IBD vs 67 non-IBD controls, P < .001), and highly correlated with gut inflammation in ulcerative colitis (UC) and Crohn's disease (CD) (both P < .001). FPR1 receptor is predominantly expressed in leukocytes, and we showed significantly higher FPR1+ve neutrophils in inflamed gut tissue section in IBD (17 CD and 24 UC; both P < .001). Further analysis in 6 independent IBD (data available under Gene Expression Omnibus accession numbers GSE59071, GSE206285, GSE73661, GSE16879, GSE92415, and GSE235970) showed an association with active gut inflammation and treatment resistance to infliximab, ustekinumab, and vedolizumab. FPR1 gene deletion is protective in murine DSS colitis with lower gut neutrophil inflammation. In the human ex vivo neutrophil system, mitochondrial FP, nicotinamide adenine dinucleotide dehydrogenase subunit-6 (ND6) is a potent activator of neutrophils resulting in higher CD62L shedding, CD63 expression, reactive oxygen species production, and chemotactic capacity; these effects are inhibited by cyclosporin H. We screened for mitochondrial ND6 in IBD (n = 54) using ELISA and detected ND6 in stools with median values of 2.2 gg/mL (interquartile range [IQR] 0.0-4.99; range 0-53.3) but not in blood. Stool ND6 levels, however, were not significantly correlated with paired stool calprotectin, C-reactive protein, and clinical IBD activity. Conclusions: Our data suggest that FPR1-mediated neutrophilic inflammation is a tractable target in IBD; however, further work is required to clarify the clinical utility of mitochondrial FPs as a potential mechanistic marker for future stratification.

Therapeutic Potential of Human Intestinal Organoids in Tissue Repair Approaches in Inflammatory Bowel Diseases.

Inflammatory bowel diseases (IBDs) are chronic immune-mediated conditions characterized by significant gut tissue damage due to uncontrolled inflammation. Anti-inflammatory treatments have improved, but there are no current prorepair approaches. Organoids have developed into a powerful experimental platform to study mechanisms of human diseases. Here, we specifically focus on its role as a direct tissue repair modality in IBD. We discuss the scientific rationale for this, recent parallel advances in scientific technologies (CRISPR [clustered regularly interspaced short palindromic repeats]/Cas9 and metabolic programming), and in addition, the clinical IBD context in which this therapeutic approach is tractable. Finally, we review the translational roadmap for the application of organoids and the need for this as a novel direction in IBD.

We provide an overview of the translational potential of human intestinal organoids as a prorepair therapy in inflammatory bowel disease. We focus on the key areas of clinical application and the necessary steps toward tangible progress in this novel approach.

Intraperitoneal local anaesthetic instillation versus no intraperitoneal local anaesthetic instillation for laparoscopic cholecystectomy.

BACKGROUND: Pain is one of the important reasons for delayed discharge after laparoscopic cholecystectomy. Use of intraperitoneal local anaesthetic for laparoscopic cholecystectomy may be a way of reducing pain. A previous version of this Cochrane Review found very low-certainty evidence on the benefits and harms of the intervention. OBJECTIVES: To assess the benefits and harms of intraperitoneal instillation of local anaesthetic agents in people undergoing laparoscopic cholecystectomy. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and three other databases to 19 January 2021 together with reference checking of studies retrieved. We also searched five online clinical trials registries to identify unpublished or ongoing trials to 10 September 2021. We contacted study authors to identify additional studies. SELECTION CRITERIA: We only considered randomised clinical trials (irrespective of language, blinding, publication status, or relevance of outcome measure) comparing local anaesthetic intraperitoneal instillation versus placebo, no intervention, or inactive control during laparoscopic cholecystectomy, for the review. We excluded non-randomised studies, and studies where the method of allocating participants to a treatment was not strictly random (e.g. date of birth, hospital record number, or alternation). DATA COLLECTION AND ANALYSIS: Two review authors collected the data independently. Primary outcomes included all-cause mortality, serious adverse events, and quality of life. Secondary outcomes included length of stay, pain, return to activity and work, and non-serious adverse events. The analysis included both fixed-effect and random-effects models using RevManWeb. We performed subgroup, sensitivity, and meta-regression analyses. For each outcome, we calculated the risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CIs). We assessed risk of bias using predefined domains, graded the certainty of the evidence using GRADE, and presented outcome results in a summary of findings table. MAIN RESULTS: Eighty-five completed trials were included, of which 76 trials contributed data to one or more of the outcomes. This included a total of 4957 participants randomised to intraperitoneal local anaesthetic instillation (2803 participants) and control (2154 participants). Most trials only included participants undergoing elective laparoscopic cholecystectomy and those who were at low anaesthetic risk (ASA I and II). The most commonly used local anaesthetic agent was bupivacaine. Methods of instilling the local anaesthetic varied considerably between trials; this included location and timing of application. The control groups received 0.9% normal saline (69 trials), no intervention (six trials), or sterile water (two trials). One trial did not specify the control agent used. None of the trials provided information on follow-up beyond point of discharge from hospital. Only two trials were at low risk of bias. Seven trials received external funding, of these three were assessed to be at risk of conflicts of interest, a further 17 trials declared no funding. We are very uncertain about the effect intraperitoneal local anaesthetic versus control on mortality; zero mortalities in either group (8 trials; 446 participants; very low-certainty evidence); serious adverse events (RR 1.07; 95% CI 0.49 to 2.34); 13 trials; 988 participants; discharge on same day of surgery (RR 1.43; 95% CI 0.64 to 3.20; 3 trials; 242 participants; very low-certainty evidence). We found that intraperitoneal local anaesthetic probably results in a small reduction in length of hospital stay (MD -0.10 days; 95% CI -0.18 to -0.01; 12 trials; 936 participants; moderate-certainty evidence). No trials reported data on health-related quality of life, return to normal activity or return to work. Pain scores, as measured by visual analogue scale (VAS), were lower in the intraperitoneal local anaesthetic instillation group compared to the control group at both four to eight hours (MD -0.99 cm VAS; 95% CI -1.19 to -0.79; 57 trials; 4046 participants; low-certainty of evidence) and nine to 24 hours (MD -0.68 cm VAS; 95% CI -0.88 to -0.49; 52 trials; 3588 participants; low-certainty of evidence). In addition, we found two trials that were still ongoing, and one trial that was completed but with no published results. All three trials are registered on the WHO trial register. AUTHORS' CONCLUSIONS: We are very uncertain about the effect estimate of intraperitoneal local anaesthetic for laparoscopic cholecystectomy on all-cause mortality, serious adverse events, and proportion of patients discharged on the same day of surgery because the certainty of evidence was very low. Due to inadequate reporting, we cannot exclude an increase in adverse events. We found that intraperitoneal local anaesthetic probably results in a small reduction in length of stay in hospital after surgery. We found that intraperitoneal local anaesthetic may reduce pain at up to 24 hours for low-risk patients undergoing laparoscopic cholecystectomy. Future randomised clinical trials should be at low risk of systematic and random errors, should fully report mortality and side effects, and should focus on clinical outcomes such as quality of life.