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<p>Haag C, Stadel D, Zhou S, <I>et al</I>. Identification of c-FLIPL and c-FLIPS as critical regulators of death receptor-induced apoptosis in pancreatic cancer cells. <I>Gut</I> 2011;60:225-237. doi: 10.1136/gut.2009.202325</p>
<p>Figure 9a illustrates the downregulation of c-FLIP by Cisplatin. The authors observed that while five Western Blot lanes depict the effect of increasing Cisplatin concentrations on c-FLIP protein, six lanes are presented for the loading control beta-Actin. Thus, the 6th lane of the loading control beta-Actin has unintentionally been included in Figure 9a.</p>
<p>The authors sincerely apologise for this unintentional error.</p>
<p>doi:10.1136/gut.2009.202325corr1</p>
<p>Oesophageal adenocarcinoma (OAC) is a devastating disease with an average 5-year survival of around 15%.<cross-ref type="bib" refid="R1">1</cross-ref> Moreover, rates of OAC have increased substantially in recent decades, adding greatly to the clinical and economic burden of this disease.<cross-ref type="bib" refid="R2">2</cross-ref></p> <p>OAC arises out of a metaplastic precursor in which the normal squamous lining of the oesophagus is replaced with columnar, mucin-secreting cells. This is termed Barrett’s oesophagus (BO) and is thought to form as a protective mechanism in response to gastro-oesophageal reflux disease (GORD).</p> <p>The cells that make up this oesophageal metaplasia can take several forms, roughly being broken down into gastric-type (GM) and intestinal-type (IM) metaplasias and are often composed of a mixture of differentiation cell types. GM should not be confused with IM of the stomach, which largely phenocopies oesophageal IM and also carries a risk of progression to adenocarcinoma. It has been suggested that in the...
<p>Tumour-reactive T cells infiltrating solid tumours are often rendered exhausted, a cell differentiation state characterised by upregulation of inhibitory receptors and reduced effector function. The process of T-cell exhaustion permits cancer progression and interferes with immunotherapy response. Efforts to overcome T-cell exhaustion, such as immune checkpoint blockade (ICB), can lead to remarkable clinical responses in some patients with cancer. However, only a minority of patients respond to ICB, responses often lack durability, and undesirable immune-related toxicities are prevalent. Thus, elucidating additional factors that limit T-cell function in cancer may reveal new therapeutic targets to safely promote tumour eradication.</p> <p>While persistent T-cell receptor (TCR) signalling due to chronic tumour antigen is a major driver of exhaustion, the suppressive tumour microenvironment (TME) also contributes.<cross-ref type="bib" refid="R1">1</cross-ref> Over the last two decades, the ectoenzymes CD39 and CD73, which degrade extracellular ATP to adenosine, have been implicated in T-cell exhaustion.<cross-ref type="bib" refid="R2">2 3</cross-ref><cross-ref...
<p>Acute pancreatitis (AP) is a common disease with an annual incidence of 34 (23–49) per 100 000 population.<cross-ref type="bib" refid="R1">1</cross-ref> Patients with acute interstitial pancreatitis have a shorter self-limiting disease course while acute necrotising pancreatitis (ANP) is a much more severe disease with major local and systemic complications mandating prolonged hospitalisation.<cross-ref type="bib" refid="R2">2</cross-ref> Among the local complications, acute necrotic fluid collections and walled-off necrosis require interventions preferably minimally invasively such as percutaneous and per-oral endoscopic drainage, and necrosectomy.<cross-ref type="bib" refid="R3">3</cross-ref> Although the majority of patients survive the illness but their misery doesn't end there with potential long-term serious consequences. This is the focus of the cohort study comprising of 373 patients with a median follow-up of 13.5 years published in <I>Gut</I> by Hollemans <I>et al.</I><cross-ref type="bib" refid="R4">4</cross-ref></p> <p>The word ‘chronic’ literally refers to disease duration. The Centers for Disease Control (CDC) define chronic diseases broadly as conditions that last 1...
<p>Human ferritins are expressed in essentially all cells of the human body. From an evolutionary perspective, human ferritins are part of a diverse ferritin-like superfamily—the ‘rubrerythins’, that include plant ferritins and bacterioferritins, where they cover a wide range of biological functions.<cross-ref type="bib" refid="R1">1</cross-ref> Although best known as a 24-meric intracellular iron storage protein, ferritin is also present in the human circulation, where its biological functions are still being unravelled. Recent studies have shown that ferritin can be actively secreted from cells in extracellular vesicles (EVs). These ferritin-laden EVs can contribute to the pathogenesis of liver steatosis and fibrogenesis by shuttling iron from hepatocytes to hepatic stellate cells.<cross-ref type="bib" refid="R2">2</cross-ref> Hence, in patients with metabolic syndrome, serum ferritin is more than a surrogate of body iron status.<cross-ref type="bib" refid="R3">3</cross-ref> Especially in metabolic dysfunction-associated steatotic liver disease (MASLD), which is the now preferred term for a disease that has until recently...
<p>Chronic liver diseases are prevalent, particularly among patients with type 2 diabetes, who have a higher incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) and are subject to other liver diseases.<cross-ref type="bib" refid="R1">1</cross-ref> With no pharmacotherapy for these liver conditions, recent attention was given to glucagon-like peptide-1 receptor agonists (GLP1a) for their effectiveness in treating type 2 diabetes and obesity and in reducing liver enzyme levels and liver fat levels.<cross-ref type="bib" refid="R2">2</cross-ref> A 72-week, phase II, placebo-controlled randomised trial in patients with non-alcoholic steatohepatitis (NASH) and liver fibrosis found that the GLP1a semaglutide improves the resolution of NASH but does not affect fibrosis regression.<cross-ref type="bib" refid="R2">2</cross-ref> By its limited size, however, this trial could not provide effectiveness data on major liver outcomes (MALO), such as decompensated cirrhosis, hepatocellular carcinoma, liver transplantation or liver-related death, despite its long-term follow-up. Non-randomised observational studies can be useful to address such questions.</p> <p>In...
<sec id="s1"><st>Message</st> <p>Endoscopic neoplasia detection in inflammatory bowel disease (IBD) remains challenging. We developed and validated a novel artificial intelligence (AI) model for lesion detection and characterisation in 478 images from 30 patients with IBD, 10 of whom had a total of 25 neoplastic lesions (including 8 sessile serrated polyps); sensitivity and specificity for lesion detection were 93.5% and 80.6%, respectively. The IBD model was then further validated during a real-time endoscopic assessment of a further 30 consecutive patients with 25 neoplastic lesions found in 11/30 of them and achieved lesion detection rate, lesion per colonoscopy and neoplasia per colonoscopy of 90.4%, 4.6% and 0.96. respectively. The sensitivity and specificity of lesion characterisation were 87.5% and 80.6%, respectively.</p> </sec> <sec id="s2"><st>In more details</st><sec id="s2-1"><st>Development of the IBD deep learning model</st> <p>Deep learning (DL) is a subset of AI that uses multilayered computer algorithms (also called deep artificial neural networks)...
<sec><st>Objective</st>
<p>Whether gastric metaplasia (GM) of the oesophagus should be considered as Barrett’s oesophagus (BO) is controversial. Given concern intestinal metaplasia (IM) may be missed due to sampling, the UK guidelines include GM as a type of BO. Here, we investigated whether the risk of misdiagnosis and the malignant potential of GM warrant its place in the UK surveillance.</p>
</sec>
<sec><st>Design</st>
<p>We performed a thorough pathology and endoscopy review to follow clinical outcomes in a novel UK cohort of 244 patients, covering 1854 person years of follow-up. We complemented this with a comparative genomic analysis of 160 GM and IM specimens, focused on early molecular hallmarks of BO and oesophageal adenocarcinoma (OAC).</p>
</sec>
<sec><st>Results</st>
<p>We found that 58 of 77 short-segment (<I><</I>3 cm) GM (SS-GM) cases (75%) continued to be observed as GM-only across a median of 4.4 years of follow-up. We observed that disease progression in GM-only cases and GM+IM cases (cases with reported GM on some occasions, IM on others) was significantly lower than in the IM-only cases (Kaplan-Meier, p=0.03). Genomic analysis revealed that the mutation burden in GM is significantly lower than in IM (p<0.01). Moreover, GM does not bear the mutational hallmarks of OAC, with an absence of associated signatures and driver gene mutations. Finally, we established that GM found adjacent to OAC is evolutionarily distant from cancer.</p>
</sec>
<sec><st>Conclusion</st>
<p>SS-GM is a distinct entity from SS-IM and the malignant potential of GM is lower than IM. It is questionable whether SS-GM warrants inclusion in BO surveillance.</p>
</sec>
<sec id="s1"><st>Case presentation</st> <p>An 18-year-old woman presented with a 4-day history of worsening abdominal pain. Physical examination revealed tenderness in the left mid abdomen, without rebound tenderness. Laboratory workups revealed neutrophilia (10 890/µL), elevated C reactive protein (38.59 mg/L) and increased faecal calprotectin (>50 µg/g). Haemoglobin, liver function, renal function and urinalysis results were within normal range. Immunological investigations, including immunoglobulin levels, antineutrophil cytoplasmic antibodies and antinuclear antibodies, were all normal. An abdominal CT scan demonstrated wall thickening of the distal duodenum and proximal jejunum (<cross-ref type="fig" refid="F1">figure 1A</cross-ref>). To further evaluate the small intestine, a gastrointestinal barium contrast radiograph was performed, which confirmed dilatation of the horizontal duodenum (<cross-ref type="fig" refid="F1">figure 1B</cross-ref>). Consequently, supportive care measures were initiated, including nil by mouth, nasogastric decompression, antibiotic therapy (piperacillin sodium/tazobactam sodium, 4.5 g every 8 hours intravenously) and acid suppression with omeprazole. Despite these interventions, the patient showed no improvement, prompting the need for oesophagogastroduodenoscopy...
<sec><st>Objective</st>
<p>Endoscopic mucosal resection (EMR) is the preferred treatment for non-invasive large (≥20 mm) non-pedunculated colorectal polyps (LNPCPs) but is associated with an early recurrence rate of up to 30%. We evaluated whether standardised EMR training could reduce recurrence rates in Dutch community hospitals.</p>
</sec>
<sec><st>Design</st>
<p>In this multicentre cluster randomised trial, 59 endoscopists from 30 hospitals were randomly assigned to the intervention group (e-learning and 2-day training including hands-on session) or control group. From April 2019 to August 2021, all consecutive EMR-treated LNPCPs were included. Primary endpoint was recurrence rate after 6 months.</p>
</sec>
<sec><st>Results</st>
<p>A total of 1412 LNPCPs were included; 699 in the intervention group and 713 in the control group (median size 30 mm vs 30 mm, 45% vs 52% size, morphology, site and access (SMSA) score IV, 64% vs 64% proximal location). Recurrence rates were lower in the intervention group compared with controls (13% vs 25%, OR 0.43; 95% CI 0.23 to 0.78; p=0.005) with similar complication rates (8% vs 9%, OR 0.93; 95% CI 0.64 to 1.36; p=0.720). Recurrences were more often unifocal in the intervention group (92% vs 76%; p=0.006). In sensitivity analysis, the benefit of the intervention on recurrence rate was only observed in the 20–40 mm LNPCPs (5% vs 20% in 20–29 mm, p=0.001; 10% vs 21% in 30–39 mm, p=0.013) but less evident in ≥40 mm LNPCPs (24% vs 31%; p=0.151). In a post hoc analysis, the training effect was maintained in the study group, while in the control group the recurrence rate remained high.</p>
</sec>
<sec><st>Conclusion</st>
<p>A compact standardised EMR training for LNPCPs significantly reduced recurrences in community hospitals. This strongly argues for a national dedicated training programme for endoscopists performing EMR of ≥20 mm LNPCPs. Interestingly, in sensitivity analysis, this benefit was limited for LNPCPs ≥40 mm.</p>
</sec>
<sec><st>Trial registration number</st>
<p>NTR7477.</p>
</sec>
<sec><st>Objective</st>
<p>Chronic obstructive pulmonary disease (COPD) is a major cause of global illness and death, most commonly caused by cigarette smoke. The mechanisms of pathogenesis remain poorly understood, limiting the development of effective therapies. The gastrointestinal microbiome has been implicated in chronic lung diseases via the gut-lung axis, but its role is unclear.</p>
</sec>
<sec><st>Design</st>
<p>Using an <I>in vivo</I> mouse model of cigarette smoke (CS)-induced COPD and faecal microbial transfer (FMT), we characterised the faecal microbiota using metagenomics, proteomics and metabolomics. Findings were correlated with airway and systemic inflammation, lung and gut histopathology and lung function. Complex carbohydrates were assessed in mice using a high resistant starch diet, and in 16 patients with COPD using a randomised, double-blind, placebo-controlled pilot study of inulin supplementation.</p>
</sec>
<sec><st>Results</st>
<p>FMT alleviated hallmark features of COPD (inflammation, alveolar destruction, impaired lung function), gastrointestinal pathology and systemic immune changes. Protective effects were additive to smoking cessation, and transfer of CS-associated microbiota after antibiotic-induced microbiome depletion was sufficient to increase lung inflammation while suppressing colonic immunity in the absence of CS exposure. Disease features correlated with the relative abundance of <I>Muribaculaceae, Desulfovibrionaceae</I> and <I>Lachnospiraceae</I> family members. Proteomics and metabolomics identified downregulation of glucose and starch metabolism in CS-associated microbiota, and supplementation of mice or human patients with complex carbohydrates improved disease outcomes.</p>
</sec>
<sec><st>Conclusion</st>
<p>The gut microbiome contributes to COPD pathogenesis and can be targeted therapeutically.</p>
</sec>
<sec><st>Objective</st>
<p>Epidemiological studies highlight an association between pancreatic ductal adenocarcinoma (PDAC) and oral carriage of the anaerobic bacterium <I>Porphyromonas gingivalis</I>, a species highly linked to periodontal disease. We analysed the potential for <I>P. gingivalis</I> to promote pancreatic cancer development in an animal model and probed underlying mechanisms.</p>
</sec>
<sec><st>Design</st>
<p>We tracked <I>P. gingivalis</I> bacterial translocation from the oral cavity to the pancreas following administration to mice. To dissect the role of <I>P. gingivalis</I> in PDAC development, we administered bacteria to a genetically engineered mouse PDAC model consisting of inducible acinar cell expression of mutant <I>Kras</I> (<I>Kras</I> <sup>+</sup>/LSL-G12D; Ptf1a-CreER, iKC mice). These mice were used to study the cooperative effects of <I>Kras</I> mutation and <I>P. gingivalis</I> on the progression of pancreatic intraepithelial neoplasia (PanIN) to PDAC. The direct effects of <I>P. gingivalis</I> on acinar cells and PDAC cell lines were studied in vitro.</p>
</sec>
<sec><st>Results</st>
<p> <I>P. gingivalis</I> migrated from the oral cavity to the pancreas in mice and can be detected in human PanIN lesions. Repetitive <I>P. gingivalis</I> administration to wild-type mice induced pancreatic acinar-to-ductal metaplasia (ADM), and altered the composition of the intrapancreatic microbiome. In iKC mice, <I>P. gingivalis</I> accelerated PanIN to PDAC progression. In vitro, <I>P. gingivalis</I> infection induced acinar cell ADM markers SOX9 and CK19, and intracellular bacteria protected PDAC cells from reactive oxygen species-mediated cell death resulting from nutrient stress.</p>
</sec>
<sec><st>Conclusion</st>
<p>Taken together, our findings demonstrate a causal role for <I>P. gingivalis</I> in pancreatic cancer development in mice.</p>
</sec>
<sec><st>Objective</st>
<p>To describe the long-term consequences of necrotising pancreatitis, including complications, the need for interventions and the quality of life.</p>
</sec>
<sec><st>Design</st>
<p>Long-term follow-up of a prospective multicentre cohort of 373 necrotising pancreatitis patients (2005–2008) was performed. Patients were prospectively evaluated and received questionnaires. Readmissions (ie, for recurrent or chronic pancreatitis), interventions, pancreatic insufficiency and quality of life were compared between initial treatment groups: conservative, endoscopic/percutaneous drainage alone and necrosectomy. Associations of patient and disease characteristics during index admission with outcomes during follow-up were assessed.</p>
</sec>
<sec><st>Results</st>
<p>During a median follow-up of 13.5 years (range 12–15.5 years), 97/373 patients (26%) were readmitted for recurrent pancreatitis. Endoscopic or percutaneous drainage was performed in 47/373 patients (13%), of whom 21/47 patients (45%) were initially treated conservatively. Pancreatic necrosectomy or pancreatic surgery was performed in 31/373 patients (8%), without differences between treatment groups. Endocrine insufficiency (126/373 patients; 34%) and exocrine insufficiency (90/373 patients; 38%), developed less often following conservative treatment (p<0.001 and p=0.016, respectively). Quality of life scores did not differ between groups. Pancreatic gland necrosis >50% during initial admission was associated with percutaneous/endoscopic drainage (OR 4.3 (95% CI 1.5 to 12.2)), pancreatic surgery (OR 3.2 (95% CI 1.1 to 9.5) and development of endocrine insufficiency (OR13.1 (95% CI 5.3 to 32.0) and exocrine insufficiency (OR6.1 (95% CI 2.4 to 15.5) during follow-up.</p>
</sec>
<sec><st>Conclusion</st>
<p>Acute necrotising pancreatitis carries a substantial disease burden during long-term follow-up in terms of recurrent disease, the necessity for interventions and development of pancreatic insufficiency, even when treated conservatively during the index admission. Extensive (>50%) pancreatic parenchymal necrosis seems to be an important predictor of interventions and complications during follow-up.</p>
</sec>
<sec><st>Objective</st>
<p>Hepatitis B virus (HBV) can integrate into the chromosomes of infected hepatocytes, contributing to the production of hepatitis B surface antigen (HBsAg) and to hepatocarcinogenesis. In this study, we aimed to explore whether transcriptionally active HBV integration events spread throughout the liver tissue in different phases of chronic HBV infection, especially in patients with HBsAg loss.</p>
</sec>
<sec><st>Design</st>
<p>We constructed high-resolution spatial transcriptomes of liver biopsies containing 13 059 tissue spots from 18 patients with chronic HBV infection to analyse the occurrence and relative distribution of transcriptionally active viral integration events. Immunohistochemistry was performed to evaluate the expression of HBsAg and HBV core antigen. Intrahepatic covalently closed circular DNA (cccDNA) levels were quantified by real-time qPCR.</p>
</sec>
<sec><st>Results</st>
<p>Spatial transcriptome sequencing identified the presence of 13 154 virus-host chimeric reads in 7.86% (1026 of 13 059) of liver tissue spots in all patients, including three patients with HBsAg loss. These HBV integration sites were randomly distributed on chromosomes and can localise in host genes involved in hepatocarcinogenesis, such as <I>ALB, CLU</I> and <I>APOB</I>. Patients who were receiving or had received antiviral treatment had a significantly lower percentage of viral integration-containing spots and significantly fewer chimeric reads than treatment-naïve patients. Intrahepatic cccDNA levels correlated well with viral integration events.</p>
</sec>
<sec><st>Conclusion</st>
<p>Transcriptionally active HBV integration occurred in chronically HBV-infected patients at different phases, including in patients with HBsAg loss. Antiviral treatment was associated with a decreased number and extent of transcriptionally active viral integrations, implying that early treatment intervention may further reduce the number of viral integration events.</p>
</sec>
<sec><st>Objective</st>
<p>Liver fibrosis is a prelude to a host of end-stage liver diseases. Hepatic stellate cells (HSCs), switching from a quiescent state to myofibroblasts, are the major source for excessive production of extracellular matrix proteins. In the present study, we investigated the role of Suv39h1, a lysine methyltransferase, in HSC-myofibroblast transition and the implication in liver fibrosis.</p>
</sec>
<sec><st>Design</st>
<p>HSC-specific or myofibroblast-specific Suv39h1 deletion was achieved by crossbreeding the <I>Suv39h1</I> <sup>f/f</sup> mice to the <I>Lrat</I>-Cre mice or the <I>Postn</I>-Cre<sup>ERT2</sup> mice. Liver fibrosis was induced by CCl<SUB>4</SUB> injection or bile duct ligation.</p>
</sec>
<sec><st>Results</st>
<p>We report that Suv39h1 expression was universally upregulated during HSC-myofibroblast transition in different cell and animal models of liver fibrosis and in human cirrhotic liver tissues. Consistently, Suv39h1 knockdown blocked HSC-myofibroblast transition in vitro. HSC-specific or myofibroblast-specific deletion of Suv39h1 ameliorated liver fibrosis in mice. More importantly, Suv39h1 inhibition by a small-molecule compound chaetocin dampened HSC-myofibroblast transition in cell culture and mitigated liver fibrosis in mice. Mechanistically, Suv39h1 bound to the promoter of heme oxygenase 1 (HMOX1) and repressed HMOX1 transcription. HMOX1 depletion blunted the effects of Suv39h1 inhibition on HSC-myofibroblast transition in vitro and liver fibrosis in vivo. Transcriptomic analysis revealed that HMOX1 might contribute to HSC-myofibroblast transition by modulating retinol homeostasis. Finally, myofibroblast-specific HMOX1 overexpression attenuated liver fibrosis in both a preventive scheme and a therapeutic scheme.</p>
</sec>
<sec><st>Conclusions</st>
<p>Our data demonstrate a previously unrecognised role for Suv39h1 in liver fibrosis and offer proof-of-concept of its targetability in the intervention of cirrhosis.</p>
</sec>
<sec><st>Objective</st>
<p>Hyperferritinaemia is associated with liver fibrosis severity in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), but the longitudinal implications have not been thoroughly investigated. We assessed the role of serum ferritin in predicting long-term outcomes or death.</p>
</sec>
<sec><st>Design</st>
<p>We evaluated the relationship between baseline serum ferritin and longitudinal events in a multicentre cohort of 1342 patients. Four survival models considering ferritin with confounders or non-invasive scoring systems were applied with repeated five-fold cross-validation schema. Prediction performance was evaluated in terms of Harrell’s C-index and its improvement by including ferritin as a covariate.</p>
</sec>
<sec><st>Results</st>
<p>Median follow-up time was 96 months. Liver-related events occurred in 7.7%, hepatocellular carcinoma in 1.9%, cardiovascular events in 10.9%, extrahepatic cancers in 8.3% and all-cause mortality in 5.8%. Hyperferritinaemia was associated with a 50% increased risk of liver-related events and 27% of all-cause mortality. A stepwise increase in baseline ferritin thresholds was associated with a statistical increase in C-index, ranging between 0.02 (lasso-penalised Cox regression) and 0.03 (ridge-penalised Cox regression); the risk of developing liver-related events mainly increased from threshold 215.5 µg/L (median HR=1.71 and C-index=0.71) and the risk of overall mortality from threshold 272 µg/L (median HR=1.49 and C-index=0.70). The inclusion of serum ferritin thresholds (215.5 µg/L and 272 µg/L) in predictive models increased the performance of Fibrosis-4 and Non-Alcoholic Fatty Liver Disease Fibrosis Score in the longitudinal risk assessment of liver-related events (C-indices>0.71) and overall mortality (C-indices>0.65).</p>
</sec>
<sec><st>Conclusions</st>
<p>This study supports the potential use of serum ferritin values for predicting the long-term prognosis of patients with MASLD.</p>
</sec>
<sec><st>Objective</st>
<p>Phase II trials suggest glucagon-like peptide-1 receptor (GLP1) agonists resolve metabolic dysfunction-associated steatohepatitis but do not affect fibrosis regression. We aimed to determine the long-term causal effect of GLP1 agonists on the risk of major adverse liver outcomes (MALO) in patients with any chronic liver disease and type 2 diabetes.</p>
</sec>
<sec><st>Design</st>
<p>We used observational data from Swedish healthcare registers 2010–2020 to emulate a target trial of GLP1 agonists in eligible patients with chronic liver disease and type 2 diabetes. We used an inverse-probability weighted marginal structural model to compare parametric estimates of 10-year MALO risk (decompensated cirrhosis, hepatocellular carcinoma, liver transplantation or MALO-related death) in initiators of GLP1 agonists with non-initiators. We randomly sampled 5% of the non-initiators to increase computational efficiency.</p>
</sec>
<sec><st>Results</st>
<p>GLP1 agonist initiators had a 10-year risk of MALO at 13.3% (42/1026) vs 14.6% in non-initiators (1079/15 633) in intention-to-treat analysis (risk ratio (RR)=0.91, 95% CI=0.50 to 1.32). The corresponding 10-year per-protocol risk estimates were 7.4% (22/1026) and 14.4% (1079/15 633), respectively (RR=0.51, 95% CI=0.14 to 0.88). The per-protocol risk estimates at 6 years were 5.4% (21/1026) vs 9.0% (933/15 633) (RR=0.60, 95% CI=0.29 to 0.90) and at 8 years 7.2% (22/1026) vs 11.7% (1036/15 633) (RR=0.61, 95% CI=0.21 to 1.01).</p>
</sec>
<sec><st>Conclusion</st>
<p>In patients with chronic liver disease and type 2 diabetes who adhered to therapy over time, GLP1 agonists may result in lower risk of MALO. This suggests that GLP1 agonists are promising agents to reduce risk of chronic liver disease progression in patients with concurrent type 2 diabetes, although this needs to be corroborated in randomised trials.</p>
</sec>
<p>Serum antibodies to the autoantigen transglutaminase 2 (TG2) are increasingly harnessed to diagnose coeliac disease. Diagnostic guidelines for children give recommendation for a no-biopsy-based diagnosis through detection of high amounts of IgA anti-TG2 antibodies in serum with confirmation of positivity in a separate blood sample by characteristic autoantibody-staining of tissue. While measurement of IgA anti-TG2 also is important in the diagnostic workup of adults, the adult guidelines still mandate examination of gut biopsies. This requirement might well change in the future, as might the necessity for confirming autoantibody positivity by tissue staining. The key role of autoantibody serology for diagnosis of coeliac disease is paradoxical. Coeliac disease was considered, and still can be considered, a food intolerance disorder where autoantibodies at face value are out of place. The immunological mechanisms underlying the formation of autoantibodies in response to gluten exposure have been dissected. This review presents the current insights demonstrating that the autoantibodies in coeliac disease are intimately integrated in the maladapted immune response to gluten.</p>
<sec><st>Background</st>
<p>Intestinal fibrosis resulting in stricture formation and obstruction in Crohn’s disease (CD) and increased wall stiffness leading to symptoms in ulcerative colitis (UC) is among the largest unmet needs in inflammatory bowel disease (IBD). Fibrosis is caused by a multifactorial and complex process involving immune and non-immune cells, their soluble mediators and exposure to luminal contents, such as microbiota and environmental factors. To date, no antifibrotic therapy is available. Some progress has been made in creating consensus definitions and measurements to quantify stricture morphology for clinical practice and trials, but approaches to determine the degree of fibrosis within a stricture are still lacking.</p>
</sec>
<sec><st>Objective</st>
<p>We herein describe the current state of stricture pathogenesis, measuring tools and clinical trial endpoints development.</p>
</sec>
<sec><st>Design</st>
<p>Data presented and discussed in this review derive from the past and recent literature and the authors’ own research and experience.</p>
</sec>
<sec><st>Results and conclusions</st>
<p>Significant progress has been made in better understanding the pathogenesis of fibrosis, but additional studies and preclinical developments are needed to define specific therapeutic targets.</p>
</sec>
<sec id="s1"><st>Basic science</st><sec id="s1-1"><st>How ketogenic and vegan diets shape host immunity and gut microbial functions</st> <p>Link V, Subramanian P, Cheung F, <I>et al</I>. Differential peripheral immune signatures elicited by vegan versus ketogenic diets in humans. <I>Nat Med</I> 2024; 302: 560–572. doi: 10.1038/s41591-023-02761-2.</p> <p>Nutritional intervention has therapeutic potential against diseases directly or via the gut microbiota. However, the link between nutrition and the host immunity remains largely unknown. Link <I>et al</I> applied a multiomics approach including flow cytometry, transcriptomic, proteomic, metabolomic and metagenomic analysis to collectively access the effect of diet and dietary switch on host immunity and gut microbiota. A group of 40 participants admitted to the study were divided into two groups, and provided with a 2-week ketogenic diet and a 2-week vegan diet on a different order. RNA sequencing of whole blood and flow cytometry analysis on peripheral blood mononuclear cells has revealed a change, independent of...
<p>We read with interest the article by Marasco <I>et al</I> evaluating the prevalence of gastrointestinal (GI) symptoms and post-COVID-19 disorders of gut–brain interaction after hospitalisation for SARS-CoV-2 infection.<cross-ref type="bib" refid="R1">1</cross-ref> The author found that COVID-19 is associated with a modest increased risk of irritable bowel syndrome (IBS).</p> <p>Postinfectious IBS (PI-IBS) is a common disease in which GI symptoms begin after an episode of infective gastroenteritis. Acute gastroenteritis following infection with bacterial or viral pathogens is an important risk factor for IBS. Our previous study also confirmed that the odds of developing IBS are increased after acute GI infection.<cross-ref type="bib" refid="R2">2</cross-ref> The first formal description of PI-IBS was published Chaudhary and Truelove.<cross-ref type="bib" refid="R3">3</cross-ref> SARS-CoV-2 could also lead to GI symptoms, which involve abdominal pains, diarrhoea, nausea and vomiting. Our previous meta-analysis including 31 studies with 4682 COVID-19 patients found that SARS-CoV-2 infection was associated with diarrhoea, anorexia, abdominal pain...
<p>Your recent ‘Chinese Consensus Report on Family-based Helicobacter pylori infection Control and management (2021 Edition)’<cross-ref type="bib" refid="R1">1</cross-ref> and ‘Large-scale, national, family-based epidemiological study on Helicobacter pylori infection in China: the time to change practice for related disease prevention’<cross-ref type="bib" refid="R2">2</cross-ref> will encourage more doctors in China to consider <I>Helicobacter pylori</I> as a curable aetiology for gastrointestinal symptoms, and as a smart way to prevent gastric cancer in the ageing population. The paper is based on results of a very large new study of <I>H. pylori</I> prevalence in China whereby investigators completed a China-wide breath-test survey of 10 735 families. Unfortunately, 70% of families had at least one positive family member although younger, educated and Eastern-China families had less, with 28% of persons being infected but only 20% of children being infected. In contrast, some North-Western provinces had 85% of families infected and 19% had all family members infected. The parents...
<p>We thank Ludvigsson for his interest in our work and for providing additional insights. As noted, our joint works implicate the role of antibiotics in the development of inflammatory bowel disease (IBD), however, there are limitations as well as unique strengths to our study design which should be noted.<cross-ref type="bib" refid="R1">1 2</cross-ref><cross-ref type="bib" refid="R2"></cross-ref></p> <p>Although confounding may exist, our prospective cohort study design limits this possibility. For example, if an individual is not prescribed an antibiotic course for the first 10 years of follow-up, they will initially contribute at-risk time to the ‘no antibiotic exposure’ group. If, however, they are then prescribed an antibiotic course, the following 1–5 years will contribute time to the ‘antibiotic exposure group.’ At the end of these 5 years, the individual will then return and contribute additional time to the ‘no antibiotic exposure’ group until another course is prescribed. In this way, confounding is reduced,...
<p>We read the Maastricht VI/Florence consensus report published in GUT with great interest.<cross-ref type="bib" refid="R1">1</cross-ref> The report suggested that vonoprazan-based therapy is superior, or not inferior, to conventional proton pump inhibitor (PPI)-based triple therapies for <I>Helicobacter pylori</I> eradication.<cross-ref type="bib" refid="R1">1</cross-ref> However, the number of randomised controlled trials (RCTs) was small and the majority of previous trials were conducted in Japan.<cross-ref type="bib" refid="R2">2–5</cross-ref><cross-ref type="bib" refid="R3"></cross-ref><cross-ref type="bib" refid="R4"></cross-ref><cross-ref type="bib" refid="R5"></cross-ref> Recently, several new RCTs from other populations have been reported.<cross-ref type="bib" refid="R6">6–8</cross-ref><cross-ref type="bib" refid="R7"></cross-ref><cross-ref type="bib" refid="R8"></cross-ref> Therefore, we conducted an updated systematic review and meta-analysis of RCTs to compare the efficacy and tolerability of vonoprazan and PPI-based therapies for <I>H. pylori</I> eradication.</p> <p>Detailed methods of the inclusion and exclusion criteria, systematic review, and statistical methods were shown in , and the registration number is CRD42023394825. Of the 489 articles identified, 476 articles were excluded (). A total of 13 RCTs were...
<p>Eosinophilic oesophagitis (EoE) is an immune-mediated disease of uncertain aetiology. The diagnosis of EoE relies on the epithelial infiltration of eosinophils (peak eosinophil count of ≥15 per high-power field (HPF)) and on the presence of symptoms. Consequently, a combined clinical–histological endpoint has been devised to assess response to treatments in clinical trials. Recent guidelines drafted by the British Society of Gastroenterology have confirmed the pivotal role of swallowed topical steroid and, for the first time, explicitly considered the use of biological therapy in case of a coexisting severe allergic condition.<cross-ref type="bib" refid="R1">1</cross-ref> These guidelines have appraised the results of pivotal trials leading to the approval of orodispersible budesonide and dupilumab, a monoclonal antibody targeting interleukin (IL)-14 and IL-13, since they both met the aforementioned coprimary endpoint.<cross-ref type="bib" refid="R2">2 3</cross-ref><cross-ref type="bib" refid="R3"></cross-ref> Additionally, dupilumab also proved to enhance distensibility of the oesophagus wall. These results, along with the proved efficacy...
<p>We read with interest the recent article by Haifer <I>et al</I> (Gut, 2022, 2022–3 27 742), which reported that donor gut microbiome stability and species evenness were associated with higher donor species engraftment in patients with UC following faecal microbiota transplantation (FMT). This has brought us one step closer towards the selection of optimal FMT donors. However, the high prevalence of extended-spectrum beta-lactamase organisms and the COVID-19 pandemic have restricted the recruitment of FMT donors.<cross-ref type="bib" refid="R1">1</cross-ref> An alternative means to increase the stability and species evenness is to pool the stool samples from multiple eligible FMT donors, which has been shown to be associated with higher clinical efficacy in UC.<cross-ref type="bib" refid="R2">2</cross-ref> In obesity-related metabolic disorders, outcomes following FMT have been variable.<cross-ref type="bib" refid="R3">3–8</cross-ref><cross-ref type="bib" refid="R4"></cross-ref><cross-ref type="bib" refid="R5"></cross-ref><cross-ref type="bib" refid="R6"></cross-ref><cross-ref type="bib" refid="R7"></cross-ref><cross-ref type="bib" refid="R8"></cross-ref> Although the underlying mechanisms are unclear, the efficacy of FMT is likely to be affected by...
<p>Recently, Lopes <I>et al</I> quantified the effect of modifiable lifestyle factors in inflammatory bowel disease (IBD) prevention using population attributable risk, and reported that 42.9% of Crohn’s disease (CD) cases and 44.4% of ulcerative colitis (UC) cases could have been prevented by lifestyle interventions. This interesting result was based on 6 prospective cohorts including 3 US cohorts with 208 070 participants and 3 large European cohorts that were used for validation.<cross-ref type="bib" refid="R1">1</cross-ref> Undoubtedly, this well-performed study illustrates the possible merits of lifestyle modification as a prevention strategy for IBD.</p> <p>However, we would like to argue that lifestyle modification as such cannot be uncoupled from the genetic background. Although the importance of genetic susceptibility in the development of IBD is widely accepted,<cross-ref type="bib" refid="R2">2</cross-ref> this was unfortunately not assessed in Lopes <I>et al</I> ‘s study. We recently conducted a prospective cohort study on the UK Biobank in >450 000 individuals,...
<p>We read with great interest the study of Wester <I>et al</I><cross-ref type="bib" refid="R1">1</cross-ref> that suggested a potential hepatoprotective effect of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in mitigating the risk of major adverse liver outcomes among patients with type 2 diabetes (T2D). Currently, several studies indicate that GLP-1RAs provide functional protection for chronic liver diseases.<cross-ref type="bib" refid="R2">2 3</cross-ref><cross-ref type="bib" refid="R3"></cross-ref> However, uncertainties persist regarding the beneficial effect of GLP-1RAs on chronic liver disease-related outcomes, such as fibrosis progression, primarily due to the limited follow-up time<cross-ref type="bib" refid="R4">4</cross-ref> and the presence of potential confounding factors (eg, synergistic effects of GLP-1RA on weight).<cross-ref type="bib" refid="R5">5</cross-ref> Therefore, we sought to investigate the effects of GLP-1RAs on liver outcomes by using drug target Mendelian randomisation (MR).<cross-ref type="bib" refid="R6">6</cross-ref> Meanwhile, we aim to elucidate whether and to what degree the protective effect of GLP-1RAs was mediated by T2D control and weight loss.</p> <p>Genetic instrumental variables...
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