Alimentary Pharmacology & Therapeutics最新文献

{"title":"Review Article: Novel Enzyme Therapy Design for Gluten Peptide Digestion Through Exopeptidase Supplementation","authors":"Erin R. Bonner,&nbsp;Werner Tschollar,&nbsp;Robert Anderson,&nbsp;Sulayman Mourabit","doi":"10.1111/apt.70014","DOIUrl":"10.1111/apt.70014","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Dietary peptides are increasingly linked to inflammatory gastrointestinal diseases, exemplified by coeliac disease. Coeliac disease is caused by an acquired immune response to proline- and glutamine-rich gluten peptides, which bottleneck proteolysis and provide substrates for immune recognition. Enzyme therapies aim to eliminate gluten immunogenic peptides as an adjunct to gluten-free diet.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>To investigate overlooked aspects of enzyme development given difficulties in translating preclinical efficacy into clinical benefit.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We assessed mode-of-action, target organ and drug delivery in the context of digestive physiology and motility for gluten-digesting enzymes on the market or in development until 1 December 2024.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Most enzymes were gastric endopeptidases specific for proline or glutamine residues. Gastric enzymes may achieve poor enzyme–substrate exposure due to limited mixing and rapid emptying of water-soluble particles. Moreover, endopeptidases cleave proteins/peptides into shorter peptides but do not systematically cleave protein into absorbable fractions. Natural digestive physiology provides thorough mixing at the intestinal brush border, which produces exopeptidases necessary to fully digest proline-rich peptides. Despite reduced activity in patients with coeliac disease, exopeptidases remain underexplored as therapeutic agents. Given limited substrate scope and end-to-end digestion, exopeptidases are ineffective as single agents, requiring functional combinations. Furthermore, vulnerability to gastric acid requires stabilisation or formulation for rapid enteric release.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Enzymes should be stabilised throughout the gastrointestinal tract including the small intestine. Exopeptidases perform a critical function by systematically generating absorbable fractions, warranting future investigation as therapeutic agents. Sensitive and translational biomarkers are needed to better assess enzyme efficacy in real-meal conditions.</p>\u0000 </section>\u0000 </div>","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"61 7","pages":"1123-1139"},"PeriodicalIF":6.6,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apt.70014","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143418435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Course and Prognosis of Long-Term Survivors of Hepatocellular Carcinoma","authors":"Soon Sun Kim,&nbsp;Jonghyun Lee,&nbsp;Sang Bong Ahn,&nbsp;Young Eun Chon,&nbsp;Eileen Yoon,&nbsp;Soung Won Jeong,&nbsp;Dae Won Jun","doi":"10.1111/apt.70004","DOIUrl":"10.1111/apt.70004","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>This study investigated the long-term prognosis and clinical course of patients who survived for more than 5 years after hepatocellular carcinoma (HCC) diagnosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This retrospective cohort study used data from the Korean National Health Insurance Service database. A total of 35,348 subjects newly diagnosed with HCC between January 2008 and December 2010 were followed up until December 2018.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 11,514 (32.6%) survived for 5 years after diagnosis of HCC among 35,348 patients diagnosed with HCC. Long-term survivors (≥ 5 years) had a higher proportion of females, younger age, more frequent aetiology of hepatitis B virus, less frequent liver cirrhosis, diabetes mellitus and hypertension, and received curative treatment more frequently than nonsurvivors (&lt; 5 years). The additional 1-, 3- and 5-year cumulative survival probabilities were 90.7%, 77.6% and 68.4% respectively. Patients who underwent curative treatment as the first treatment for HCC showed a higher additional 5-year cumulative survival probabilities than those treated with noncurative therapy (74.5% vs. 64.2%). Among the long-term survivors, 44.4% underwent HCC retreatment 5 years after HCC diagnosis. The additional 5-year cumulative survival probability was 54.9% in the HCC retreatment group. The overall 5- and 10-year cumulative probabilities of second primary malignancies in long-term survivors were 15.36% and 27.54% respectively. The most frequent second primary malignancy was prostate cancer, followed by colorectal and pancreatic cancers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our study highlights that a significant proportion of patients with HCC achieve long-term survival beyond 5 years, with favourable outcomes associated with curative treatments.</p>\u0000 </section>\u0000 </div>","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"61 8","pages":"1333-1342"},"PeriodicalIF":6.6,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Letter: The Hidden Truth of IBD Risk—From Antibiotics to Environmental Factors","authors":"Xueneng Yang,&nbsp;Ruijuan Li","doi":"10.1111/apt.18517","DOIUrl":"10.1111/apt.18517","url":null,"abstract":"&lt;p&gt;Editors,&lt;/p&gt;&lt;p&gt;Inflammatory bowel disease (IBD) has shown a significant rise in global incidence over the past few decades, with particularly rapid increase in children and adolescents [&lt;span&gt;1, 2&lt;/span&gt;]. Early-life antibiotic use has profound effects on the gut microbiome and immune system, linking it to an elevated risk of IBD [&lt;span&gt;1, 3&lt;/span&gt;]. Despite growing research, the specific impacts of different antibiotic types, doses and timing on IBD risk remain unclear. Furthermore, the interplay between environmental factors and the gut microbiota requires further investigation. Bridging these knowledge gaps is crucial for alleviating the growing burden of IBD among children and adolescents.&lt;/p&gt;&lt;p&gt;We commend Dr. Mårild et al. [&lt;span&gt;4&lt;/span&gt;] for their work in investigating the relationship between early-life infections, antibiotic use and the risk of IBD in children and adolescents. They demonstrated that early-life antibiotic use, particularly of penicillin, was significantly associated with an increased risk of IBD (adjusted hazard ratio: 1.33), while infection frequency at ages 0–1 and 1–3 years showed no significant association. This provides critical evidence for understanding the long-term effects of antibiotics on the gut microbiome and immune system. However, some limitations in the study warrant further exploration.&lt;/p&gt;&lt;p&gt;First, the study relied solely on usage frequency without analysing antibiotic dosage and duration, which limits the understanding of their impact on gut microbiome disruption. Second, environmental factors such as sanitation, dietary patterns and air pollution were not included, despite their potential relevance to IBD through their effects on the gut microbiome and immune system [&lt;span&gt;5, 6&lt;/span&gt;]. Lastly, the study did not explicitly exclude children with underlying health conditions, potentially confounding the causal relationship between antibiotic use and IBD risk [&lt;span&gt;7, 8&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;To address these limitations, future studies should include analyses of antibiotic dosage and duration to evaluate their effects on the gut microbiome and IBD risk. Additionally, environmental factors should be integrated into study models to quantify their interactions with antibiotic use and IBD development. Rigorous screening of children with underlying health conditions is essential, with subgroup analyses or multivariable adjustments used to control for potential confounders. Multi-omics approaches might be employed to dynamically analyse the impact of antibiotics on the microbiome and immune system, uncovering causal links between microbial imbalance and IBD onset.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Xueneng Yang:&lt;/b&gt; writing – original draft, writing – review and editing, conceptualization. &lt;b&gt;Ruijuan Li:&lt;/b&gt; writing – original draft, writing – review and editing, conceptualization.&lt;/p&gt;&lt;p&gt;The authors have nothing to report.&lt;/p&gt;&lt;p&gt;The authors declare no conflicts of interest.&lt;/p&gt;&lt;p&gt;This article is linked to Mårild et al paper. To view this a","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"61 6","pages":"1090-1091"},"PeriodicalIF":6.6,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apt.18517","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Endoscopic Activity is an Essential Tool for Patients' Management, Even in Mild Crohn's Disease","authors":"Marco Mendolaro,&nbsp;Marco Daperno","doi":"10.1111/apt.70015","DOIUrl":"10.1111/apt.70015","url":null,"abstract":"&lt;p&gt;Endoscopic activity is one of the most relevant prognostic markers in Crohn's disease: worse endoscopic features and more severe endoscopic activity are associated with poorer outcomes, while healing of lesions is associated with more favourable outcomes [&lt;span&gt;1, 2&lt;/span&gt;]. While most available evidence on the prognostic role of endoscopic activity is based on data from moderately to severely active Crohn's disease [&lt;span&gt;3&lt;/span&gt;], a large proportion of patients report clinical remission or very mild disease activity during their lifespan [&lt;span&gt;4&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Peraza and colleagues have reported their multicentre retrospective study on the prognostic role of endoscopic severity focusing on individuals with mild Crohn's disease of long duration [&lt;span&gt;5&lt;/span&gt;]. The authors recruited 177 surgery-naïve patients with Crohn's disease, with a predominantly uncomplicated disease course; only 1 in 4 patients had previously undergone immunosuppressive treatment and only 1 in 10 had been treated with biologics. Perianal disease was present in only 1 in 10 patients and, despite a long disease duration (median 17 years; range 0–55), individuals had a remarkably low endoscopic disease activity score (2 out of 3 patients had a SES-CD score between 0 and 3 points). The authors reported a significantly elevated hazards ratio (HR) of 2.5 for patients with higher endoscopic activity (SES-CD ≥ 7), demonstrating that endoscopic activity affects Crohn's disease outcomes even in those with mild disease phenotypes.&lt;/p&gt;&lt;p&gt;There are some points to consider in interpreting the results. First, although most patients presented with mild clinical disease, those with a more severe endoscopic activity may have been treated more aggressively based on endoscopic findings, leading to an overestimation of the prognostic negative effects of such features. Second, endoscopic severity was graded prospectively in each institution, but only local scores recorded at the time of endoscopy were considered, and no image or video re-assessment was undertaken. As local readers tend to overestimate endoscopic scores [&lt;span&gt;6&lt;/span&gt;], this could have biased the results. However, the authors reported a sensitivity analysis showing that even considering a ±1 point cut-off value (i.e., considering SES-CD of 6 or 8 and higher), HRs were not substantially different. Finally, the generalisability of the results may be limited by the specifics of the study population: it is unclear if the results can be extrapolated to newly diagnosed patients or those exposed to more advanced therapies.&lt;/p&gt;&lt;p&gt;It remains clear that it is difficult to define mild Crohn's disease effectively. Clinical features must be integrated with biomarkers (e.g., C-reactive protein and faecal calprotectin), but also with multidimensional non-invasive disease severity or disability indices like the Disease Severity Index [&lt;span&gt;7&lt;/span&gt;] or the IBD Disk [&lt;span&gt;8&lt;/span&gt;], eventually integrated with other patient-reported out","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"61 7","pages":"1240-1241"},"PeriodicalIF":6.6,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apt.70015","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143418437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Examining Perianal Fistulising Crohn's Disease Through the Lens of Wound Repair","authors":"Tim Eglinton","doi":"10.1111/apt.70001","DOIUrl":"10.1111/apt.70001","url":null,"abstract":"&lt;p&gt;Perianal fistulising Crohn's disease (PFCD), a chronic debilitating condition affecting a third of patients with CD [&lt;span&gt;1&lt;/span&gt;], carries substantial associated morbidity and negatively impacts quality of life (QoL). The three basic tenets of PFCD management have been to drain sepsis, control inflammation and heal the fistula, if appropriate. The caveat is attached to the third tenet because not all Crohn's fistulas are suitable for curative treatment; the principal focus of management is QoL, driven by the patient's expectations, as formally recognised in the recent comprehensive classification of PFCD [&lt;span&gt;2&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Control of inflammation in PFCD improved greatly with biologic medications and, since the ACCENT trials [&lt;span&gt;3&lt;/span&gt;], anti-TNFa therapy has been the mainstay of treatment. While newer medical therapies show promise in PFCD, none has matched its efficacy. Despite this, response rates to medical therapy are incomplete and recurrences common, and long-term fistula healing rates remain low [&lt;span&gt;4&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;McCurdy et al. have addressed reasons for these failures, challenging us to consider PFCD management through the lens of the phases of wound repair: localised inflammation, cell recruitment and tissue remodelling. These three phases lead to the possible outcomes of healing, tract epithelialisation or persistent chronic wounds. Consideration of the molecular and structural mechanisms operating in these phases provides a rationale for different treatment strategies, particularly for some where controversy persists [&lt;span&gt;5&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;For instance, the inflammatory phase is characterised by the presence of specific bacteria and pathogen-associated mucosal patterns that support the use of antibiotics in this phase and during the induction of anti-TNFa therapy [&lt;span&gt;6&lt;/span&gt;]. Wound repair involves tightly controlled homeostatic mechanisms; under- or over-activity of these leads to dysfunctional repair, very evident in the epithelialisation of PFCD tracts. While re-epithelialisation is crucial for healing of open wounds, its extension into tubular structures such as fistulas impairs healing. In many cryptoglandular fistulas, this can be circumvented by fistulotomy, but this is usually not possible in PFCD.&lt;/p&gt;&lt;p&gt;This makes timing of seton removal crucial—targeting the point where inflammation is controlled but tract epithelialisation is yet to occur. While the recommendation of removing setons after the second induction dose of infliximab often appears too soon to control inflammation, the median of 8 months reported in many centres may well be too long and impair, rather than facilitate, healing [&lt;span&gt;7&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;To prevent epithelialisation and persistent inflammatory stimulus in the fistula, control of the internal opening remains key. Both PISA II [&lt;span&gt;8&lt;/span&gt;] and ADMIRE-CDII [&lt;span&gt;9&lt;/span&gt;], that utilised the ‘scrape and close’ technique, supported surgical intervention in addition to seton r","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"61 6","pages":"1073-1074"},"PeriodicalIF":6.6,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apt.70001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Revolutionising Steatotic Liver Disease Diagnosis With Phosphatidylethanol","authors":"Karen Cheuk-Ying Ho,&nbsp;Lung-Yi Mak","doi":"10.1111/apt.18529","DOIUrl":"10.1111/apt.18529","url":null,"abstract":"&lt;p&gt;The recent re-naming and reclassification of ‘non-alcoholc fatty liver disease (NAFLD)’ to steatotic liver disease (SLD) subcategories aims to clarify the different aetiologies associated with liver fat accumulation, particularly alcohol consumption and/or metabolic dysfunction [&lt;span&gt;1&lt;/span&gt;]. A novel entity, coined as ‘metabolic and alcohol related/associated liver disease (MetALD)’ was introduced to capture individuals whose alcohol intake exceeds traditional NAFLD thresholds but not yet meet the thresholds of alcohol-related liver disease (ALD) [&lt;span&gt;1&lt;/span&gt;]. The shift in terminology highlights the complexity between alcohol consumption and metabolic dysfunction on pathophysiology, natural course and treatment implications in SLD. Accurate quantification of alcohol consumption is therefore crucial. However, current alcohol consumption estimations rely solely on patients' self-report, where underreporting is common leading to misclassification. An objective alcohol biomarker is pivotal in providing an accurate assessment of an individual's drinking pattern. Phosphatidylethanol (PEth) levels in the blood is a promising biomarker that has garnered significant attention in the field of alcohol research. Being an abnormal phospholipid that is only formed in the presence of ethanol, not only it is easily measured in blood, but it also has a long detection window lasting for 2–4 weeks.&lt;/p&gt;&lt;p&gt;Tavaglione et al. conducted a cross-sectional study to compare PEth with other indirect alcohol biomarkers for the diagnosis of MetALD versus metabolic dysfunction-associated steatotic liver disease (MASLD) in 374 subjects who were obese (body mass index [BMI] ≥ 25 kg/m&lt;sup&gt;2&lt;/sup&gt;) with imaging-confirmed SLD (magnetic resonance imaging-proton density fat fraction or transient elastography). Alcohol use was quantified using a questionnaire (AUDIT score and Lifetime Drinking History) and DSM-V criteria. PEth was shown to have high diagnostic accuracy in the detection of MetALD (AUROC 0.81, 95% CI 0.73–0.89) with the optimal cut-off level of 25 ng/mL. It showed superiority over traditional biomarkers including aspartate aminotransferase/alanine aminotransferase ratio, mean corpuscular volume, gamma glutamyltransferase and ALD/NAFLD index (&lt;i&gt;p&lt;/i&gt; &lt; 0.05) in diagnosing MetALD in a cohort of SLD. A positive linear correlation between PEth levels and daily alcohol intake and AUDIT score was also demonstrated [&lt;span&gt;2&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;This paper provides timely insight into the role of using biomarkers in redefining subcategories of SLD. The results align with recent compelling evidence affirming the accuracy of utilising blood PEth levels to predict the quantity of alcohol consumption [&lt;span&gt;3&lt;/span&gt;], and the recent joint position statement to recommend its use [&lt;span&gt;4&lt;/span&gt;]. Given that PEth is derived from human erythrocytes, the precision of PEth measurements may be impacted by conditions such as cirrhosis, anaemia, or hypersplenism [&lt;span&gt;5&lt;/span&gt;]. S","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"61 6","pages":"1069-1070"},"PeriodicalIF":6.6,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apt.18529","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Revolutionising Steatotic Liver Disease Diagnosis With Phosphatidylethanol—Authors' Reply","authors":"Federica Tavaglione,&nbsp;Rohit Loomba","doi":"10.1111/apt.70006","DOIUrl":"10.1111/apt.70006","url":null,"abstract":"&lt;p&gt;We thank Ho and Mak for their positive comments on our recently published work, in which we demonstrate that phosphatidylethanol (PEth) is an accurate, quantitative, objective, blood-based alcohol biomarker for diagnosing the newly defined metabolic dysfunction and alcohol-related liver disease (MetALD) [&lt;span&gt;1&lt;/span&gt;]. Leveraging a well-characterised United States (U.S.) cohort of 374 community-dwelling individuals with overweight or obesity and steatotic liver disease (SLD) assessed through advanced magnetic resonance imaging (MRI) techniques [&lt;span&gt;2&lt;/span&gt;], we showed that PEth exhibited a robust diagnostic accuracy in differentiating MetALD from metabolic dysfunction-associated steatotic liver disease (MASLD) (AUROC 0.81, 95% CI 0.73–0.89) with an optimal cut-off of 25 ng/mL, and outperformed indirect alcohol biomarkers, including aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio, gamma glutamyltransferase (GGT), mean corpuscular volume (MCV) and the ALD/non-alcoholic fatty liver disease index (ANI).&lt;/p&gt;&lt;p&gt;PEth is an abnormal cellular membrane phospholipid formed in human erythrocytes exclusively during alcohol ingestion. Specifically, PEth is synthesised from phosphatidylcholine through a transphosphatidylation reaction catalysed by the enzyme phospholipase D only in the presence of ethanol (Figure 1) [&lt;span&gt;3&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Given the physiopathology underlying PEth formation and degradation, Ho and Mak astutely highlighted that factors such as anaemia, cirrhosis and drinking patterns may significantly influence PEth levels [&lt;span&gt;4&lt;/span&gt;]. However, a handful of studies have specifically investigated the impact of these conditions on PEth levels. Limited evidence suggests that the elimination of PEth, rather than its formation, may be affected by conditions that alter red blood cell turnover and the presence of cirrhosis [&lt;span&gt;3, 5, 6&lt;/span&gt;]. Additional research is required to fully address these questions.&lt;/p&gt;&lt;p&gt;Regarding drinking patterns, PEth has shown potential as a biomarker for identifying excessive drinking episodes and binge drinking behaviours, but this area of research warrants further investigation in the SLD population [&lt;span&gt;3, 7&lt;/span&gt;]. Notably, another important question that needs to be addressed clearly is the exact quantity of ethanol that must be consumed over a specific time period to yield a positive PEth test [&lt;span&gt;3&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;In conclusion, a body of evidence from studies conducted in medical settings outside of SLD, such as screening in emergency departments, alcohol detoxification programs, pre-employment medical examinations, liver transplant evaluation and forensic context, demonstrated that PEth is a reliable biomarker for detecting heavy alcohol consumption [&lt;span&gt;7-9&lt;/span&gt;]. Our study represents an initial effort within the setting of the newly defined SLD to support PEth as a quantitative, objective biomarker for identifying SLD subcategories and enhancing SLD subclassificatio","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"61 6","pages":"1071-1072"},"PeriodicalIF":6.6,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apt.70006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143418436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Letter: Clinical Trial: Treatment of Functional Dyspepsia According to Subtype Compared With Empirical Proton Pump Inhibitor","authors":"Shoko Miyahara,&nbsp;Takeshi Yamashina,&nbsp;Takehiro Ohyama,&nbsp;Masahiro Banno","doi":"10.1111/apt.70011","DOIUrl":"10.1111/apt.70011","url":null,"abstract":"&lt;p&gt;The study by Chuah et al. [&lt;span&gt;1&lt;/span&gt;] offers valuable insight that can significantly influence daily outpatient practice. The findings, while valuable, suggest that certain aspects of the study's design and scope could benefit from further refinement to guide future research effectively.&lt;/p&gt;&lt;p&gt;First, the absence of blinding and a placebo group may have contributed to an overestimation of the observed efficacy in both intervention and control arms due to the well documented influence of placebo and nocebo effects in patients with functional dyspepsia (FD) [&lt;span&gt;2&lt;/span&gt;]. While the authors stated that both groups received active medical therapy, and thus any placebo or nocebo effects might have been distributed similarly, this assumption requires further investigation. Open-label designs can lead to psychological biases and may confound results.&lt;/p&gt;&lt;p&gt;Second, patients with severe anxiety or depression, defined as requiring medication or experiencing daily functional impairment, were excluded. However, the criteria for exclusion were not clearly defined. This lack of clarity raises concerns about potential bias, particularly if patients with mild symptoms were excluded. As FD is frequently associated with coexisting mental health conditions [&lt;span&gt;3&lt;/span&gt;], understanding the proportions of patients with mild mental health problems in both groups would have provided valuable context. The lack of this information may limit the interpretation of the study's findings and applicability to real-world clinical settings.&lt;/p&gt;&lt;p&gt;Third, the &lt;i&gt;post hoc&lt;/i&gt; analysis provides useful insights into responder rates by subtype, particularly in those with epigastric pain syndrome and postprandial distress syndrome (EPS-PDS) overlap. However, the lack of detailed statistical considerations for this analysis may limit the clarity and reliability of these findings. As with all &lt;i&gt;post hoc&lt;/i&gt; analyses, spurious associations are possible, so these results should be interpreted with care.&lt;/p&gt;&lt;p&gt;Furthermore, the small sample size of certain subtypes, such as EPS, may have influenced the statistical power and reliability of the outcomes. Future studies could benefit from incorporating randomised allocation within subtypes or using stratified analyses to better explore subtype-specific effects. Increasing the sample size would also strengthen the findings and provide a clearer understanding of the role of subtypes in treatment outcomes.&lt;/p&gt;&lt;p&gt;In conclusion, this study has the potential to significantly influence routine FD care. Addressing the four points discussed above could further enhance its impact and contribute significantly to shaping future strategies for the treatment of FD in clinical practice.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Shoko Miyahara:&lt;/b&gt; conceptualization, writing – original draft, writing – review and editing, formal analysis. &lt;b&gt;Takeshi Yamashina:&lt;/b&gt; writing – review and editing, formal analysis, supervision. &lt;b&gt;Takehiro Ohyama:&lt;/b&gt; writing – review and editing, fo","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"61 6","pages":"1086-1087"},"PeriodicalIF":6.6,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apt.70011","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Letter: Clinical Trial: Treatment of Functional Dyspepsia According to Subtype Compared With Empirical Proton Pump Inhibitor: Authors' Reply","authors":"Kee Huat Chuah,&nbsp;Sanjiv Mahadeva","doi":"10.1111/apt.70025","DOIUrl":"10.1111/apt.70025","url":null,"abstract":"&lt;p&gt;We thank Dr. Miyahara et al. for their interest in our paper [&lt;span&gt;1&lt;/span&gt;] and for their constructive comments [&lt;span&gt;2&lt;/span&gt;]. We agree that certain aspects of the study design could be improved to enhance its robustness.&lt;/p&gt;&lt;p&gt;Placebo-controlled studies are widely regarded as the gold standard for evaluating the efficacy and safety of drugs. However, in the context of functional dyspepsia (FD), numerous placebo-controlled trials have already been conducted. Additionally, well-conducted meta-analyses have pooled these studies to report on treatment outcomes [&lt;span&gt;3&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;The unique design of our study aimed to address the utility of treatment strategies for FD according to subtypes, compared to empirical proton pump inhibitor (PPI) therapy [&lt;span&gt;1&lt;/span&gt;]. The Rome IV consensus recommends subdividing FD into postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS) subtypes. This symptom-based subdivision reflects the putative differences in pathophysiology and may inform tailored treatment approaches [&lt;span&gt;4&lt;/span&gt;]. The first Asian consensus on FD has also adopted this subtype-based approach to treatment [&lt;span&gt;5&lt;/span&gt;]. In contrast, American and Canadian guidelines suggested empiric PPI therapy for all patients with FD [&lt;span&gt;6&lt;/span&gt;]. However, it is unclear which treatment strategy is superior. Our findings provide a valuable alternative to PPI in FD, specifically the use of prokinetics. While PPIs are generally considered safe, widespread overuse has raised concerns about potential adverse effects [&lt;span&gt;7&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Our study was underpowered to provide definitive conclusions on treatment efficacy for individual FD subtypes. However, randomized controlled trials have demonstrated that prokinetics perform better than placebo in FD [&lt;span&gt;8&lt;/span&gt;]. Our study included a representative distribution of FD subtypes, with most patients presenting with PDS or PDS-EPS overlap, reflecting global subtype trends. Our findings suggest that a prokinetic is at least as effective as PPIs for these subtypes. However, our study was not designed to determine the optimal treatment for the EPS subtype independently [&lt;span&gt;1&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Miyahara and colleagues expressed concern that we did not exclude “mild” psychological disorders, which may have influenced our study findings. However, the significance of mild psychological disorders in FD and DGBI remains uncertain. In a cross-sectional study of patients with FD, we demonstrated that only higher anxiety scores, as assessed by the Hospital Anxiety and Depression Scale (HADS), were associated with more severe dyspepsia symptoms; lower HADS scores showed no significant correlation [&lt;span&gt;9&lt;/span&gt;]. Furthermore, in a longitudinal study of patients with DGBI in secondary care, we found that poorer symptom improvement at follow-up was associated with clinically diagnosed anxiety and depression [&lt;span&gt;10&lt;/span&gt;]. Based on these findings, it is reasonable to assume that mild","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"61 6","pages":"1088-1089"},"PeriodicalIF":6.6,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apt.70025","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Trial to Assess the Safety and Tolerability of Anti-IL 23 Monoclonal Antibody Guselkumab in Patients With Alcohol-Associated Liver Disease","authors":"Luis Antonio Diaz,&nbsp;Sheldon Morris,&nbsp;Shravan Dave,&nbsp;Susy M. Kim,&nbsp;Wathnita Sarik,&nbsp;Lisa Richards,&nbsp;Egbert Madamba,&nbsp;Ricki Bettencourt,&nbsp;Christian Fulinara,&nbsp;Thuy Pham,&nbsp;Grant Miller,&nbsp;Raquel Carvalho-Gontijo Weber,&nbsp;Jeremiah D. Momper,&nbsp;Feng He,&nbsp;Sonia Jain,&nbsp;Catriona Jamieson,&nbsp;Tatiana Kisseleva,&nbsp;David Brenner,&nbsp;Rohit Loomba","doi":"10.1111/apt.70026","DOIUrl":"10.1111/apt.70026","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>There are no FDA-approved therapies for alcohol-associated liver disease (ALD). Preclinical studies indicate that blocking IL-23/IL-17 signalling may reverse liver injury. Guselkumab, an IL-23-specific antibody approved for psoriasis, may be beneficial for ALD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>We aimed to assess the safety and tolerability of guselkumab in patients with ALD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This phase-1 dose-escalation study included patients with ≥ 2 DSM-5 criteria for alcohol use disorder, significant steatosis (MRI-PDFF ≥ 8%) and MRE &lt; 3.63 kPa (to exclude advanced disease). Guselkumab was given subcutaneously on Days 1 and 29 in 30, 70 or 100 mg dose cohorts. Primary endpoints were adverse events (AEs) and dose-limiting toxicity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We enrolled 13 patients (three 30 mg, three 70 mg, and seven 100 mg). Eleven completed the study and two early discontinued in the 100 mg group. Of them, 77% were men, and the median age was 53 [IQR 49–61] years. The median MRI-PDFF and MRE were 18.4% [IQR 8.4%–34.0%] and 2.5 [2.2–2.6] kPa, respectively. The most frequent AEs were hyperuricemia (13%, mild only) and elevated lipase (11%, mild and moderate). There were no serious adverse events or significant variations in liver enzymes. There was a suppression of peripheral interleukin (IL)-17, IL-23, IL-1b and TNF-α in the 70 and 100 mg groups, and a significant decrease in alcohol consumption over time (AUDIT-C: 6 [3–7] vs. 5 [1–6], <i>p</i> = 0.023).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Guselkumab is safe in doses up to 100 mg and may reduce inflammation markers in ALD. These findings support further phase 2 studies to evaluate the efficacy of guselkumab in ALD, particularly in patients with severe phenotypes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":"61 7","pages":"1140-1151"},"PeriodicalIF":6.6,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}