High stroma content, as measured by tumor-stroma ratio (TSR), is generally a negative prognostic parameter for epithelial cancers, including sporadic colorectal cancer (sCRC). Inflammatory bowel disease patients have higher risk for colorectal cancer than the background population. Evidence suggests that this colitis-associated colorectal cancer (CAC) is more aggressive and occurs at younger age than sCRC. CAC also differs from sCRC in oncogenesis and prognosis. This study tests the hypothesis that TSR in CAC tumors correlates with survival. Age at CAC diagnosis relative to TSR was also explored. TSR was quantified in 36 CAC cases. In routine hematoxylin–eosin staining, the amount of stroma was estimated in categorical steps of 10% increments per image field. The area with highest amount of stroma and tumor tissue at all quadrants of the visual field boundary was scored for TSR. For statistical analysis, tumors were divided into stroma-high (> 50%) or stroma-low (≤ 50%). Of all cases, 22 were stroma-high and 14 were stroma-low. Five-year survival in the stroma-high group was 32% (n = 22), compared to 71% (n = 14) in the stroma-low group (p = 0.049). High stroma content was more frequent if cancer diagnosis was before 60 years of age (17/23) compared to after 60 years of age (5/13). Despite differences in oncogenesis and tumor biology in CAC compared to sCRC, high stroma content also predicts worse outcome in CAC and is particularly common in younger patients.

BACKGROUND/OBJECTIVES:Irritable bowel syndrome (IBS) is primarily treated via dietary modifications. Several diets have been shown to improve symptoms with similar efficacy. Other aspects of IBS, such as insufficient nutrient intake and being overweight, should also be considered when planning treatment options. The present scoping review aimed to identify various diets investigated in IBS-related clinical trials and to map the measured outcomes. METHODS:We performed a systematic search of three databases: PubMed, Embase, and CINAHL Ultimate. Our search was limited to papers published between January 2000 and February 2026, and included human studies published as peer-reviewed original articles in English that described dietary interventions in adult patients (≥18 years) with IBS. RESULTS:The titles and abstracts of 1261 studies were screened; 1147 studies were excluded; and 114 full-text articles were assessed for eligibility. Excluding articles outside the scope of our research resulted in a total of 71 included articles from 57 unique clinical trials. The most common interventions were low fermentable oligo-, di-, and monosaccharides and polyols (FODMAP) (n = 43), traditional dietary advice (n = 13), and gluten-free diets (n = 11). The most common primary outcomes were the effect on IBS symptoms (n = 48), efficacy in terms of improving quality of life (n = 10), psychological well-being (n = 7), nutrient intake (n = 7), and adherence/applicability/feasibility to the diet (n = 7). CONCLUSIONS:In conclusion, the most studied dietary intervention in IBS was low FODMAP, and an effect on GI symptoms was the most common outcome. Considering other conditions associated with IBS, the effects on anthropometric, endocrine, metabolic, and nutritional parameters should also be evaluated.

OBJECTIVES:Diarrhea is common and can exert a profound negative impact on social life due to unpredictable bowel movements and fecal incontinence. Liraglutide has been documented to be effective in patients with bile acid diarrhea (BAD), but documentation for the effect of semaglutide in patients with unspecific diarrhea is lacking. We report experiences with compassionate use of weekly semaglutide in patients with diarrhea of different etiologies. METHODS:Our cases comprised 15 patients with BAD, nine with idiopathic diarrhea, four with short bowel syndrome, two with collagenous colitis and one with radiation enteritis. All patients had undergone routine work-up for chronic diarrhea. Despite the use of anti-diarrheal agents, all patients were severely handicapped in social functioning and work-life due to extreme urgency, nocturnal diarrhea and fecal incontinence. After informed consent, the patients started treatment with semaglutide 0.25 mg every seven days titrated to an individually tailored dosage. RESULTS:After semaglutide was initiated, the median number of daily bowel movements decreased from 8 (interquartile range (IQR) 5-12) to 2 (IQR 1-3), p < .0001. All patients reported an almost immediate relief of urgency, fecal incontinence and nocturnal diarrhea. Fourteen patients shortened their dosing interval of semaglutide to every fifth or sixth day due to a time-dependent decrease in effect. One patient stopped treatment due to nausea, and in another, the dosage was reduced due to constipation. CONCLUSION:Semaglutide may represent a rational symptomatic treatment option for selected patients with severe diarrhea, including those with BAD, short bowel syndrome and idiopathic diarrhea.

Acyl ghrelin increases cardiac output (CO) and contractility in patients with heart failure with reduced ejection fraction (HFrEF). In healthy humans, acyl ghrelin increases gastric emptying rate (GER) and hunger, a potential add-on benefit for HFrEF patients suffering from cachexia with symptoms of delayed gastric emptying and loss of appetite. The aim of this study was to determine if post-prandial acyl ghrelin infusion increases GER and hunger in HFrEF patients compared to CO. HFrEF patients (n = 29) arrived fasted and received a 500-kcal breakfast followed by 1.5 g paracetamol. They next received placebo (vehicle, n = 15) or acyl ghrelin infusion (0.1 µg/kg/min, n = 14) for 120 min. Blood was tapped for plasma at 0, 30, 60, 120, and 150 min into the meal. Hunger scores and CO were recorded. Plasma paracetamol was measured to assess GER. Paracetamol concentration peaked at 30 min in 8 of 14 (57

BACKGROUND:The role of Helicobacter pylori (H. pylori) screening and eradication on reducing upper gastrointestinal bleeding (UGIB) complications after acute myocardial infarction (MI) is uncertain. The HELicobacter pylori screening to prevent gastrointestinal bleeding in patients with acute MI (HELP-MI SWEDEHEART) trial aims to determine whether systematic H. pylori screening compared to usual care reduces UGIB, mortality, and cardiovascular outcomes after MI. METHODS:A cluster randomized, crossover, registry-based clinical trial using SWEDEHEART as trial platform for study population definition and source for data collection in combination with nationwide Swedish health data registries. Thirty-five Swedish hospitals, organized into 18 clusters based on percutaneous coronary intervention networks, were randomized to either routine H. pylori screening for adults with acute type-1 MI or usual care. After 1 year, a 2-month blanking period was followed by a crossover to the alternate allocation for 1 year. The trial enrolment was concluded after one additional year of registry-based follow-up. The primary endpoint is UGIB. Secondary endpoints include all-cause death, cardiovascular death, readmission for MI, stroke, or heart failure. Endpoints will be reported combined (Net Adverse Clinical Events; Major Adverse Cardiac or Cerebrovascular Events) and separately. The primary analysis will include all available follow-up time corresponding to a maximum follow-up time of 3 years and 2 months. CONCLUSION:HELP-MI SWEDEHEART aims to determine the utility of routine H. pylori screening to reduce UGIB and improve cardiovascular outcomes after MI. By integrating national registry follow-up data with a pragmatic trial design, it has the potential to provide evidence for the effect of the implementation of routine H. pylori screening as part of acute MI care. TRIAL REGISTRATION:ClinicalTrials.gov, NCT05024864.

BACKGROUND:Chronic constipation is a prevalent, burdensome gastrointestinal disorder whose etiology and pathophysiology remain poorly understood. Differences in the composition of the intestinal microbiota have been shown between constipated patients and healthy people. Data indicate that these microbial differences contribute to the disorder. METHODS:Preclinical studies in mice examined the effects of Lactobacillus gasseri on intestinal motility ex vivo, the reversal of motility inhibition by μ-opioid receptor agonists ex vivo and in vivo in mice, and the effects on capsaicin-stimulated transient receptor potential vanilloid 1 (TRPV1) in Jurkat cells. Thereafter, a clinical study of 40 women with functional constipation was conducted to investigate the effects of Lactobacillus gasseri with a randomized parallel design. After 14 days of baseline recording, treatment with Lactobacillus gasseri or placebo was given over 28 days, with 14 days of follow-up. Outcomes with complete spontaneous bowel movements (CSBM), spontaneous bowel movements, emptying frequency, abdominal pain, time spent for defecation, Bristol stool form scale, use of rescue laxatives, and impact on sex life were investigated. KEY RESULTS:In preclinical studies, Lactobacillus gasseri increased intestinal motility in an ex vivo model, reversed the motility inhibition caused by μ-opioid receptor agonist ex vivo and in vivo in mice, and counteracted capsaicin-stimulated activity of TRPV1 in Jurkat cells. In the clinical trial, Lactobacillus gasseri showed a significant reduction in abdominal pain, along with a correlation and tendency for an increased number of CSBM. Few adverse events were encountered. CONCLUSIONS AND INFERENCES:Treatment with Lactobacillus gasseri can alleviate pain sensations in functional constipation, possibly with an improved bowel-emptying function.

INTRODUCTION:Understanding meal-induced changes of gut hormones, gastric motility, and appetite is crucial for developing therapies for obesity. We investigated glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1), ghrelin, and motilin influences on gastric motility and appetite, to compare healthy individuals and people with obesity. METHODS:Subjects (healthy n = 41; obesity n = 32) consumed a 270-kcal meal and a wireless motility capsule. GIP, active GLP-1, acyl-ghrelin, and motilin were measured by electrochemiluminescence. MotiliGI and GIMS software were used for motility analysis, while visual analog scoring measured appetite. RESULTS:Gastric emptying was more rapid in people with obesity than in healthy individuals (p < 0.01). Gastric emptying time was negatively associated with motility index and hunger contractions (p < 0.01, p < 0.05) in healthy individuals, but not in individuals with obesity. In controls, gastric motility index correlated positively with acyl-ghrelin (p < 0.01) and motilin (p < 0.0001), and negatively with GIP (p < 0.05), but not aGLP-1. In people with obesity, no gut hormones correlated with the motility index. In both groups, GIP and aGLP-1 correlated with decreased hunger (p < 0.0001, p = 0.001) and (p < 0.0001, p < 0.05), along with increased satiety in controls (p < 0.0001, p = 0.001) and people with obesity (p = 0.049, p = 0.01). Acyl-ghrelin correlated positively with hunger (p < 0.0001) and negatively with satiety (p = 0.049) in controls, but not in obesity. Motilin was neither associated with hunger nor satiety. CONCLUSION:In the gastric phase, people with obesity show rapid gastric emptying with altered hormone and motility meal responses. In healthy individuals, GIP promotes satiety, and ghrelin and motilin promote hunger through actions on motility. Like GIP, GLP-1 promotes satiety along with trending suppression of gastric motility.

Background: Inflammatory bowel disease (IBD) is associated with vague gastrointestinal (GI) discomfort even when inflammation is in clinical remission. In Crohn’s disease (CD) and ulcerative coliti ...

Abstract Background Acyl ghrelin (ghrelin) increases cardiac output (CO) and contractility in patients with heart failure with reduced ejection fraction (HFrEF). In healthy humans, ghrelin increases gastric emptying rate (GER) and hunger, a potential add-on benefit for HFrEF patients suffering from cachexia with symptoms of delayed gastric emptying and loss of appetite. Aim Determine if post-prandial ghrelin infusion increases GER and hunger in HFrEF patients; compare to CO. Methods This study was a component of a double-blind placebo-controlled trial of acyl ghrelin vs. placebo in HFrEF. Patients (n=29) arrived fasted and received a 500 kcal breakfast and 1.5 g paracetamol. They next received placebo (vehicle, n=15) or ghrelin infusion (0.1 µg/kg/min, n=14) for 120 min. Blood was tapped for plasma at 0, 30, 60, 120 and 150 min into the meal. Plasma concentration of paracetamol was measured to assess GER of a liquid bolus. Hunger scores and CO were recorded. Mann-Whitney rank sum test was used for statistics. Results Paracetamol peaked at 30 min in 8 of 14 (57%) in the ghrelin treatment group versus 1 of 15 (7%) in the placebo group (P=0.004, Fig 1). Remaining patients peaked at later time points. There were no anomalous peaks at 0 min baseline or 2880 min (2 days). The ghrelin treatment group data was segregated into rapid (peak at 30 min, n=8) and slow (peak >30 min, n=6) GER subgroups. The rapid subgroup had a ghrelin treatment effect on CO (one-way repeat measures) (P<0.001, Fig 2). Baseline (t=0) CO for the rapid GER subgroup was 4.06 ±1.41 L/min (median ±SD) and 3.95 ±0.62 L/min for the slow GER subgroup (P=0.31). Data points shown are median ± SEM, each patient normalized to own baseline (100%); * P<0.05, ** P<0.01, *** P<0.001, pairwise comparison to baseline. Hunger gradually increased. The greatest increase in hunger was at 150 min, at which time median fold increase in hunger relative baseline was 1.6 (placebo), 1.7 (ghrelin, slow GER) and 2.3 (ghrelin, rapid GER). These hunger differences between groups did not reach significance. However, this trend was consistent with ghrelin induction of hunger, especially in those with potent GER and CO responses. Conclusions Ghrelin increases GER, and potentially hunger, in HFrEF patients in addition to increasing CO. Some HFrEF patients may benefit from this add-on effect.Fig 1.Time of paracetamol peak.Fig 2.Cardiac output.

Importance Upper gastrointestinal bleeding is common after myocardial infarction. Objective To determine whether routine screening for Helicobacter pylori infection during hospitalization for myocardial infarction reduces bleeding events and improves clinical outcomes. Design, Setting, and Participants A nationwide, open-label, 2-period, 2-sequence, cluster randomized, crossover clinical trial using a clinical registry for study population definition and data collection merged with national Swedish health data registries. From November 17, 2021, through January 17, 2024, thirty-five Swedish hospitals grouped into 18 clusters were randomized to a sequence of 1 year with routine H pylori screening of all patients with acute myocardial infarction followed by a washout period of 2 months before crossing over to 1 year with usual care or vice versa. Patients were followed up until January 17, 2025. Intervention Routine addition of H pylori screening by urea breath test to standard care in all patients hospitalized for myocardial infarction during the screening periods. Main Outcome and Measure Upper gastrointestinal bleeding, analyzed by a negative binomial model in the intention-to-treat population. Results A total of 18 466 patients (median age, 71 years [IQR, 61-79], 13 138 males [71%]) with myocardial infarction were followed up: 9245 during the screening periods and 9221 during the nonscreening periods. At admission, 2284 during the screening periods and 2275 during the nonscreening periods (both 24.7%) reported proton pump inhibitor use. During screening periods, 6480 patients (70%) had undergone testing, of those 1532 (23.6%) tested positive for H pylori. After a median follow-up of 1.9 years, 299 patients in the screening group (incidence rate, 16.8 events per 1000 person-years; cumulative hazard at 3 years, 4.1%) and 336 in the usual care group (incidence rate, 19.2 events per 1000 person-years; cumulative hazard at 3 years, 4.6%) experienced the primary end point of upper gastrointestinal bleeding (rate ratio [RR], 0.90; 95% CI, 0.77-1.05; P = .18). Predefined nonmultiplicity adjusted subgroup analyses showed a heterogeneous intervention effect; for no anemia (RR, 0.98; 95% CI, 0.80-1.21), mild anemia (RR, 0.64; 95% CI, 0.42-0.98), and moderate to severe anemia (RR, 0.44; 95% CI, 0.23-0.87; P for interaction = .03). Conclusions and Relevance Among unselected patients with acute myocardial infarction, routine H pylori screening did not significantly reduce the risk of upper gastrointestinal bleeding.

Pathogen invasion of intestinal epithelial cells (IECs) is a key gut infection event. The dynamics of this process in intact epithelia and the factors governing IEC susceptibility remain underexplored. We present a resource for live-cell infection imaging in human enteroid-/colonoid-derived IEC layers across maturation states and in the presence or absence of soluble mucus production. Utilization of this resource shows how human IEC maturation fortifies the apical surface against invasion by Salmonella Typhimurium (S.Tm). Immature IEC layers appear permissive to S.Tm invasion, but maturation toward an enterocyte/colonocyte phenotype reduces the susceptibility by up to 10-fold. This shift couples to downregulated expression of actin regulatory proteins exploited by the pathogen, an increased dependence on the S.Tm effector SipA, and the build-up of the apical IEC glycocalyx linked to surface-attached mucins like MUC13 and nullifiable by StcE-enzyme treatment. This underscores how the maturation state of human IECs governs susceptibility to bacterial invasion.

Despite their relatedness, Salmonella and Shigella enteropathogens differ in infectious dose, pathogenesis, and disease kinetics. The prototype strains Salmonella enterica serovar Typhimurium (Salmonella) and Shigella flexneri (Shigella) use Type-3-secretion-systems (T3SSs) to colonize intestinal epithelial cells (IECs). However, they have evolved unique sets of T3SS effectors and accessory virulence factors. A synthesis of how these differences impact the temporal progression of infection in non-transformed human epithelia is missing. Here, we followed Salmonella and Shigella infections of human enteroids and colonoids by time-lapse imaging to pinpoint virulence factor modules that shape the divergent epithelial colonization strategies. By an apical targeting module that integrates flagella and the SPI-4-encoded adhesin system with T3SS-1, Salmonella accomplishes appreciable numbers of apical IEC invasion events. These are promptly counteracted by IEC death, thus fostering a polyclonal iterative epithelial colonization strategy. The lack of a corresponding apical targeting module in Shigella makes this pathogen reliant on external factors, for example, preexisting damage, for rare apical access to the intraepithelial environment. However, Shigella compensates for this ineptness by an intraepithelial expansion module reliant on the tight coupling of OspC3-dependent temporal delay of cell death and IcsA-mediated mobility. This module enables intraepithelial Shigella to evade the IEC death response just long enough to expand laterally, thus fostering an essentially monoclonal colonization strategy. Taken together, the study reveals how a small set of virulence factors shapes divergent epithelial colonization strategies by related enterobacteria.IMPORTANCEPathogenic bacteria employ partially overlapping sets of virulence factor functions to colonize host epithelia but can differ markedly in their pathogenesis and disease kinetics. This work combines bacterial genetics and real-time microscopy in enteroids and colonoids to decipher the divergent colonization strategies of Salmonella enterica Typhimurium and Shigella flexneri-two major enteropathogens-in non-transformed human intestinal epithelia. The results reveal how virulence factor modules enabling efficiency at either the invasion step (Salmonella) or the intraepithelial expansion stage (Shigella) drive the radically different infection cycles of these related enterobacteria. Moreover, our work emphasizes how real-time studies in infection models that retain primary host cell features are critical to understanding infectious disease progression.

Intestinal enteroids are stem cell-based ″mini-guts″ that mimic many aspects of the corresponding epithelial barrier in vivo. Here, we established and characterized differentiated apical-out (AO) and basal-out (BO) jejunal enteroids in suspension and followed their differentiation by quantitative global proteomics and different microscopic techniques. The barrier integrity and function and subcellular location of nutrient and clinically important drug transporters were investigated in the matured enteroids using live-cell microscopy. The presystemic metabolism of two drugs by CYP3A4 was determined and the results were used to predict the pharmacokinetics after oral administration by a PBPK population model. The differentiated AO enteroids displayed a protein profile that overlapped both qualitatively and quantitatively with that of freshly isolated jejunal enterocytes and tissue. They exhibited a morphology that recapitulates the mature villus enterocyte in vivo, formed an intact barrier with a well-developed glycocalyx and are impermeable to the hydrophilic low molecular weight compound lucifer yellow and transported a medium chain fatty acid derivative by FATP4 into lipid deposits. The clinically important ABC-transporters Pgp and BCRP were expressed at near in vivo levels, had the correct subcellular localization and effluxed their substrates. Terfenadine and midazolam were metabolized by CYP3A4 and the results were used to predict the clinical pharmacokinetics of the drugs after oral administration with good accuracy. We conclude that suspended 3D AO enteroids provide a physiologically relevant model for studies of intestinal function that offers convenient access to the apical surface and is easy to dispense in multi-wells formats for large scale experimentation. ### Competing Interest Statement The authors have declared no competing interest.

AIM:In this paper, we aim to explain the reason why iron deficiency (ID) is common in patients with inflammatory bowel disease (IBD), how to better apply diagnostic tools to uncover the state of ID as well as how to interpret the results, and not least, how to treat ID in this group of patients. METHODS:This article is an expert review and opinion paper on a topic that is too often forgotten in clinical practice. We have not performed a systematic review, but we present the most important research allocated to the topic to substantiate an expert opinion. RESULTS:This position paper summarises the pathophysiology of ID and gives recommendations on the monitoring and treatment of ID in IBD. ID with or without concurrent anaemia (IDA) is the most common systemic complication in patients with IBD, related to both disease activity and severity. It has consequences both for health-related quality of life and future course of disease of the IBD patient. Intravenous iron is an efficacious and well tolerated, but still underused, therapy for ID and IDA. Iron deficiency should be treated before symptoms of anaemia appear and quality of life is impacted. However, there is still limited awareness of how to detect and treat ID in clinical practice. Uncertainty regarding which diagnostic tests to use and how to interpret the results may also be responsible for variations in clinical practice. In addition, opinions on how to correct ID and IDA differ, in relation to both clinical efficacy and safety. CONCLUSION:The consequences of ID in patients with IBD are significant. Guidelines on diagnosis, treatment and follow-up of ID should be implemented. IDA is a manifestation of severe ID and preventive strategies focusing on efficient treatment of ID regardless of the level of haemoglobin should therefore be explored.

BackgroundVentricular cerebrospinal fluid (CSF) was analysed peri- and postoperatively to elucidate the pathophysiology of Idiopathic normal pressure hydrocephalus (iNPH).ObjectiveTo capture the dynamics of biomarkers and their relation to clinical symptoms.MethodsIn 113 consecutively diagnosed patients, the Hellström iNPH scale was used to quantify symptom burden pre- and postoperatively. CSF was collected at shunt insertion and postoperatively by shunt reservoir puncture, and analyzed for concentrations of GFAP, YKL40, MCP-1, NfL, Aβ40, sAβPPα, sAβPPβ, GAP43, Alzheimer's disease biomarkers Aβ42, Aβ42/40, total tau (T-tau), phosphorylated tau (P-tau), and neurogranin.ResultsConcentrations increased postoperatively for Aβ40 (134%), Aβ42 (106%), sAβPPα (112%), sAβPPβ (83%), NfL (128%), YKL40 (86%), GAP43 (124%), and MCP-1 (5%) (p < 0.001, MCP-1 (p = 0.03)), while mean concentration reductions were seen in T-tau (32%), GFAP (31%), neurogranin (49%), and Aβ42/40 (10%) (p < 0.001). A higher perioperative concentration of AβPPβ correlated with less pronounced gait disturbance (Rp 0.20 (0.01-0.38) (95% CI)), whereas higher levels of NfL (-0.23 (-0.41-(-)0.04) and MCP-1 (-0.21 (-0.37-(-)0.01)) correlated with impaired cognition. Higher MCP-1 correlated with a lower balance domain score (-0.20 (-0.37-(-)0.01)). Postoperative increases in levels of Aβ40 (Rs 0.27 (0.05-0.46)), Aβ42 (Rs 0.24 (0.02-0.44)) and YKL40 (Rs 0.22 (-0.00-0.43)) correlated with gait improvement, and a postoperative increase in Aβ40 (Rs 0.36 (0.05-0.60)) was associated with improvement in urinary continence (p 0.01-0.05).ConclusionsCSF biomarker concentrations change after shunt insertion. These changes, seen as increased concentrations for some biomarkers and decreased concentrations for others, are associated with improvement in core clinical symptoms and may illustrate reversibility of pathophysiological mechanisms in iNPH.