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Gut
LuminalShanghai fever—a Pseudomonas aeruginosa enteric disease

Shanghai fever, first documented in 1918, is a syndrome comprising fever, diarrhoea and sepsis, and is caused by enteric Pseudomonas aeruginosa infection. Community-acquired cases were subsequently reported in children without pre-existing conditions, primarily from Taiwan, Hong Kong and China. The disease usually leads to serious complications and is associated with high mortality. Sadly our understanding of this disease is still incomplete and its pathogenesis remains unknown. In this issue of Gut, Chuang et al present the most comprehensive study to date on the clinical features of Shanghai fever (table 1) and the host and microbial factors associated with the infection. The data presented offer a glimmer of hope in the fight against this deadly disease.

In colon cancer, it's not just if a gene is mutated, but where, that matters

Cancer in general is viewed as being...


The stratified squamous epithelium of the oesophageal mucosa usually forms a tight protective barrier against noxious components of gastro-oesophageal reflux (such as acid and bile acids), a necessary function since the distal oesophageal mucosa is exposed to physiological reflux events, even in health.

If there is a disruption to the effectiveness of this epithelial barrier (a so-called impairment of the mucosal integrity), its protective function is likely to be compromised, resulting in reflux-induced symptoms.

Non-erosive reflux disease (NERD) is the phenotype of gastro-oesophageal reflux disease most frequently encountered in clinical practice, and may be more difficult to treat than erosive reflux disease.1 Contrary to endoscopic appearances, the oesophageal mucosa in patients with NERD is not completely normal and integrity of the mucosal barrier is impaired. This has been demonstrated by morphological and functional studies. In NERD, the basal layer of oesophageal mucosal epithelium demonstrates dilated intercellular spaces...


Why are grams of metformin recommended to lower hyperglycaemia in type 2 diabetic patients whereas the dose ranges from micrograms to milligrams for all other antidiabetic agents? Why is that 50% of the patients should discontinue or reduce the daily therapeutic doses to avoid diarrhoea? Why has the previously established mode of action of metformin been continuously disputed and re-evaluated by the scientific community? To these questions, Shin et al1 shifted again the paradigm related to numerous modes of action of metformin described so far to show that the drug lowers glycaemia by targeting gut microbiota. The gutsy role of metformin might have been uncovered.

For the last 50 years, ever since the biosynthesis of metformin by Emil Werner and James Bell in 1922, the scientific community has been revisiting the mode of action of the oral antidiabetic agent. Metformin has previously been demonstrated to control...


The recent explosion in cancer genomics provides an unprecedented view of the genetic changes present in solid tumours. The characterisation of colorectal cancer samples via DNA sequencing has confirmed the importance of established oncogene and tumour suppressor pathways (including the ‘mountains’ of Apc, Tp53 and Ras) but has also identified novel cancer genes that are mutated in a small percentage of patient samples (hills).1 2 Furthermore, these studies give a new appreciation of the spectrum of gene mutations present in cancers, especially in candidate tumour suppressor genes (TSGs). While classic genetics teaches that two hits are required to inactivate TSGs, sequencing studies show that heterozygous mutations are also quite frequent. Some of these are loss of function alleles, while others are recurrent missense mutations known as ‘hotspots’. Now, researchers are charged with the task of understanding how these genetic changes contribute to cancer development,...


There is an urgent need for new therapeutic options for hepatocellular carcinoma (HCC), which is currently the third cause of cancer-related death worldwide.1 HCC develops most frequently in the setting of cirrhosis. This premalignant condition occurs as a consequence of chronic liver disease, mainly as a result of hepatitis B and C viral infection, alcohol abuse and obesity. The poor efficacy of many antiproliferative agents against HCC is due in part to the inefficient drug delivery and metabolism in cirrhotic livers, leading to unbearable drug toxicity. Novel therapies for HCC could be developed after the identification of oncogenic addiction loops or primary ‘gatekeeper’ and ‘driver’ mutations that would allow for HCC initiation and progression, respectively.

To this end, previous large-scale studies in HCC have focused on searching for DNA mutations and transcriptome alterations. This allowed the classification of HCCs with DNA mutations that affect different pathways, that...


Objective

As a major cellular defence mechanism, the Nrf2/Keap1 pathway regulates expression of genes involved in detoxification and stress response. Here we hypothesise that Nrf2 is involved in oesophageal barrier function and plays a protective role against gastro-oesophageal reflux disease (GERD).

Design

Human oesophageal biopsy samples, mouse surgical models and Nrf2–/– mice were used to assess the role of the Nrf2/Keap1 pathway in oesophageal barrier function. Trans-epithelial electrical resistance (TEER) was measured with mini-Ussing chambers. HE staining and transmission electron microscopy were used to examine tissue morphology, while gene microarray, immunohistochemistry, western blotting and chromatin immunoprecipitation (ChIP) analysis were used to assess gene expression.

Results

Nrf2 was expressed in normal oesophageal epithelium and activated in GERD of both humans and mice. Nrf2 deficiency and gastro-oesophageal reflux in mice, alone or in combination, reduced TEER and increased intercellular space in oesophageal epithelium. Nrf2 target genes and gene sets associated with oxidoreductase activity, mitochondrial biogenesis and energy production were downregulated in the oesophageal epithelium of Nrf2–/– mice. Consistent with the antioxidative function of Nrf2, a DNA oxidative damage marker (8OHdG) dramatically increased in oesophageal epithelial cells of Nrf2–/– mice compared with those of wild-type mice. Interestingly, ATP biogenesis, Cox IV (a mitochondrial protein) and Claudin 4 (Cldn4) expression were downregulated in the oesophageal epithelium of Nrf2–/– mice, suggesting that energy-dependent tight junction integrity was subject to Nrf2 regulation. ChIP analysis confirmed the binding of Nrf2 to Cldn4 promoter.

Conclusions

Nrf2 deficiency impairs oesophageal barrier function through disrupting energy-dependent tight junction.


Objective

Limited data exist on the impact of regurgitation on health-related quality of life (HRQOL) in gastro-oesophageal reflux disease (GORD). We assessed the relationship between regurgitation frequency and HRQOL before and after acid suppression therapy in GORD.

Method

We used data from two randomised trials of AZD0865 25–75 mg/day versus esomeprazole 20 or 40 mg/day in non-erosive reflux disease (NERD) (n=1415) or reflux oesophagitis (RO) (n=1460). The Reflux Disease Questionnaire was used to select patients with frequent and intense heartburn for inclusion and to assess treatment response. The Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire was used to assess HRQOL.

Results

At baseline, 93% of patients in both the NERD and RO groups experienced regurgitation. Mean QOLRAD scores were similar for NERD and RO at baseline and at week 4 and disclosed decremental HRQOL with increasing frequency of regurgitation; a clinically relevant difference of >0.5 in mean QOLRAD scores was seen with regurgitation ≥4 days/week versus <4 days/week. The prevalence of frequent, persistent regurgitation (≥4 days/week) at week 4 among heartburn responders (≤1 day/week of mild heartburn) was 28% in NERD and 23% in RO. QOLRAD scores were higher among heartburn responders. There was a similar pattern of impact related to regurgitation frequency in heartburn responders compared with the group as a whole.

Conclusions

Frequent regurgitation was associated with a clinically relevant, incremental decline in HRQOL beyond that associated with heartburn before and after potent acid suppression in both NERD and RO.

Clinical trial numbers

NCT00206284 and NCT00206245.


Background

Recent evidence indicates that the composition of the gut microbiota contributes to the development of metabolic disorders by affecting the physiology and metabolism of the host. Metformin is one of the most widely prescribed type 2 diabetes (T2D) therapeutic agents.

Objective

To determine whether the antidiabetic effect of metformin is related to alterations of intestinal microbial composition.

Design

C57BL/6 mice, fed either a normal-chow diet or a high-fat diet (HFD), were treated with metformin for 6 weeks. The effect of metformin on the composition of the gut microbiota was assessed by analysing 16S rRNA gene sequences with 454 pyrosequencing. Adipose tissue inflammation was examined by flow cytometric analysis of the immune cells present in visceral adipose tissue (VAT).

Results

Metformin treatment significantly improved the glycaemic profile of HFD-fed mice. HFD-fed mice treated with metformin showed a higher abundance of the mucin-degrading bacterium Akkermansia than HFD-fed control mice. In addition, the number of mucin-producing goblet cells was significantly increased by metformin treatment (p<0.0001). Oral administration of Akkermansia muciniphila to HFD-fed mice without metformin significantly enhanced glucose tolerance and attenuated adipose tissue inflammation by inducing Foxp3 regulatory T cells (Tregs) in the VAT.

Conclusions

Modulation of the gut microbiota (by an increase in the Akkermansia spp. population) may contribute to the antidiabetic effects of metformin, thereby providing a new mechanism for the therapeutic effect of metformin in patients with T2D. This suggests that pharmacological manipulation of the gut microbiota in favour of Akkermansia may be a potential treatment for T2D.


Background

Shanghai fever, a community-acquired enteric illness associated with sepsis caused by Pseudomonas aeruginosa, was first described in 1918. The understanding of Shanghai fever is incomplete.

Objective

To delineate the clinical features and to examine the host and microbial factors associated with Shanghai fever.

Methods

We prospectively enrolled 27 consecutive previously healthy children with community-acquired P aeruginosa enteritis and sepsis between July 2003 and June 2012. An immunological investigation, including measurement of serum immunoglobulin levels and lymphocyte subpopulations, was performed. The clonal relationship of bacterial isolates was determined by multilocus sequence typing (MLST) and the virulence of isolates was measured using cellular and animal models.

Results

The median age of the patients was 7 months; 24 (89%) were aged <1 year. The most common clinical manifestations were fever (100%), diarrhoea (96%) and shock (81%). Leucopenia, thrombocytopenia, high C-reactive protein levels, coagulopathy and hypoalbuminaemia were the key laboratory findings. Necrotising enteritis with or without bowel perforation, ecthyma gangrenosum and seizures were main complications. The death rate was 15%. No common primary immune deficiency was identified. MLST genotypes indicated that isolates from Shanghai fever were non-clonal, but they shared similar phenotypes which were invariably cytotoxic, invasive and adhesive in cellular experiments and caused prolonged gut colonisation and more death than respiratory and laboratory control strains in mice.

Conclusions

Shanghai fever is a sporadic community-acquired disease of previously healthy infants that manifests as sepsis associated with P aeruginosa enteric disease. Both host and microbial factors play a role in pathogenesis.


Objective

To determine the role of colonic barrier defects and low-grade inflammation in irritable bowel syndrome (IBS)-like symptoms in quiescent inflammatory bowel disease (IBD).

Design

Caecal biopsies were collected from 51 IBS, 49 quiescent IBD (31 Crohn's disease (CD) and 18 ulcerative colitis (UC)) patients and 27 controls. IBS was assessed using the Rome III criteria and the IBS severity score. Epithelial barrier integrity was evaluated by determining the paracellular permeability of biopsies mounted in Ussing chambers and the mRNA expression of tight junction proteins (ZO-1, α-catenin and occludin). Low-grade inflammation was evaluated by counting cells, including intraepithelial lymphocytes (IELs), eosinophils and mast cells, and by determining the mRNA and protein expression of tumour necrosis factor (TNF)-α in biopsies and culture supernatants.

Results

IBS-like symptoms were present in 35.4 and 38% of CD and UC patients, respectively. Paracellular permeability was significantly increased in both quiescent IBD with IBS-like symptoms and IBS compared with quiescent IBD without IBS-like symptoms (p<0.01, respectively) or controls (p<0.01, respectively). Significantly lower expression of ZO-1 and α-catenin was detected in IBS and quiescent IBD with IBS-like symptoms. IELs and TNF-α were significantly increased in quiescent IBD with IBS-like symptoms, but not in IBS.

Conclusions

In quiescent IBD, IBS-like symptoms related to persistent subclinical inflammation associated with increased colonic paracellular permeability. A persistent increase in TNF-α in colonic mucosa may contribute to the epithelial barrier defects associated with abdominal pain in quiescent IBD, but not in IBS. Optimisation of anti-inflammatory therapy may be considered in quiescent IBD with IBS-like symptoms.


Objectives

Faecal serine proteases (FSPs) may play a role in irritable bowel syndrome with diarrhoea (IBS-D), but their origin is unclear. We aimed to structurally characterise them and define the impact of colonic cleansing and transit time.

Design

Faecal samples were obtained from 30 healthy volunteers (HV) and 79 patients with IBS-D participating in a trial of ondansetron versus placebo. Colonic transit was measured using radio-opaque markers. Samples were also obtained from 24 HV before and after colonic cleansing with the osmotic laxative MoviPrep. FSPs were purified from faecal extracts using benzamidine-Sepharose affinity chromatography. SDS-PAGE profiled components were identified using trypsinolysis and tandem mass spectrometry. Functional protease activity in faecal extracts was measured using a colorimetric assay based on the proteolysis of azo-casein.

Results

Protein analysis identified the most abundant FSPs as being of human origin and probably derived from pancreatic juice. Functional assays showed increased faecal protease (FP) and amylase in patients with IBS-D compared with HV. Those with higher amylase had significantly higher FP and greater anxiety. FP activity correlated negatively with whole gut transit in patients with IBS-D (Spearman r=–0.32, p=0.005) and HV (r=–0.55, p=0.014). Colon cleansing caused a significant rise in FP activity in HV from a baseline of median (IQR) 253 (140–426) to 1031 (435–2296), levels similar to those seen in patients with IBS-D. FSP activity correlated positively with days/week with urgency.

Conclusions

The most abundant FSPs are of human origin. Rapid transit through the colon and/or decreased (possibly bacterial) proteolytic degradation increases their faecal concentration and could contribute to visceral hypersensitivity in patients with IBS-D.

ClinicalTrials.gov

NCT00745004.


Objective

Colonic mucosa-associated Escherichia coli are increased in Crohn's disease (CD) and colorectal cancer (CRC). They variously haemagglutinate, invade epithelial cell lines, replicate within macrophages, translocate across M (microfold) cells and damage DNA. We investigated genes responsible for these effects and their co-association in colonic mucosal isolates.

Design

A fosmid library yielding 968 clones was prepared in E coli EPI300-T1 using DNA from a haemagglutinating CRC isolate, and resulting haemagglutinating clones were 454-pyrosequenced. PCR screening was performed on 281 colonic E coli isolates from inflammatory bowel disease (IBD) (35 patients), CRC (21) and controls (24; sporadic polyps or irritable bowel syndrome).

Results

454-Pyrosequencing of fosmids from the haemagglutinating clones (n=8) identified the afimbrial adhesin afa-1 operon. Transfection of afa-1 into E coli K-12 predictably conferred diffuse adherence plus invasion of HEp-2 and I-407 epithelial cells, and upregulation of vascular endothelial growth factor. E coli expressing afaC were common in CRC (14/21, p=0.0009) and CD (9/14, p=0.005) but not ulcerative colitis (UC; 8/21) compared with controls (4/24). E coli expressing both afaC and lpfA (relevant to M-cell translocation) were common in CD (8/14, p=0.0019) and CRC (14/21, p=0.0001), but not UC (6/21) compared with controls (2/24). E coli expressing both afaC and pks (genotoxic) were common in CRC (11/21, p=0.0015) and UC (8/21, p=0.022), but not CD (4/14) compared with controls (2/24). All isolates expressed dsbA and htrA relevant to intra-macrophage replication, and 242/281 expressed fimH encoding type-1 fimbrial adhesin.

Conclusions

IBD and CRC commonly have colonic mucosal E coli that express genes that confer properties relevant to pathogenesis including M-cell translocation, angiogenesis and genotoxicity.


Objective

Population-based studies have shown a slightly decreased life expectancy in patients with Crohn's disease (CD). The primary aim of the present study was to evaluate mortality and causes of death 20 years after the diagnosis in a well defined population-based cohort of CD patients in Norway.

Design

The Inflammatory Bowel South-Eastern Norway study has prospectively followed all patients diagnosed with CD in the period between 1 January 1990 and 31 December 1993 in four geographically well-defined areas. All patients (n=237) were age and sex matched with 25 persons from the same county selected at random from the general population. Data on death and causes of deaths were collected from the Norwegian Causes of Death Register. All causes and cause-specific mortality (gastrointestinal cancer, cancer and heart disease) were modelled with Cox regression model stratified by matched sets. Results are expressed as HRs with 95% CIs.

Results

There was no significant difference between CD patients and controls in overall mortality (HR=1.35, 95% CI 0.94 to 1.94, p=0.10). Furthermore, there were no marked differences in deaths from gastrointestinal cancer, other cancers or cardiovascular diseases in the CD group compared with the controls. In the CD group, 13.9% had died compared with 12.7% in the control group (p=0.578).

Conclusions

In our population-based inception cohort followed for 20 years, there was no increased mortality or more deaths from cancer compared with the general population.


Introduction

Dietary fats influence intestinal inflammation and regulate mucosal immunity. Data on the association between dietary fat and risk of Crohn's disease (CD) and ulcerative colitis (UC) are limited and conflicting.

Methods

We conducted a prospective study of women enrolled in the Nurses’ Health Study cohorts. Diet was prospectively ascertained every 4 years using a validated semi-quantitative food frequency questionnaire. Self-reported CD and UC were confirmed through medical record review. We examined the effect of energy-adjusted cumulative average total fat intake and specific types of fat and fatty acids on the risk of CD and UC using Cox proportional hazards models adjusting for potential confounders.

Results

Among 170 805 women, we confirmed 269 incident cases of CD (incidence 8/100 000 person-years) and 338 incident cases of UC (incidence 10/100 000 person-years) over 26 years and 3 317 338 person-years of follow-up. Cumulative energy-adjusted intake of total fat, saturated fats, unsaturated fats, n-6 and n-3 polyunsaturated fatty acids (PUFAs) were not associated with risk of CD or UC. However, greater intake of long-chain n-3 PUFAs was associated with a trend towards lower risk of UC (HR 0.72, 95% CI 0.51 to 1.01). In contrast, high long-term intake of trans-unsaturated fatty acids was associated with a trend towards an increased incidence of UC (HR 1.34, 95% CI 0.94 to 1.92).

Conclusions

A high intake of dietary long-chain n-3 PUFAs may be associated with a reduced risk of UC. In contrast, high intake of trans-unsaturated fats may be associated with an increased risk of UC.


Objective

Virtual chromoendoscopy (CE) is expected to enhance adenoma yield and reduce variation in performance between colonoscopists. This study aimed to compare the efficacy of narrow band imaging (NBI), flexible spectral imaging CE (FICE) and white light (WL) colonoscopy and their impact for less experienced endoscopists.

Methods

We performed a randomised tandem colonoscopy trial controlling for withdrawal time and bowel preparation. Average-risk adults undergoing screening colonoscopy were enrolled and randomly assigned to first withdrawal with one of the three imaging modalities (NBI (NBI-WL group), FICE (FICE-WL group) and WL (WL-WL group)). Eight colonoscopists were categorised into expert and non-expert subgroups.

Results

1650 subjects (mean age 51.4 years, 63.9% men) were included (550 in each group). Compared with WL, neither NBI nor FICE increased the mean number of adenomas detected per patient (0.37 vs 0.35 and 0.36; p=0.591) or the percentage of patients with adenoma (25.3% vs 24.5% and 23.6%; p=0.753). For all three modalities, expert subgroups had higher yields of adenomas than non-expert subgroups. Learning curves were observed only for non-expert subgroups with all three modalities. The percentage of missed adenomas did not differ between the three groups (20.8% by WL vs 22.9% by NBI and 26.0% by FICE, p=0.300) and was not affected by endoscopists’ expertise.

Conclusions

Neither NBI nor FICE improved adenoma detection or miss rates, with no difference in diagnostic efficacy between the two systems. Virtual CE had no additional benefits over WL for non-experts.

Clinical trial registration number:

KCT0000570.


Objective

FBXW7 encodes the substrate recognition component of a ubiquitin ligase that degrades targets such as Notch1, c-Jun, c-Myc and cyclin E. FBXW7 mutations occur in several tumour types, including colorectal cancers. The FBXW7 mutation spectrum in cancers is unusual. Some tumours have biallelic loss of function mutations but most have monoallelic missense mutations involving specific arginine residues at β-propellor tips involved in substrate recognition.

Design

FBXW7 functional studies have generally used null systems. In order to analyse the most common mutations in human tumours, we created a Fbxw7fl(R482Q)/+ mouse and conditionally expressed this mutation in the intestines using Vill-Cre. We compared these mice with heterozygous null (Fbxw7+/–) mutants.

Results

A few sizeable intestinal adenomas occurred in approximately 30% of R482Q/+ and Fbxw7+/– mice at age >300 days. Breeding the R482Q allele onto Apc mutant backgrounds led to accelerated morbidity and increased polyp numbers and size. Within the small bowel, polyp distribution was shifted proximally. Elevated levels of two particular Fbxw7 substrates, Klf5 and Tgif1, were found in normal intestine and adenomas of R482Q/+, R482Q/R482Q and Fbxw7–/– mice, but not Fbxw7+/– animals. On the Apc mutant background, Fbxw7+/– mutants had a phenotype intermediate between Fbxw7 wild-type and R482Q/+ mice.

Conclusions

Heterozygous Fbxw7 propellor tip (R482Q) mutations promote intestinal tumorigenesis on an Apc mutant background. Klf5 and Tgif1 are strong candidates for mediating this effect. Although heterozygous null Fbxw7 mutations also promote tumour growth, these have a weaker effect than R482Q. These findings explain the FBXW7 mutation spectrum found in human cancers, and emphasise the need for animal models faithfully to reflect human disease.


Objective

Genome-wide association studies have identified a large number of single nucleotide polymorphisms (SNPs) associated with a wide array of cancer sites. Several of these variants demonstrate associations with multiple cancers, suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesised that SNPs previously associated with other cancers may additionally be associated with colorectal cancer. In a large-scale study, we examined 171 SNPs previously associated with 18 different cancers for their associations with colorectal cancer.

Design

We examined 13 338 colorectal cancer cases and 40 967 controls from three consortia: Population Architecture using Genomics and Epidemiology (PAGE), Genetic Epidemiology of Colorectal Cancer (GECCO), and the Colon Cancer Family Registry (CCFR). Study-specific logistic regression results, adjusted for age, sex, principal components of genetic ancestry, and/or study specific factors (as relevant) were combined using fixed-effect meta-analyses to evaluate the association between each SNP and colorectal cancer risk. A Bonferroni-corrected p value of 2.92x10–4 was used to determine statistical significance of the associations.

Results

Two correlated SNPs—rs10090154 and rs4242382—in Region 1 of chromosome 8q24, a prostate cancer susceptibility region, demonstrated statistically significant associations with colorectal cancer risk. The most significant association was observed with rs4242382 (meta-analysis OR=1.12; 95% CI 1.07 to 1.18; p=1.74x10–5), which also demonstrated similar associations across racial/ethnic populations and anatomical sub-sites.

Conclusions

This is the first study to clearly demonstrate Region 1 of chromosome 8q24 as a susceptibility locus for colorectal cancer; thus, adding colorectal cancer to the list of cancer sites linked to this particular multicancer risk region at 8q24.


Objective

Bile acids are important regulators of intestinal physiology, and the nuclear bile acid receptor, farnesoid X receptor (FXR), is emerging as a promising therapeutic target for several intestinal disorders. Here, we investigated a role for FXR in regulating intestinal fluid and electrolyte transport and the potential for FXR agonists in treating diarrhoeal diseases.

Design

Electrogenic ion transport was measured as changes in short-circuit current across voltage-clamped T84 cell monolayers or mouse tissues in Ussing chambers. NHE3 activity was measured as BCECF fluorescence in Caco-2 cells. Protein expression was measured by immunoblotting and cell surface biotinylation. Antidiarrhoeal efficacy of GW4064 was assessed using two in vivo mouse models: the ovalbumin-induced diarrhoea model and cholera toxin (CTX)-induced intestinal fluid accumulation.

Results

GW4064 (5 μmol/L; 24 h), a specific FXR agonist, induced nuclear translocation of the receptor in T84 cells and attenuated Cl secretory responses to both Ca2+ and cAMP-dependent agonists. GW4064 also prevented agonist-induced inhibition of NHE3 in Caco-2 cells. In mice, intraperitoneal administration of GW4064 (50 mg/mL) also inhibited Ca2+ and cAMP-dependent secretory responses across ex vivo colonic tissues and prevented ovalbumin-induced diarrhoea and CTX-induced intestinal fluid accumulation in vivo. At the molecular level, FXR activation attenuated apical Cl currents by inhibiting expression of cystic fibrosis transmembrane conductance regulator channels and inhibited basolateral Na+/K+-ATPase activity without altering expression of the protein.

Conclusions

These data reveal a novel antisecretory role for the FXR in colonic epithelial cells and suggest that FXR agonists have excellent potential for development as a new class of antidiarrheal drugs.


Background

Diabetes mellitus (DM) is common in the general population and it poses a heavy burden to society in the form of long-term disability, healthcare use and costs. The pancreas is a key player in glucose homeostasis, but the occurrence of newly diagnosed DM after acute pancreatitis (AP), the most frequent disease of the pancreas, has never been assessed systematically. The aim of this study was to conduct a systematic literature review to determine the prevalence and time course of DM and related conditions after the first attack of AP as well as the impact of covariates.

Methods

Relevant literature cited in three electronic databases (Scopus, EMBASE and MEDLINE) was reviewed independently by two authors. The main outcome measures studied were newly diagnosed prediabetes, DM, or DM treated with insulin. Pooled prevalence and 95% CIs were calculated for all outcomes.

Results

A total of 24 prospective clinical studies, involving 1102 patients with first episode of AP, met all the eligibility criteria. Prediabetes and/or DM was observed in 37% (95% CI 30% to 45%) individuals after AP. The pooled prevalence of prediabetes, DM and treatment with insulin after AP was 16% (95% CI 9% to 24%), 23% (95% CI 16% to 31%), and 15% (95% CI 9% to 21%), respectively. Newly diagnosed DM developed in 15% of individuals within 12 months after first episode of AP and the risk increased significantly at 5 years (relative risk 2.7 (95% CI 1.9 to 3.8)). A similar trend was observed with regard to treatment with insulin. The severity of AP, its aetiology, individuals’ age and gender had minimal effect on the studied outcomes.

Conclusions

Patients with AP often develop prediabetes and/or DM after discharge from hospital, and have a greater than twofold increased risk of DM over 5 years. Further studies are warranted to determine the optimal strategy for its detection and whether the risk of developing DM after AP can be reduced.


Objective

Hepatocellular carcinoma (HCC) is a heterogeneous tumour displaying a complex variety of genetic and epigenetic changes. In human cancers, aberrant post-transcriptional modifications, such as alternative splicing and RNA editing, may lead to tumour specific transcriptome diversity.

Design

By utilising large scale transcriptome sequencing of three paired HCC clinical specimens and their adjacent non-tumour (NT) tissue counterparts at depth, we discovered an average of 20 007 inferred A to I (adenosine to inosine) RNA editing events in transcripts. The roles of the double stranded RNA specific ADAR (Adenosine DeAminase that act on RNA) family members (ADARs) and the altered gene specific editing patterns were investigated in clinical specimens, cell models and mice.

Results

HCC displays a severely disrupted A to I RNA editing balance. ADAR1 and ADAR2 manipulate the A to I imbalance of HCC via their differential expression in HCC compared with NT liver tissues. Patients with ADAR1 overexpression and ADAR2 downregulation in tumours demonstrated an increased risk of liver cirrhosis and postoperative recurrence and had poor prognoses. Due to the differentially expressed ADAR1 and ADAR2 in tumours, the altered gene specific editing activities, which was reflected by the hyper-editing of FLNB (filamin B, β) and the hypo-editing of COPA (coatomer protein complex, subunit α), are closely associated with HCC pathogenesis. In vitro and in vivo functional assays prove that ADAR1 functions as an oncogene while ADAR2 has tumour suppressive ability in HCC.

Conclusions

These findings highlight the fact that the differentially expressed ADARs in tumours, which are responsible for an A to I editing imbalance, has great prognostic value and diagnostic potential for HCC.


Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death and is currently the main event leading to death in patients with cirrhosis. Evolving information suggests that the metabolic syndrome with non-alcoholic liver disease may be an important cause of HCC in addition to viral hepatitis and alcohol-induced liver disease. The molecular pathogenesis is extremely complex and heterogeneous. To date the molecular information has not impacted on treatment decisions. Periodic surveillance imaging of patients with cirrhosis is widely practiced, especially because diagnostic, radiographic criteria for early-stage HCC have been defined (including nodules between 1 and 2 cm) and effective treatment is available for tumours detected at an early stage. Worldwide the approach to resection versus transplantation varies depending upon local resources, expertise and donor availability. The criteria for transplantation are discussed, and the controversial areas highlighted with evidence-based recommendations provided. Several approaches are available for intermediate stage disease, including radiofrequency ablation, transarterial chemoembolisation and radioembolisation; the rationale for these therapies is buttressed by appropriate outcome-based studies. For advanced disease, systemic therapy with sorafenib remains the option best supported by current data. Thus, while several trials have failed to improve the benefits of established therapies, studies assessing the sequential or combined application of those already known to be beneficial are needed. Also, new concepts are provided in regards to selecting and stratifying patients for second-line studies, which may help explain the failure of prior studies.


Clinical presentation

A 37-year-old Caucasian male presented to our institution for progressive weight loss and recurrent abdominal pain. An enteral CT performed in another centre showed a diffuse thickening of the duodenal walls suggestive of lymphoma or Crohn’s disease.

Esophagogastroduodenoscopy showed a normal appearance of gastroesophageal mucosa while the duodenal and proximal jejunal mucosa appeared completely covered with pseudo-polypoid lesions with maximum size of 5 mm (figure 1A,B). At the ileocolonoscopy, the colorectal mucosa was diffusely micronodular (figure 1D), while the terminal ileum presented same lesions detected in the duodenum (figure 1C).

Enteroscopy confirmed the presence of pseudopolypoid lesions also in the jejunum and ileum, but fewer compared with the duodenum (see online supplementary video).

Serial gastrointestinal biopsies were performed.

Laboratory tests showed marked reduction of IgA, IgM and mild reduction of IgG level (also in IgG1 and IgG4 subclasses).

Antibodies specific for...


Basic scienceThe complexities of host-microbiota interaction

 Faith JJ, Ahern PP, Ridaura VK, et al. Identifying gut microbe-host phenotype relationships using combinatorial communities in gnotobiotic mice. Sci Trans Med 2014;6:220ra11.

Identifying which members of the colonic microbiota actively participate in processes that affect physiology, metabolism, immunity and disease progression is challenging. Gut commensal bacteria and metabolites they produce, including short chain fatty acids, have been shown to regulate colonic regulatory T (Treg) cells in mice. These cells express the transcription factor Foxp3, secrete interleukin 10 and are critical in controlling intestinal inflammation by limiting proliferation of effector CD4 T cells. This highlights the complex effects of inflammation on microbial composition/activity and the host's ability to protect itself from a dysbiotic microbiota. This work has further demonstrated how colonic bacteria shape the immune landscape, and shows that the consortium of bacteria capable of shaping the Treg response spans different...


We read with great interest the recent paper by Rosendahl et al1 describing the incidence of variants in CFTR, SPINK1, CTRC and PRSS1 in a German cohort of chronic pancreatitis cases. The authors conclude that chronic pancreatitis is a complex genetic disease and the net effect of mutations in multiple susceptibility genes underlies increased disease risk. Indeed, in the studied cohort, at least one genetic risk factor was identified in 36.7% of patients. Surprisingly, however, only 6.5% of cases carried multiple risk factors, which seems to contradict the complex genetics theory of chronic pancreatitis. While it is likely that more susceptibility genes are yet to be discovered, we submit that known risk genes may have been incompletely characterised resulting in underestimation of the true genetic burden in chronic pancreatitis. Discovery studies tend to focus on exons and exon-intron boundaries and may thus miss many intronic variants....


Non-alcoholic fatty liver disease (NAFLD) represents the most common hepatic manifestation of chronic liver diseases in developed countries. Since non-alcoholic steatohepatitis (NASH) is responsible for a large proportion of cryptogenic cirrhosis and cirrhosis represents the main risk factor for hepatocellular carcinoma (HCC), HCC is a severe complication of end-stage NAFLD.1

Recent evidence published in this journal showed the therapeutic potential of an inhibition of the chemokine (C-C motif) ligand 2 (CCL2)/monocyte chemoattractant protein-1 (MCP-1) in NASH.2 The study by Baeck et al elegantly demonstrated that the pharmacological administration of an RNA oligonucleotide against MCP-1 ameliorates murine steatosis and inflammation. Since mice deficient of the MCP-1 receptor also showed attenuated fibrosis, MCP-1 was suggested as a critical link in the axis steatosis–inflammation–fibrosis.2

Here, we report that animals with a liver-specific overexpression of the insulin-like growth factor 2 (IGF2) mRNA-binding protein p62/IMP2-2/IGF2BP2-2 exhibit distinctly...


We read with interest the article from Chung et al,1 which suggests limited benefits in adenoma detection with narrow band imaging or flexible spectral imaging compared with standard white light examination. After a short learning curve period, there was no difference in adenoma detection even for the less experienced endoscopist. These are important results as we are increasingly inundated with new technologies or adjuncts that are hypothesised to improve adenoma detection rate (ADR). Adopting these technologies often involves high capital expenditure and a learning curve often for unsubstantiated clinical benefits.

Similarly, when high-definition colonoscopes (HDC) were introduced, they were thought to improve ADR in several retrospective studies; however, this was refuted in a subsequent meta-analysis.2 We routinely use both standard video colonoscopes (SVC) and HDC in our practice, and have noted an increase in patient discomfort associated with the latter. Procedure comfort reflects...


Dear Sir,

I read with interest the study by Khalili et al,1 which confirms the association between oral contraceptive use and increased risk for Crohn's disease in two impressively large cohorts. When we studied this some years ago, we found that oral contraceptive use associated much more strongly with isolated colonic Crohn's disease than with small intestinal disease.2 Further analysis of our cases and those previously published as case reports suggested that most of these had non–granulomatous colitis—the diagnosis of Crohn's being based mainly on marked rectal sparing, suggesting a possible ischaemic aetiology. It would be very interesting to know whether the cohorts described by Khalili et al also showed a predominance of isolated colonic Crohn's disease among those taking oral contraceptives.

Competing interests

None.

Provenance and peer review

Not commissioned; internally peer reviewed.