Acid suppression and Barrett's oesophagus: what do we really know?
Although widely believed, the data supporting the premise that suppression of hydrochloric acid exposure to the oesophagus decreases the risk of oesophageal adenocarcinoma is inconsistent at best. In addition, it is known that bile acids may play a role in the formation of Barrett's oesophagus and oesophageal cancer, which would mean medicines like proton pump inhibitors (PPI) may not affect cancer formation in the oesophagus. This led Singh and colleagues to perform a systematic review with meta-analysis of studies evaluating the association between acid-suppressive medications (PPIs and histamine receptor antagonists (H2RA)) and the risk of oesophageal adenocarcinoma or high-grade dysplasia in patients with Barrett's oesophagus. They found seven observational studies that included a total of 2813 patients with Barrett's oesophagus and 317 cases of patients with high-grade dysplasia or oesophageal cancer, of which >80% were PPI users. On...
The prevalence of obesity and type 2 diabetes is increasing worldwide at an alarming rate. As of 2008, the worldwide prevalence of type 2 diabetes was estimated to be approximately 9% of the global adult population.1 While pharmacotherapeutic options for the treatment of type 2 diabetes are expanding, patients suffering from type 2 diabetes continue to experience a significantly higher risk of developing comorbidities such as cardiovascular disease, kidney disease and cancer.2 Therefore, the development of new therapeutic modalities for the treatment of obesity and type 2 diabetes is crucial.
Bariatric surgery is currently considered the most effective therapeutic modality for the long-term treatment of obesity.3 Furthermore, certain bariatric procedures have been reported to result in relatively high rates of type 2 diabetes resolution. It is important to note that variation exists in the efficacy of different bariatric procedures to produce diabetes resolution....
Huang et al1 identified and tested the role of a specific microRNA (miRNA) in the pathogenesis of IBD. The study of microRNAs is a burgeoning field within epigenetics. These small non-coding RNAs mediate translation-level repression of protein expression by binding to the 3' -untranslated region of specific messenger RNA transcripts. In the innate and adaptive immune response, miRNAs play an important role in negative regulation of inflammatory conditions in the intestine. Inflammatory regulators such as IL-6, tumor necrosis factor (TNF) and toll-like receptors have been shown to induce miRNA expression in both acute and chronic inflammation. The roles for miRNAs in IBD are emerging from recent studies that compare miRNA expression in colonoscopic and peripheral blood draw biopsies from colitis patients with healthy individuals.2 Despite this, the vast majority of miRNAs identified in microarray analyses of colitis patients have yet to be investigated in experimental...
Inflammatory bowel diseases (IBD) such as Crohn’s disease (CD) or ulcerative colitis (UC) comprise the two most common forms of intestinal inflammation characterised by a chronic relapsing disease course. The aetiology of both disorders has still not yet been identified. Whereas it has been elegantly demonstrated in many studies in the last years that genetic factors are crucially involved, other so-called environmental factors are much less well defined.1 In recent years evidence was accumulating that the gut microbiota and its manipulation might constitute one of those relevant ‘environmental’ factors. Trillions of microbes compose the intestinal microbiota of healthy individuals and several studies have demonstrated in the past that IBD patients exhibit a pronounced dysbiosis. It remains, however, speculative whether observed changes are causally involved in IBD pathogenesis or reflect simply epiphenomena due to inflammation.2
Whereas several clinical aspects strongly support a role for intestinal bacteria...
Despite recent advances in neonatal practice, necrotising enterocolitis (NEC) remains the most common and devastating gastrointestinal emergency in premature infants. In fact, as more extremely premature infants survive, the incidence appears to be increasing worldwide.1 Severe NEC is characterised by coagulative necrosis of the distal ileum and proximal colon with clinical presentation ranging from abdominal distension, pneumatosis intestinalis, frank blood in stools, intestinal gangrene, bowel perforation, sepsis and shock. Approximately 9000 infants develop NEC in the USA each year and mortality rates range from 10%–50%.23 The associated costs—both financial and personal—are significant; the average hospital stay for infants with surgical NEC is an additional 43.1 days at an average additional cost of US$200 000 per child compared with extremely low birthweight infants without NEC.4 Treatment strategies are mainly supportive and include administration of antibiotics and fluids, blood product replacement and withholding...
IBD includes Crohn's Disease and ulcerative colitis (UC), which are multifaceted chronic inflammatory conditions. Their aetiology is thought to involve the interaction of genetic, immunological and environmental factors. Current therapeutics have not succeeded in eliminating the burden of these diseases. Some are associated with side effects, which themselves can cause discomfort for the patient, leading to a decrease in compliance and a return to the status quo prior to medication. In addition, the cost of current therapeutics is very high.1 All of these considerations require the development of less toxic, better tolerated, more efficacious and cheaper drugs.
Enteric glial cells (EGCs) are major constituents of the enteric nervous system, outnumbering neurones by 4–1.2 They are thought to help control motility, secretion, nutrient uptake and blood flow via their interactions with enteric nerves. Evidence of their importance in the transduction of inflammatory signals is now emerging....
A major breakthrough in the treatment of chronic hepatitis B virus (HBV) infection had been the approval of nucleoside and nucleotide analogues (NUCs), which inhibit the reverse transcriptase and, thereby, dramatically suppress HBV DNA. To date, five NUCs are approved for the treatment of hepatitis B, with tenofovir and entecavir considered as first-line therapy.1 Treatment with tenofovir or entecavir leads to viral suppression below the limit of detection in almost 100% of adherent patients.1 This is associated with regression of fibrosis or even cirrhosis.23 Furthermore, some studies suggest a lowered incidence of hepatocellular carcinoma (HCC) with long-term NUC treatment. However, a significant risk for HCC development remains despite low HBV DNA, especially in patients with cirrhosis.4 Data from the REVEAL study suggest that higher HBsAg in low viremic patients is associated with an increased risk for HCC, underlining...
A multidisciplinary panel of 18 physicians and 3 non-physicians from eight countries (Sweden, UK, Argentina, Australia, Italy, Finland, Norway and the USA) reviewed the literature on diagnosis and management of adult coeliac disease (CD). This paper presents the recommendations of the British Society of Gastroenterology. Areas of controversies were explored through phone meetings and web surveys. Nine working groups examined the following areas of CD diagnosis and management: classification of CD; genetics and immunology; diagnostics; serology and endoscopy; follow-up; gluten-free diet; refractory CD and malignancies; quality of life; novel treatments; patient support; and screening for CD.
Acid-suppressive medications, particularly proton pump inhibitors (PPIs), may decrease the risk of oesophageal adenocarcinoma (OAC) in patients with Barrett's oesophagus (BO). We performed a systematic review with meta-analysis of studies evaluating the association between acid-suppressive medications (PPIs and histamine receptor antagonists (H2RAs)) and risk of OAC or high-grade dysplasia (BO-HGD) in patients with BO.
We performed a systematic search of multiple electronic databases and conference proceedings up to June 2013 to identify studies reporting the association between use of acid-suppressive medications and risk of OAC and/or BO-HGD in patients with BO. Summary ORs with 95% CIs were estimated.
We identified seven observational studies (2813 patients with BO, 317 cases of OAC or BO-HGD, 84.4% PPI users). On meta-analysis, PPI use was associated with a 71% reduction in risk of OAC and/or BO-HGD in patients with BO (adjusted OR 0.29; 95% CI 0.12 to 0.79). There was a trend towards a dose–response relationship with PPI use for >2–3 years protective against OAC or BO-HGD (three studies; PPI use >2–3 years vs <2–3 years: OR 0.45 (95% CI 0.19 to 1.06) vs 1.09 (0.47 to 2.56)). Considerable heterogeneity was observed. Two studies reported the association between H2RA use and risk of OAC and/or BO-HGD (1352 patients with BO, 156 cases of OAC, 25.4% on H2RAs), and both studies did not show a significant effect.
Based on meta-analysis of observational studies, the use of PPIs is associated with a decreased risk of OAC and/or BO-HGD in patients with BO. None of the studies showed an increased risk of OAC. PPI use should be considered in BO, and chemopreventive trials of PPIs in patients with BO are warranted.
Surgical interventions that prevent nutrient exposure to the duodenum are among the most successful treatments for obesity and diabetes. However, these interventions are highly invasive, irreversible and often carry significant risk. The duodenal-endoluminal sleeve (DES) is a flexible tube that acts as a barrier to nutrient-tissue interaction along the duodenum. We implanted this device in Zucker Diabetic Fatty (ZDF) rats to gain greater understanding of duodenal nutrient exclusion on glucose homeostasis.
ZDF rats were randomised to four groups: Naive, sham ad libitum, sham pair-fed, and DES implanted. Food intake, body weight (BW) and body composition were measured for 28 days postoperatively. Glucose, lipid and bile acid metabolism were evaluated, as well as histological assessment of the upper intestine.
DES implantation induced a sustained decrease in BW throughout the study that was matched by pair-fed sham animals. Decreased BW resulted from loss of fat, but not lean mass. DES rats were also found to be more glucose tolerant than either ad libitum-fed or pair-fed sham controls, suggesting fat mass independent metabolic benefits. DES also reduced circulating triglyceride and glycerol levels while increasing circulating bile acids. Interestingly, DES stimulated a considerable increase in villus length throughout the upper intestine, which may contribute to metabolic improvements.
Our preclinical results validate DES as a promising therapeutic approach to diabetes and obesity, which offers reversibility, low risk, low invasiveness and triple benefits including fat mass loss, glucose and lipid metabolism improvement which mechanistically may involve increased villus growth in the upper gut.
Emerging evidence suggests that microRNA (miRNA)-mediated gene regulation influences a variety of autoimmune disease processes, including Crohn's disease (CD), but the biological function of miRNAs in CD remains unclear. We examine miRNA level in colon tissues and study the potential functions of miRNAs that regulate pathological genes during the inflammation process.
miRNA levels were assayed in the inflamed colon of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced and IL-10 knockout (KO) chronic colitis mice and CD patients by microarray or qRT-PCR. The influence of differently expressed miR-141 on its putative target genes, CXCL12β, and leukocyte migration was investigated in colonic epithelia cells, colitis models and CD patients. The role of miR-141 was further studied in the experimental colitis mice by intracolonic administration of miR-141 precursors or inhibitors.
An inverse correlation between miR-141 and CXCL12β/total-CXCL12 was observed predominantly in the epithelial cells of the inflamed colons from colitic mice and CD patients. Further study demonstrated that miR-141 directly regulated CXCL12β expression and CXCL12β-mediated leukocyte migration. Upregulation or downregulation of miR-141 in the TNBS-induced or IL-10 KO colitic colon regulated leukocyte infiltration and alleviated or aggravated experimental colitis, respectively. Additionally, colonic overexpression of CXCL12β abolished the therapeutic effect of miR-141 in TNBS-induced colitis.
This study showed that the pathway of miR-141 targeting CXCL12β is a possible mechanism underlying inflammatory cell trafficking during colonic inflammation process. Inhibiting colonic CXCL12β expression and blocking colonic immune cell recruitment by using miRNA precursors represents a promising approach that may be valuable for CD treatment.
To characterise the temporal evolution of antibodies to infliximab (ATI).
Prospective observational study of infliximab-treated patients with inflammatory bowel disease between 2009 and 2012.
Trough levels of infliximab and ATI were measured before each infusion by anti- ELISA. Patients were monitored for disease activity by clinical activity indexes and for dose-intensification or infliximab cessation. The occurrence of transient ATI disappearing spontaneously without intervention was recorded separately.
125 patients were included (98 Crohn's disease, 27 ulcerative colitis, median follow-up 11.5±22 months) and 1119 sera were analysed for infliximab and ATI levels. Kaplan-Meier analysis showed that 42% of patients remained ATI-free by 4 years of treatment. Most (90%) of the patients who developed ATI did so within the first 12 months of therapy, whereas transient ATI were detected throughout the duration of infliximab therapy (p<0.001). ATI incidence was similar between patients who received infliximab previously (episodic/interrupted therapy patients, n=14) and scheduled-therapy patients (n=111). In the scheduled group, combination immunomodulator+infliximab resulted in longer ATI-free survival compared with monotherapy (p=0.003, logrank test). Survival free of clinical loss of response was enjoyed by 51% of patients, and serial measurements showed that ATI development often preceded the onset of clinical flare.
When followed prospectively, most patients who develop ATI do so within the first 12 months of therapy. This incidence is reduced by concomitant immunomodulator even in scheduled-therapy patients. In contrast, transient ATI, which are of little clinical significance, can appear haphazardly at any time during treatment. The onset of clinical loss of response may lag behind the appearance of anti-infliximab antibodies.
Altered microbiota composition, changes in immune responses and impaired intestinal barrier functions are observed in IBD. Most of these features are controlled by proteases and their inhibitors to maintain gut homeostasis. Unrestrained or excessive proteolysis can lead to pathological gastrointestinal conditions. The aim was to validate the identified protease IBD candidates from a previously performed systematic review through a genetic association study and functional follow-up.
We performed a genetic association study in a large multicentre cohort of patients with Crohn's disease (CD) and UC from five European IBD referral centres in a total of 2320 CD patients, 2112 UC patients and 1796 healthy controls. Subsequently, we did an extensive functional assessment of the candidate genes to explore their causality in IBD pathogenesis.
Ten single nucleotide polymorphisms (SNPs) in four genes were significantly associated with CD: CYLD, USP40, APEH and USP3. CYLD was the most significant gene with the intronically located rs12324931 the strongest associated SNP (pFDR=1.74e-17, OR=2.24 (1.83 to 2.74)). Five SNPs in four genes were significantly associated with UC: USP40, APEH, DAG1 and USP3. CYLD, as well as some of the other associated genes, is part of the ubiquitin proteasome system (UPS). We therefore determined if the IBD-associated adherent-invasive Escherichia coli (AIEC) can modulate the UPS functioning. Infection of intestinal epithelial cells with the AIEC LF82 reference strain modulated the UPS turnover by reducing poly-ubiquitin conjugate accumulation, increasing 26S proteasome activities and decreasing protein levels of the NF-B regulator CYLD. This resulted in IB-α degradation and NF-B activation. This activity was very important for the pathogenicity of AIEC since decreased CYLD resulted in increased ability of AIEC LF82 to replicate intracellularly.
Our results reveal the UPS, and CYLD specifically, as an important contributor to IBD pathogenesis, which is favoured by both genetic and microbial factors.
Bacteria play an important role in the onset and perpetuation of intestinal inflammation in inflammatory bowel disease (IBD). Unlike in Crohn's disease (CD), in which dysbiosis has been better characterised, in ulcerative colitis (UC), only small cohorts have been studied and showed conflicting data. Therefore, we evaluated in a large cohort if the microbial signature described in CD is also present in UC, and if we could characterise predominant dysbiosis in UC. To assess the functional impact of dysbiosis, we quantified the bacterial metabolites.
The predominant microbiota from 127 UC patients and 87 age and sex-matched controls was analysed using denaturing gradient gel electrophoresis (DGGE) analysis. Differences were quantitatively validated using real-time PCR. Metabolites were quantified using gas chromatography–mass spectrometry.
Based on DGGE analysis, the microbial signature previously described in CD was not present in UC. Real-time PCR analysis revealed a lower abundance of Roseburia hominis (p<0.0001) and Faecalibacterium prausnitzii (p<0.0001) in UC patients compared to controls. Both species showed an inverse correlation with disease activity. Short-chain fatty acids (SCFA) were reduced in UC patients (p=0.014), but no direct correlation between SCFA and the identified bacteria was found.
The composition of the fecal microbiota of UC patients differs from that of healthy individuals: we found a reduction in R hominis and F prausnitzii, both well-known butyrate-producing bacteria of the Firmicutes phylum. These results underscore the importance of dysbiosis in IBD but suggest that different bacterial species contribute to the pathogenesis of UC and CD.
Necrotising enterocolitis (NEC) is a major source of neonatal morbidity and mortality. The management of infants with NEC is currently complicated by our inability to accurately identify those at risk for progression of disease prior to the development of irreversible intestinal necrosis. We hypothesised that integrated analysis of clinical parameters in combination with urine peptide biomarkers would lead to improved prognostic accuracy in the NEC population.
Infants under suspicion of having NEC (n=550) were prospectively enrolled from a consortium consisting of eight university-based paediatric teaching hospitals. Twenty-seven clinical parameters were used to construct a multivariate predictor of NEC progression. Liquid chromatography/mass spectrometry was used to profile the urine peptidomes from a subset of this population (n=65) to discover novel biomarkers of NEC progression. An ensemble model for the prediction of disease progression was then created using clinical and biomarker data.
The use of clinical parameters alone resulted in a receiver-operator characteristic curve with an area under the curve of 0.817 and left 40.1% of all patients in an ‘indeterminate’ risk group. Three validated urine peptide biomarkers (fibrinogen peptides: FGA1826, FGA1883 and FGA2659) produced a receiver-operator characteristic area under the curve of 0.856. The integration of clinical parameters with urine biomarkers in an ensemble model resulted in the correct prediction of NEC outcomes in all cases tested.
Ensemble modelling combining clinical parameters with biomarker analysis dramatically improves our ability to identify the population at risk for developing progressive NEC.
Intestinal permeability and psychological stress have been implicated in the pathophysiology of IBD and IBS. Studies in animals suggest that stress increases permeability via corticotropin-releasing hormone (CRH)-mediated mast cell activation. Our aim was to investigate the effect of stress on intestinal permeability in humans and its underlying mechanisms.
Small intestinal permeability was quantified by a 2 h lactulose–mannitol urinary excretion test. In a first study, 23 healthy volunteers were subjected to four different conditions: control; indomethacin; public speech and anticipation of electroshocks. In a second study, five test conditions were investigated in 13 volunteers: control; after pretreatment with disodium cromoglycate (DSCG); administration of CRH; DSCG+CRH and DSCG+public speech.
Indomethacin, as a positive comparator (0.071±0.040 vs 0.030±0.022; p<0.0001), and public speech (0.059±0.040; p<0.01), but not the shock protocol increased intestinal permeability. Similarly, salivary cortisol was only increased after public speech. Subgroup analysis demonstrated that the effect of public speech on permeability was only present in subjects with a significant elevation of cortisol. CRH increased the lactulose–mannitol ratio (0.042±0.021 vs 0.028±0.009; p=0.02), which was inhibited by the mast cell stabiliser DSCG. Finally, intestinal permeability was unaltered by public speech with DSCG pretreatment.
Acute psychological stress increases small intestinal permeability in humans. Peripheral CRH reproduces the effect of stress and DSCG blocks the effect of both stress and CRH, suggesting the involvement of mast cells. These findings provide new insight into the complex interplay between the central nervous system and GI function in man.
Enteric glia activation has been reported to amplify intestinal inflammation via the enteroglial-specific S100B protein. This neurotrophin promotes macrophage recruitment in the mucosa, amplify colonic inflammation and interacts with toll-like receptors (TLR). Molecules inhibiting S100B-driven enteric activation might mitigate the course of ulcerative colitis (UC). This study aims to investigate the effects of palmitoylethanolammide (PEA), a drug able to counteract astroglial activation in the central nervous system, on intestinal inflammation, in humans and mice.
Mouse models of dextran sodium sulphate (DSS)-induced colitis, colonic biopsies deriving from UC patients and primary cultures of mouse and human enteric glial cells (EGC), have been used to assess the effects of PEA, alone or in the presence of specific PPARα or PPAR antagonists, on: macroscopic signs of UC (DAI score, colon length, spleen weight, macrophages/neutrophils infiltration); the expression and release of proinflammatory markers typical of UC; TLR pathway in EGCs.
PEA treatment improves all macroscopic signs of UC and decreases the expression and release of all the proinflammatory markers tested. PEA anti-inflammatory effects are mediated by the selective targeting of the S100B/TLR4 axis on ECG, causing a downstream inhibition of nuclear factor kappa B (NF-kB)-dependent inflammation. Antagonists at PPARα, but not PPAR, abolished PEA effects, in mice and in humans.
Because of its lack of toxicity, its ability in reducing inflammation and its selective PPARα action, PEA might be an innovative molecule to broaden pharmacological strategies against UC.
Non-oxidative metabolism of ethanol (NOME) produces fatty acid ethyl esters (FAEEs) via carboxylester lipase (CEL) and other enzyme action implicated in mitochondrial injury and acute pancreatitis (AP). This study investigated the relative importance of oxidative and non-oxidative pathways in mitochondrial dysfunction, pancreatic damage and development of alcoholic AP, and whether deleterious effects of NOME are preventable.
Intracellular calcium ([Ca2+]C), NAD(P)H, mitochondrial membrane potential and activation of apoptotic and necrotic cell death pathways were examined in isolated pancreatic acinar cells in response to ethanol and/or palmitoleic acid (POA) in the presence or absence of 4-methylpyrazole (4-MP) to inhibit oxidative metabolism. A novel in vivo model of alcoholic AP induced by intraperitoneal administration of ethanol and POA was developed to assess the effects of manipulating alcohol metabolism.
Inhibition of OME with 4-MP converted predominantly transient [Ca2+]C rises induced by low ethanol/POA combination to sustained elevations, with concurrent mitochondrial depolarisation, fall of NAD(P)H and cellular necrosis in vitro. All effects were prevented by 3-benzyl-6-chloro-2-pyrone (3-BCP), a CEL inhibitor. 3-BCP also significantly inhibited rises of pancreatic FAEE in vivo and ameliorated acute pancreatic damage and inflammation induced by administration of ethanol and POA to mice.
A combination of low ethanol and fatty acid that did not exert deleterious effects per se became toxic when oxidative metabolism was inhibited. The in vitro and in vivo damage was markedly inhibited by blockade of CEL, indicating the potential for development of specific therapy for treatment of alcoholic AP via inhibition of FAEE generation.
Little is known about the long-term clinical outcome and durability of HBsAg seroclearance following nucleos(t)ide analogue (NUC) therapy in patients with chronic hepatitis B (CHB).
During a median follow-up period of 6 years (33 567 patient-years) of 5409 CHB patients who were initially treated with lamivudine or entecavir, a total of 110 achieved HBsAg seroclearance (0.33% annual seroclearance rate) and were included in this study.
Baseline alanine aminotransferase (ALT) level >5 times of upper limit of normal was associated with higher probability of HBsAg seroclearance (HR 1.80, p<0.01), while HBeAg positivity (HR 0.46, p<0.01), high HBV DNA level (log10 IU/mL; HR 0.61, p<0.01), and cirrhosis (HR 0.48, p<0.01) were inversely associated with the probability of HBsAg seroclearance by multivariable analysis. During follow-up for 287 patient-years after HBsAg seroclearance, only two patients with baseline cirrhosis developed hepatocellular carcinoma (HCC) or died (0.7% annual risk), which was of a significantly lower rate compared with propensity score-matched patients without HBsAg seroclearance (HR 0.09, p<0.01). HBsAg reversion and/or HBV DNA reversion occurred in 18 patients, most of which were transient with extremely low serum levels of HBsAg (0.05–1.00 IU/mL) and HBV DNA (17-1818 IU/mL). None required retreatment. The cumulative probability of anti-HBs seroconversion (detection of anti-HBs) at 4 years was 67.4% by Kaplan–Meier analysis. Selection for lamivudine-resistance HBV mutants during treatment was not associated with composite reversion (p=0.66).
HBsAg seroclearance achieved after NUC treatment was associated with favourable clinical outcomes and was durable in most cases during long-term follow-up.
Smoothened (SMO), a coreceptor of the Hedgehog (Hh) pathway, promotes fibrogenic repair of chronic liver injury. We investigated the roles of SMO+ myofibroblast (MF) in liver regeneration by conditional deletion of SMO in α smooth muscle actin (αSMA)+ cells after partial hepatectomy (PH).
αSMA-Cre-ERT2xSMO/flox mice were treated with vehicle (VEH) or tamoxifen (TMX), and sacrificed 24–96 h post-PH. Regenerating livers were analysed for proliferation, progenitors and fibrosis by qRT-PCR and quantitative immunohistochemistry (IHC). Results were normalised to liver segments resected at PH. For lineage-tracing studies, αSMA-Cre-ERT2xROSA-Stop-flox-yellow fluorescent protein (YFP) mice were treated with VEH or TMX; livers were stained for YFP, and hepatocytes isolated 48 and 72 h post-PH were analysed for YFP by flow cytometric analysis (FACS).
Post-PH, VEH-αSMA-SMO mice increased expression of Hh-genes, transiently accumulated MF, fibrosis and liver progenitors, and ultimately exhibited proliferation of hepatocytes and cholangiocytes. In contrast, TMX-αSMA-SMO mice showed loss of whole liver SMO expression, repression of Hh-genes, enhanced accumulation of quiescent HSC but reduced accumulation of MF, fibrosis and progenitors, as well as inhibition of hepatocyte and cholangiocyte proliferation, and reduced recovery of liver weight. In TMX-αSMA-YFP mice, many progenitors, cholangiocytes and up to 25% of hepatocytes were YFP+ by 48–72 h after PH, indicating that liver epithelial cells were derived from αSMA-YFP+ cells.
Hh signalling promotes transition of quiescent hepatic stellate cells to fibrogenic MF, some of which become progenitors that regenerate the liver epithelial compartment after PH. Hence, scarring is a component of successful liver regeneration.
A 55-year-old man was admitted with a 3-week history of haematemesis with abdominal and back pain. He had a background of severe alcohol related pancreatitis 5 years previously and possible gastric varices. At presentation he was shocked (pulse 127, blood pressure 94/68, lactate 7.1 mM). Haemoglobin 8.0 g/L, platelet count 447 000/µL, liver function tests and coagulation were normal. After resuscitation and antibiotics he underwent oesophagogastroduodenoscopy in the Intensive Care Unit. Fresh blood was seen in the stomach, with thrombus adherent to an ulcer on a raised area of mucosa at the incisura (figure 1A). During therapeutic adrenaline injection, the needle was suspected of penetrating through the ulcer, and further therapy was halted. No free air was seen on erect chest X-ray. Subsequently, despite intravenous esomeprazole (8 mg/h), the patient continued to bleed and repeat oesophagogastroduodenoscopy was performed. Similar endoscopic features were seen and further submucosal injection of adrenaline...
Limited pools of resident adult stem cells are critical effectors of epithelial renewal in the intestine throughout life. Recently, significant progress has been made regarding the isolation and in vitro propagation of fetal and adult intestinal stem cells in mammals. It is now possible to generate ever-expanding, three-dimensional epithelial structures in culture that closely parallel the in vivo epithelium of the intestine. Growing such organotypic epithelium ex vivo facilitates a detailed description of endogenous niche factors or stem-cell characteristics, as they can be monitored in real time. Accordingly, this technology has already greatly contributed to our understanding of intestinal adult stem-cell renewal and differentiation. Transplanted organoids have also been proven to readily integrate into, and effect the long-term repair of, mouse colonic epithelia in vivo, establishing the organoid culture as a promising tool for adult stem cell/gene therapy. In another exciting development, novel genome-editing techniques have been successfully employed to functionally repair disease loci in cultured intestinal stem cells from human patients with a hereditary defect. It is anticipated that this technology will be instrumental in exploiting the regenerative medicine potential of human intestinal stem cells for treating human disorders in the intestinal tract and for creating near-physiological ex vivo models of human gastrointestinal disease.
The identification of a distinct syndrome, designated eosinophilic oesophagitis (EoE), with its own clinical and histopathological characteristics, was first described in the early 1990s. Meanwhile intense research has uncovered many molecular, immunological and clinical aspects of this chronic-inflammatory disorder. This article focuses exclusively on basic and clinical insights of EoE gathered during the last few years. Regarding aetiopathogenesis it has become clear that EoE is a food-triggered disease with milk and wheat as the dominant culprit food categories. However, it is still debated whether a disturbed mucosal integrity allowing allergens to cross the mucosal barrier, or changes in wheat and milk manufacturing might induce these inflammatory responses. Furthermore, basic science and clinical studies have accordingly confirmed that a chronic eosinophilic inflammation leads to a remodelling of the oesophagus with micro- and macro-morphological alterations, ending in a strictured oesophagus with impaired function. Fortunately, long-term therapeutic trials, using either topical corticosteroids or dietary allergen avoidance, have demonstrated that this sequela can be prevented or even reversed. This finding is of clinical relevance as it supports the initiation of a consistent anti-inflammatory therapy. Nevertheless, EoE is still an enigmatic disease and the long list of unanswered questions will certainly stimulate further research.
Basic scienceThe goblet cell hits the spotlight: a key player in host-microbial interaction
Wlodarska M, Thaiss CA, Nowarski R, et al. NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion. Cell 2014;156:1045–59.
The inflammasome is a cytosolic complex of proteins that hold a key role in both homeostasis and disease development. There are several proteins in the complex, such as NLR proteins, ASC and caspase-1. NLRP6 is highly expressed in colonic epithelial cells and is important in epithelial restoration and repair, response to infection and regulation of microbial luminal communities. In fact, nlrp6–/– mice are associated with colitogenic microbiota in the crypt base, but the mechanisms behind this are not understood. In this study, nlrp6–/– mice were less able to clear infection by Citrobacter rodentium, although they did display the same robust mucosal immune response as wild-type mice, including expression of inflammasome-related cytokines...
We read with great interest the leading article by Rosselli et al1 which offers a contemporary perspective to the clinical issue of interpreting progression (and regression) of chronic liver diseases (CLDs).
We fully agree with the view that the histological scoring of fibrosis is a reductive approach to the assessment of CLDs, as it does not fully reflect the complex events involved in the progression to cirrhosis. As suggested by Rosselli et al, a more insightful morphological analysis of liver biopsy should consider other important factors contributing to disease progression/regression, and possibly to cancer development. Angiogenesis represents one of such key factors.
Liver angiogenesis is a pathophysiological process characterised by changes in the phenotype of sinusoidal endothelial cells, which assume the features of capillary endothelial cells. This process, known as sinusoidal capillarisation (SC), can be routinely assessed by CD34 immunostaining, that results negative in normal liver sinusoids...
We read with interest the article entitled ‘Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease’ written by Uhlig1 and published by Gut. The study, describing the very early onset of intestinal inflammation in several orphan monogenic diseases, aimed at determining the presence of a link between the IBD-like phenotype shown by these rare diseases and the intestinal inflammation seen in typical IBD. The IBD aetiology is multifactorial: at present, genome-wide association studies have identified 163 susceptibility loci associated with an increased risk of developing IBD.2 Beside these identified genetic loci that provide little contribution to explain IBD hereditability, the number of monogenic diseases presenting IBD-like symptoms is however continuously increasing. These monogenic diseases usually exhibit very early onset and very severe symptoms; in addition, they are often unresponsive to common drugs (anti-inflammatory and immunosuppressive treatments, such as...
Schernhammer ES, Giovannucci E, Kawasaki T, et al. Dietary folate, alcohol and B vitamins in relation to LINE-1 hypomethylation in colon cancer. Gut 2010;59:794–9. In table 3, the correct unit for energy-adjusted daily vitamin B12 intake was "mg per day", but not "g per day". This error did not alter the results (other than unit), interpretation of the data or the authors' conclusions.