Approximately 50% of hepatocellular carcinoma (HCC) worldwide is attributed to chronic HBV infection.1 Data from the population-based Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-HBV REVEAL-HBV study showed that high levels of serum HBV DNA are associated with increased risk of cirrhosis, HCC and liver-related mortality.2 The REVEAL-HBV study also demonstrated that among hepatitis B surface antigen positive persons with high levels of HBV DNA at enrolment, the risk of HCC was lower in those who had decline in HBV DNA levels during follow-up compared with those with persistently high levels of HBV DNA. These data suggest that antiviral therapy may decrease the risk of HCC through suppression of HBV replication.
There has been only one randomised controlled trial of nucleos(t)ide analogue (NUC) treatment in patients with chronic hepatitis B (CHB) with HCC as one of the predefined outcomes.3 This study...
Liver fibrosis develops as a result of an excessive accumulation of extracellular matrix mostly in the context of chronic liver injury. The progression of liver fibrosis may lead to the development of cirrhosis and eventually hepatocellular carcinoma. Only in recent years has angiogenesis been considered as a concomitant process along the progression of liver fibrosis.1 Moreover, angiogenesis has been shown to be of key importance during the development, growth and progression of hepatocellular carcinoma, one of the most vascularised tumours. However, whether angiogenesis determines the progression of liver fibrosis or is merely a consequence of fibrosis progression is still unclear.
The progression from early stages of fibrosis to cirrhosis is by definition, accompanied by structural and anatomical changes in the liver affecting liver perfusion and compromising oxygen supply. Moreover, deposition of extracellular matrix at the space of Disse prevents oxygen diffusion and promotes sinusoidal capillarisation.
Abdominal pain is one of the most difficult to treat symptoms in patients suffering from IBS. Recent evidence shows that abnormal perception of visceral stimuli, or visceral hypersensitivity, represents an important underlying mechanism. Of interest, similar mechanisms may be involved in abdominal pain reported by UC and Crohn's disease patients in remission. Although the underlying mechanisms are not fully understood, it becomes increasingly clear that intestinal inflammation may provide an initial stimulus for a persistent state of visceral hypersensitivity. Most insight in the role of inflammation in chronic abdominal pain comes from studies evaluating patients with postinfectious (PI)-IBS. Colonic biopsies of patients with PI-IBS reveal no signs of overt inflammation but show persistent minor increases in epithelial T lymphocytes and mast cells,1 suggesting that long-term inflammatory changes may be responsible for colonic hypersensitivity. To date, mast cells are considered to play a key role in this process....
Cougnoux and colleagues1 report a new mechanism by which select bacteria can drive colon cancer. Specifically, they discovered that colobactin-producing E. coli strains can activate growth-arrested (ie, senescent) cells to produce growth factors that drive tumor growth. These findings may, in part, underlie the association of such bacteria with carcinomas and could result in novel strategies to slow tumor growth.
Approximately 20% of cancers are considered to be a consequence of infection by bacteria and/or viruses typically classified as pathogens. Moreover, many cancers occur in tissues with high exposure to microbiota, such as colorectal cancers (CRC), suggesting microbes not typically thought of as pathogens in promoting carcinogenesis. For example, mucosa-associated Escherichia coli are present more frequently in colon tissue from patients with adenocarcinomas than in control subjects. While E. coli are typically present in the intestine of healthy persons, various strains of E. coli have ‘pathogen-like...
The GI tract is colonised by trillions of bacteria in a complex community collectively referred to as the gut microbiota. This metabolically active ‘foreign’ body contributes to host metabolism and immune system development and changes in its composition have been implicated in many chronic diseases including obesity and diabetes. Under normal conditions, this metabolically active ‘foreign’ body exists in a state of symbiotic tolerance (eubiosis) with its host and remains relatively stable over time. One of the major influences on the gut microbiota, at least in terms of our ability to modulate it, is diet. There is growing awareness that diet and lifestyle choices have a profound impact on the gut microbiota.1
The relationship between gut microbes and nutritional status is complex and has been a long-standing subject of intense debate. The composition of the gut microbiota is known to determine the efficacy of energy harvest from...
Hepcidin, a 25-amino acid peptide expressed almost exclusively in the liver, is the central regulator of systemic body iron homeostasis. Since its initial identification and characterisation as an antimicrobial peptide, it has become clear that hepcidin plays a role in many metabolic processes. Mutations in hepcidin lead to one form of the severe iron overload disorder juvenile haemochromatosis (type 2B). Hepcidin is a negative regulator of iron absorption and recycling; under normal conditions, increased iron in the body results in an enhanced secretion of hepcidin by the liver, the central organ responsible for iron regulation. Hepcidin then binds the iron transporter ferroportin, inducing its internalisation and degradation, thus reducing iron absorption by enterocytes of the duodenum, and iron recycling by macrophages.1 Hepcidin itself is also regulated by other factors besides iron levels; these include hypoxia, erythropoietic activity, proinflammatory cytokines and other hormones.2 These factors thus...
The treatment of IBD has evolved significantly over the past 15 years. Historically, steroids and immunosuppressive drugs, such as methotrexate (MTX), azathioprine (AZA) and 6-mercaptopurine (6-MP) had been the mainstay of therapy. When infliximab (IFX) was approved for the treatment of Crohn's disease, it began the era of trying to understand how best to optimise our available treatment options. Initially, antitumour necrosis factor (anti-TNF) agents were used after immunosuppressives failed. Then, evidence showed that using AZA together with IFX early in the disease course was more effective than the typical sequential treatment algorithm.1 With the addition of newer anti-TNF drugs and development of different treatment regimens,2–5 there are still significant questions related to the most effective therapeutic strategy. Perhaps the most controversial of these questions is when to use anti-TNF monotherapy versus combination therapy with 6-MP, AZA or...
Barrett's oesophagus shows appearances described as ‘intestinal metaplasia’, in structures called ‘crypts’ but do not typically display crypt architecture. Here, we investigate their relationship to gastric glands.
Cell proliferation and migration within Barrett's glands was assessed by Ki67 and iododeoxyuridine (IdU) labelling. Expression of mucin core proteins (MUC), trefoil family factor (TFF) peptides and LGR5 mRNA was determined by immunohistochemistry or by in situ hybridisation, and clonality was elucidated using mitochondrial DNA (mtDNA) mutations combined with mucin histochemistry.
Proliferation predominantly occurs in the middle of Barrett's glands, diminishing towards the surface and the base: IdU dynamics demonstrate bidirectional migration, similar to gastric glands. Distribution of MUC5AC, TFF1, MUC6 and TFF2 in Barrett's mirrors pyloric glands and is preserved in Barrett's dysplasia. MUC2-positive goblet cells are localised above the neck in Barrett's glands, and TFF3 is concentrated in the same region. LGR5 mRNA is detected in the middle of Barrett's glands suggesting a stem cell niche in this locale, similar to that in the gastric pylorus, and distinct from gastric intestinal metaplasia. Gastric and intestinal cell lineages within Barrett's glands are clonal, indicating derivation from a single stem cell.
Barrett's shows the proliferative and stem cell architecture, and pattern of gene expression of pyloric gastric glands, maintained by stem cells showing gastric and intestinal differentiation: neutral drift may suggest that intestinal differentiation advances with time, a concept critical for the understanding of the origin and development of Barrett's oesophagus.
Patients with high Rockall scores have increased risk of ulcer rebleeding after 3-day esomeprazole infusions.
To investigate whether double oral esomeprazole given after a 3-day esomeprazole infusion decreases ulcer rebleeding for patients with high Rockall scores.
We prospectively enrolled 293 patients with peptic ulcer bleeding who had achieved endoscopic haemostasis. After a 3-day esomeprazole infusion, patients with Rockall scores ≥6 were randomised into the oral double-dose group (n=93) or the oral standard-dose group (n=94) to receive 11 days of oral esomeprazole 40 mg twice daily or once daily, respectively. The patients with Rockall scores <6 served as controls (n=89); they received 11 days of oral esomeprazole 40 mg once daily. Thereafter, all patients received oral esomeprazole 40 mg once daily for two more weeks until the end of the 28-day study period. The primary end point was peptic ulcer rebleeding.
Among patients with Rockall scores ≥6, the oral double-dose group had a higher cumulative rebleeding-free proportion than the oral standard-dose group (p=0.02, log-rank test). The proportion of patients free from recurrent bleeding during the 4th–28th day in the oral double-dose group remained lower than that of the group with Rockall scores <6 (p=0.03, log-rank test). Among patients with Rockall scores ≥6, the rebleeding rate was lower in the oral double-dose group than in the oral standard-dose group (4th–28th day: 10.8% vs 28.7%, p=0.002).
Double oral esomeprazole at 40 mg twice daily after esomeprazole infusion reduced recurrent peptic ulcer bleeding in high-risk patients with Rockall scores ≥6.
Substantial evidence implicates mast cells and their main constituent histamine in the pathogenesis of visceral hypersensitivity. We explored the specific contribution of histamine H4 (H4R) and H1 (H1R) receptors to visceral hypersensitivity in a postinflammatory rat model.
Trinitrobenzenesulfonic acid (TNBS)-colitis was monitored individually by colonoscopy: first on day 3 to confirm the presence of colitis and then every 4 days, starting from day 10, to monitor convalescence and determine the exact timepoint of endoscopic healing in each rat. Experiments were performed 3 days after endoscopic resolution of colitis. Visceral sensitivity was assessed by quantifying visceromotor responses (VMRs) to colorectal distension. Colonic mast cell numbers, histamine release and H4R and H1R mRNA expression were quantified. JNJ7777120 (H4R antagonist) and/or levocetirizine (H1R antagonist) were administered 30 min prior to VMR assessment or histamine release assay.
Postcolitis rats displayed a higher number of colonic mast cells, excessive histamine release and significantly enhanced VMRs. Heightened VMRs were dose-dependently reduced by JNJ7777120 and levocetirizine; combined administration of JNJ7777120 and levocetirizine potentiated the antinociceptive effect. In the colon, both H4R and H1R mRNA were present; in the dorsal root ganglia, only H1R mRNA was found. Only colonic H4R mRNA expression was increased in postcolitis rats. Excessive histamine release in postcolitis rats was attenuated by the highest dose of JNJ7777120.
H4R and H1R antagonists dose-dependently reduce and even normalise postinflammatory visceral hypersensitivity via different underlying mechanisms but with a synergistic effect. Both receptor subtypes represent promising targets for the treatment of postinflammatory visceral hypersensitivity.
The dysfunction of immune regulation plays a critical role in the pathogenesis of a number of chronic inflammatory disorders, such as IBD. A close relationship between psychological stress and intestinal inflammation has been noted; the underlying mechanism remains elusive. This study aims to elucidate a pathological pathway between psychological stress and the dysfunction of regulatory T cells (Treg), and its effect on facilitating intestinal inflammation.
A restraint stress model was employed to induce psychological stress in mice. The functions of Tregs were determined by assessing the immune suppressor effects in the intestine. A mouse model of intestinal inflammation was established using a low dose of trinitrobenzene sulfonic acid (TNBS) or dextran sulfate sodium (DSS) together with the challenge of chronic stress.
After treating mice with restraint stress, the suppressor function of intestinal Treg was compromised, although the frequency of Treg was not changed in the intestine. Further observation revealed that stress induced Tregs in the intestine to differentiate into foxhead box P3+ interleukin (IL)-17+ tumour necrosis factor (TNF)-α+ T cells. We also observed that exposure to stress-derived prolactin induced dendritic cells (DC) to produce IL-6 and IL-23 in vitro and in vivo, which played a critical role in altering Treg's phenotypes. Treating mice with chronic stress facilitated the initiation of intestinal inflammation by a low dose of TNBS or DSS, which was abolished by pretreatment with an inhibitor of prolactin, the cabergoline.
Psychological stress-derived prolactin alters DC and Treg's properties to contribute to intestinal inflammation.
α-Haemolysin (HlyA) influences host cell ionic homeostasis and causes concentration-dependent cell lysis. As a consequence, HlyA-producing Escherichia coli is capable of inducing ‘focal leaks’ in colon epithelia, through which bacteria and antigens translocate. This study addressed the role of HlyA as a virulence factor in the pathogenesis of colitis according to the ‘leaky gut’ concept.
To study the action of HlyA in the colon, we performed oral administration of HlyA-expressing E coli-536 and its isogenic α-haemolysin-deficient mutant (HDM) in three mouse models: wild type, interleukin-10 knockout mice (IL-10–/–) and monoassociated mice. Electrophysiological properties of the colonised colon were characterised in Ussing experiments. Inflammation scores were evaluated and focal leaks in the colon were assessed by confocal laser-scanning microscopy. HlyA quantity in human colon biopsies was measured by quantitative PCR.
All three experimental mouse models infected with HlyA-producing E coli-536 showed an increase in focal leak area compared with HDM. This was associated with a decrease in transepithelial electrical resistance and an increase in macromolecule uptake. As a consequence, inflammatory activity index was increased to a higher degree in inflammation-prone mice. Mucosal samples from human colon were E coli HlyA-positive in 19 of 22 patients with ulcerative colitis, 9 of 9 patients with Crohn's disease and 9 of 12 healthy controls. Moreover, focal leaks were found together with 10-fold increased levels of HlyA in active ulcerative colitis.
E coli HlyA impairs intestinal barrier function via focal leak induction in the epithelium, thereby intensifying antigen uptake and triggering intestinal inflammation in vulnerable mouse models. Therefore, HlyA-expressing E coli strains should be considered as potential cofactors in the pathogenesis of intestinal inflammation.
Intestinal fibrosis is a clinically important issue in Crohn's disease (CD). Heat shock protein (HSP) 47 is a collagen-specific molecular chaperone involved in fibrotic diseases. The molecular mechanisms of HSP47 induction in intestinal fibrosis related to CD, however, remain unclear. Here we investigated the role of interleukin (IL)-17A-induced HSP47 expression in intestinal fibrosis in CD.
Expressions of HSP47 and IL-17A in the intestinal tissues of patients with IBD were determined. HSP47 and collagen I expressions were assessed in intestinal subepithelial myofibroblasts (ISEMFs) isolated from patients with IBD and CCD-18Co cells treated with IL-17A. We examined the role of HSP47 in IL-17A-induced collagen I expression by administration of short hairpin RNA (shRNA) to HSP47 and investigated signalling pathways of IL-17A-induced HSP47 expression using specific inhibitors in CCD-18Co cells.
Gene expressions of HSP47 and IL-17A were significantly elevated in the intestinal tissues of patients with active CD. Immunohistochemistry revealed HSP47 was expressed in α-smooth muscle actin (α-SMA)-positive cells and the number of HSP47-positive cells was significantly increased in the intestinal tissues of patients with active CD. IL-17A enhanced HSP47 and collagen I expressions in ISEMFs and CCD-18Co cells. Knockdown of HSP47 in these cells resulted in the inhibition of IL-17A-induced collagen I expression, and analysis of IL-17A signalling pathways revealed the involvement of c-Jun N-terminal kinase in IL-17A-induced HSP47 expression.
IL-17A-induced HSP47 expression is involved in collagen I expression in ISEMFs, which might contribute to intestinal fibrosis in CD.
The commensal microbiota, host immunity and metabolism participate in a signalling network, with diet influencing each component of this triad. In addition to diet, many elements of a modern lifestyle influence the gut microbiota but the degree to which exercise affects this population is unclear. Therefore, we explored exercise and diet for their impact on the gut microbiota.
Since extremes of exercise often accompany extremes of diet, we addressed the issue by studying professional athletes from an international rugby union squad. Two groups were included to control for physical size, age and gender. Compositional analysis of the microbiota was explored by 16S rRNA amplicon sequencing. Each participant completed a detailed food frequency questionnaire.
As expected, athletes and controls differed significantly with respect to plasma creatine kinase (a marker of extreme exercise), and inflammatory and metabolic markers. More importantly, athletes had a higher diversity of gut micro-organisms, representing 22 distinct phyla, which in turn positively correlated with protein consumption and creatine kinase.
The results provide evidence for a beneficial impact of exercise on gut microbiota diversity but also indicate that the relationship is complex and is related to accompanying dietary extremes.
Intestinal epithelial cells (IECs) at the internal/external interface orchestrate the mucosal immune response. Paneth cells secrete antimicrobial peptides and inflammatory mediators, protect from pathogens and shape the commensal microbiota. Prompted by the genetic association of the locus harbouring the type I interferon (IFN) receptor (IFNAR1) with Crohn's disease, and a transcriptional signature for type I IFN signalling in Paneth cells, we studied the function of IFNAR1 in IECs.
Type I IFN signalling was studied in mice with conditional deletion of Ifnar1 in IECs. Phenotype was characterised at baseline, and gut microbiota composition was assessed by 16S rDNA ribotyping. The role of IFNAR1 was also investigated in experimental colitis induced by dextran sodium sulfate (DSS) and colitis-associated cancer induced by DSS in conjunction with azoxymethane (AOM).
Ifnar1–/–(IEC) mice displayed expansion of Paneth cell numbers and epithelial hyperproliferation compared with Ifnar1-sufficient littermates. While Ifnar1–/–(IEC) mice did not exhibit spontaneous inflammation or increased severity in DSS colitis compared with Ifnar1+/+(IEC) mice, they exhibited an increased tumour burden in the AOM/DSS model. Both hyperproliferation and tumour promotion were dependent on the microbial flora, as the differences between genotypes were marked upon separately housing mice, but disappeared when Ifnar1–/–(IEC) and Ifnar1+/+(IEC) mice were co-housed. Accordingly, ribotyping revealed marked differences between Ifnar1–/–(IEC) and Ifnar1+/+(IEC) mice that where diminished upon co-housing.
IFNAR1 in IECs, and Paneth cells in particular, contributes to the regulation of the host–microbiota relationship, with consequences for intestinal regeneration and colitis-associated tumour formation.
Escherichia coli strains harbouring the pks island (pks+ E. coli) are often seen in human colorectal tumours and have a carcinogenic effect independent of inflammation in an AOM/IL-10–/– (azoxymethane/interleukin) mouse model.
To investigate the mechanism sustaining pks+ E. coli-induced carcinogenesis.
Underlying cell processes were investigated in vitro and in vivo (xenograft model) using intestinal epithelial cells infected by pks+ E. coli or by an isogenic mutant defective for pks (pks– E. coli). The results were supported by data obtained from an AOM/DSS (azoxymethane/dextran sodium sulphate) colon cancer mouse model and from human colon cancer biopsy specimens colonised by pks+ E. coli or pks– E. coli.
Colibactin-producing E. coli enhanced tumour growth in both xenograft and AOM/DSS models. Growth was sustained by cellular senescence (a direct consequence of small ubiquitin-like modifier (SUMO)-conjugated p53 accumulation), which was accompanied by the production of hepatocyte growth factor (HGF). The underlying mechanisms involve microRNA-20a-5p, which targets SENP1, a key protein regulating p53 deSUMOylation. These results are consistent with the expression of SENP1, microRNA-20a-5p, HGF and phosphorylation of HGF receptor found in human and mouse colon cancers colonised by pks+ E. coli.
These data reveal a new paradigm for carcinogenesis, in which colibactin-induced senescence has an important role.
It is generally stated that oral antiviral therapy in patients with chronic hepatitis B (CHB) decreases the risk of developing hepatocellular carcinoma (HCC). Although oral nucleos(t)ide analogues (NUCs) may induce a state similar to inactive stage CHB, the long-term risk for HCC in patients treated with NUCs compared with inactive CHB is unclear.
A total of 1378 patients who were treatment naïve and started NUC therapy and 1014 patients with inactive stage CHB who were HBeAg-negative and continuously had hepatitis B DNA <2000 IU/mL during follow-up were enrolled. The NUC group was divided into two groups by continuous viral suppression: NUC complete responder (CR) group and NUC incomplete responder (IR) group. Cumulative HCC incidence rates were compared between the groups.
The risk of developing HCC was significantly higher in the NUC CR group compared with the inactive CHB group, regardless of the presence of baseline liver cirrhosis (p<0.001). Risk factors associated with the development of HCC were treatment groups (p<0.001), age (p<0.001), sex (p<0.001) and the presence of liver cirrhosis at baseline (p=0.005). Of the NUC group, the cumulative incidence of HCC in the NUC IR group was significantly higher compared with the NUC CR group (p=0.028).
The use of potent oral antiviral therapy can effectively suppress HBV replication in patients with CHB. However, the risk of HCC development in patients treated with oral antiviral agent is still significantly higher than patients with inactive stage CHB.
Hypoxia affects body iron homeostasis; however, the underlying mechanisms are incompletely understood.
Using a standardised hypoxia chamber, 23 healthy volunteers were subjected to hypoxic conditions, equivalent to an altitude of 5600 m, for 6 h. Subsequent experiments were performed in C57BL/6 mice, CREB-H knockout mice, primary hepatocytes and HepG2 cells.
Exposure of subjects to hypoxia resulted in a significant decrease of serum levels of the master regulator of iron homeostasis hepcidin and elevated concentrations of platelet derived growth factor (PDGF)-BB. Using correlation analysis, we identified PDGF-BB to be associated with hypoxia mediated hepcidin repression in humans. We then exposed mice to hypoxia using a standardised chamber and observed downregulation of hepatic hepcidin mRNA expression that was paralleled by elevated serum PDGF-BB protein concentrations and higher serum iron levels as compared with mice housed under normoxic conditions. PDGF-BB treatment in vitro and in vivo resulted in suppression of both steady state and BMP6 inducible hepcidin expression. Mechanistically, PDGF-BB inhibits hepcidin transcription by downregulating the protein expression of the transcription factors CREB and CREB-H, and pharmacological blockade or genetic ablation of these pathways abrogated the effects of PDGF-BB toward hepcidin expression.
Hypoxia decreases hepatic hepcidin expression by a novel regulatory pathway exerted via PDGF-BB, leading to increased availability of circulating iron that can be used for erythropoiesis.
In chronic liver injury, angiogenesis, the formation of new blood vessels from pre-existing ones, may contribute to progressive hepatic fibrosis and to development of hepatocellular carcinoma. Although hypoxia-induced expression of vascular endothelial growth factor (VEGF) occurs in advanced fibrosis, we hypothesised that inflammation may endorse hepatic angiogenesis already at early stages of fibrosis.
Angiogenesis in livers of c57BL/6 mice upon carbon tetrachloride- or bile duct ligation-induced chronic hepatic injury was non-invasively monitored using in vivo contrast-enhanced micro computed tomography (µCT) and ex vivo anatomical µCT after hepatic Microfil perfusion. Functional contributions of monocyte-derived macrophage subsets for angiogenesis were explored by pharmacological inhibition of CCL2 using the Spiegelmer mNOX-E36.
Contrast-enhanced in vivo µCT imaging allowed non-invasive monitoring of the close correlation of angiogenesis, reflected by functional hepatic blood vessel expansion, with experimental fibrosis progression. On a cellular level, inflammatory monocyte-derived macrophages massively accumulated in injured livers, colocalised with newly formed vessels in portal tracts and exhibited pro-angiogenic gene profiles including upregulated VEGF and MMP9. Functional in vivo and anatomical ex vivo µCT analyses demonstrated that inhibition of monocyte infiltration by targeting the chemokine CCL2 prevented fibrosis-associated angiogenesis, but not fibrosis progression. Monocyte-derived macrophages primarily fostered sprouting angiogenesis within the portal vein tract. Portal vein diameter as a measure of portal hypertension depended on fibrosis, but not on angiogenesis.
Inflammation-associated angiogenesis is promoted by CCL2-dependent monocytes during fibrosis progression. Innovative in vivo µCT methodology can accurately monitor angiogenesis and antiangiogenic therapy effects in experimental liver fibrosis.
Gastroparesis is defined by the presence of delayed gastric emptying (GE) in the absence of mechanical obstruction. Symptoms that have been attributed to gastroparesis include postprandial fullness, early satiation nausea and vomiting. Gastroprokinetic drugs are the preferred treatment option. A number of problems with the concept of gastroparesis have been identified recently. Major overlap exists with the symptom complex of the functional dyspepsia subtype of postprandial distress syndrome. The distinguishing feature of gastroparesis is delayed GE, but the correlation between delayed emptying and symptom pattern or severity in gastroparesis is modest and the stability of delayed emptying over time is poor. Other pathophysiological mechanisms such as hypersensitivity or impaired accommodation may also underlie symptoms in patients with gastroparesis. Moreover, symptomatic response to prokinetic therapy is variable and cannot be predicted based on the degree of enhancing GE. A number of approaches have been proposed to increase clinical usefulness of a diagnosis of gastroparesis, including a higher threshold of abnormal emptying and selection of patients with a specific symptom pattern more likely to be associated with delayed emptying.
Canto MI, Harinck F, Hruban RH, et al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut 2013;62:339–47.
The Collaborator Pascal Hammell's name should read Pascal Hammel.
A previously fit and well 75-year-old Caucasian woman presented with a 2-month history of postprandial abdominal pain, vomiting and 10 kg weight loss without diarrhoea.
Blood investigations showed marked hypoalbuminaemia of 18 g/L and elevated C reactive protein (CRP) of 185 mg/L. Tissue transglutaminase IgA level was within normal limits without evidence of IgA deficiency. Faecal calprotectin was elevated at 205 µg/g.
Abdominal CT revealed subacute small bowel obstruction characterised by multiple long, thick walled, dilated loops of jejunum (figure 1) associated with lymphadenopathy. Histological findings from laparoscopic mesenteric lymph node resection showed reactive features only.
Intravenous hydrocortisone was started with subsequent symptomatic improvement in tolerated oral intake, paralleled by a reduction in CRP to 25 mg/L.
Antegrade double balloon enteroscopy (DBE) was performed to directly visualise the small bowel mucosa (figure 2).
Basic scienceMaintaining macrophage homeostasis in the intestine
Bain CC, Bravo-Blas A, Scott CL, et al. Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nat Immunol 2014;15:929–37.
Macrophages are essential for pathogen defence, tissue homeostasis and wound repair. The current paradigm that tissue resident macrophages (TRMs) derive from embryonic precursors and are independent of blood monocytes has never been studied in the intestine, which houses the largest pool of TRMs. In this study, the authors set out to investigate the origin of the intestinal TRM compartment in mice from birth until adulthood. Using a combination of immunotyping, lineage tracing and parabiosis techniques, the authors demonstrated that macrophages in the intestine are an exception to this paradigm. Specifically, intestinal macrophages under steady-state conditions are continuously replenished by blood-derived monocytes even though the yolk sac-derived macrophages are seeded to the gut tissue...