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Gut

GORD has been defined by international consensus based on symptoms of heartburn and regurgitation.1 While this definition is useful for patients with the typical reflux syndrome, these symptoms may not be present in patients with extra-oesophageal GORD. The limitations of pH testing and endoscopy were highlighted in a recent study that demonstrated that each failed to identify approximately 30% of patients with proven GORD.2 A test that establishes a diagnosis of GORD at low cost with minimal intervention would have great utility. The presence of pepsin in saliva or sputum has been proposed as a surrogate marker for reflux disease, albeit one that tells us nothing about a causal relationship between reflux and symptoms.

Pepsin may be detected in sputum or saliva by enzymatic or immunological tests.3 Enzymatic tests have several limitations and are difficult to obtain and standardise in practice settings. Attention...


In theory, any step of the hepatitis C virus (HCV) lifecycle can be a target for direct-acting antiviral (DAA) drugs (drugs that directly block a viral function), and/or host-targeted agents (HTA, drugs that block a cellular function essential to the viral lifecycle). Four classes of HCV DAAs and two classes of HTAs have reached late clinical development. The HCV DAAs include: inhibitors of the NS3/4A protease that block HCV polyprotein processing; inhibitors of the RNA-dependent RNA polymerase (RdRp), including nucleoside/nucleotide analogues and non-nucleoside inhibitors that block viral replication; and NS5A inhibitors that block viral replication, virion assembly and release. The HCV HTAs in development interact with cellular factors required for HCV replication; they include cyclophilin A inhibitors and microRNA-122 antagonists.1

In 2014, three drugs were approved in the European Union, including the nucleotide analogue sofosbuvir, the protease inhibitor simeprevir and the NS5A inhibitor daclatasvir. They can be...


Chronic infection with the hepatitis C virus (HCV) is a slow progressive disease. While fibrosis development may not be linear over time, it has been estimated that 15–20% of patients will establish cirrhosis within 20 years of HCV acquisition.1 Once cirrhosis is present, it is clear that the patient's prognosis is heavily affected, with a 3–5% annual risk of liver failure as well as hepatocellular carcinoma (HCC). Although liver transplantation may be lifesaving in selected cases, organ shortage remains an important limitation. As a result, cirrhosis-related complications are considered to be one of the main reasons why chronic HCV infection is associated with an impaired overall survival.2 Fortunately, many HCV-infected patients are not expected to develop advanced hepatic fibrosis. Are these patients unaffected by the virus? Probably not. Chronic HCV infection remains a multifaceted disease, which is not restricted to the liver. Patients may experience a...


Introduction

IBD, which primarily includes UC and Crohn's disease (CD), is a progressive, chronic and relapsing condition. This debilitating disease is steadily becoming a worldwide medical concern, with increasing prevalence and incidence in both industrialised and developing countries.1 While the exact aetiology of the disease remains unknown, genetic predisposition and various environmental and immunological causes have been identified as contributing factors.2 Generally, IBD is characterised by a dysregulated excessive immune response and tissue damage in the GI tract.3 4 This aberrant and sustained immune response is thought to be mainly facilitated by defects in the function of the intestinal epithelial barrier and in the regulation of mucosal immunity.5 Yet, tissue damage associated with IBD is commonly considered solely a downstream effect and not a contributing factor. This view has led to a concentrated focus on the development of...


Objective

Current diagnostic methods for gastro-oesophageal reflux disease (GORD) have moderate sensitivity/specificity and can be invasive and expensive. Pepsin detection in saliva has been proposed as an ‘office-based’ method for GORD diagnosis. The aims of this study were to establish normal values of salivary pepsin in healthy asymptomatic subjects and to determine its value to discriminate patients with reflux-related symptoms (GORD, hypersensitive oesophagus (HO)) from functional heartburn (FH).

Design

100 asymptomatic controls and 111 patients with heartburn underwent MII-pH monitoring and simultaneous salivary pepsin determination on waking, after lunch and dinner. Cut-off value for pepsin positivity was 16 ng/mL. Patients were divided into GORD (increased acid exposure time (AET), n=58); HO (normal AET and + Symptom Association Probability (SAP), n=26) and FH (normal AET and—SAP, n=27).

Results

1/3 of asymptomatic subjects had pepsin in saliva at low concentration (0(0–59)ng/mL). Patients with GORD and HO had higher prevalence and pepsin concentration than controls (HO, 237(52–311)ng/mL and GORD, 121(29–252)ng/mL)(p<0.05). Patients with FH had low prevalence and concentration of pepsin in saliva (0(0–40) ng/mL). A positive test had 78.6% sensitivity and 64.9% specificity for diagnosis of GORD+HO (likelihood ratio: 2.23). However, one positive sample with >210 ng/mL pepsin suggested presence of GORD+HO with 98.2% specificity (likelihood ratio: 25.1). Only 18/84 (21.4%) of GORD+HO patients had 3 negative samples.

Conclusion

In patients with symptoms suggestive of GORD, salivary pepsin testing may complement questionnaires to assist office-based diagnosis. This may lessen the use of unnecessary antireflux therapy and the need for further invasive and expensive diagnostic methods.


Objective

The two major histological types of oesophageal cancer—adenocarcinoma (AC) and squamous cell carcinoma (SCC)—are known to differ greatly in terms of risk factors and epidemiology. To date, global incidence estimates for individual subtypes are still lacking. This study for the first time quantified the global burden of oesophageal cancer by histological subtype.

Design

Where available, data from Cancer Incidence in Five Continents Vol. X (CI5X) were used to compute, age-specific, sex-specific and country-specific proportions of AC and SCC. Nine regional averages were computed for countries without CI5X data. The proportions were then applied to all oesophageal cancer cases from GLOBOCAN 2012 and age-standardised incidence rates calculated for both histological types.

Results

Worldwide, an estimated 398 000 SCCs and 52 000 ACs of the oesophagus occurred in 2012, translating to incidence rates of 5.2 and 0.7 per 100 000, respectively. Although SCCs were most common in South-Eastern and Central Asia (79% of the total global SCC cases), the highest burden of AC was found in Northern and Western Europe, Northern America and Oceania (46% of the total global AC cases). Men had substantially higher incidence than women, especially in the case of AC (male to female ratio AC: 4.4; SCC: 2.7).

Conclusions

These first global estimates of oesophageal cancer incidence by histology suggested a high concentration of AC in high-income countries with men being at much greater risk. This quantification of incidence will aid health policy makers to plan appropriate cancer control measures in the future.


Background

Epigenetic alterations accumulate in normal-appearing tissues of patients with cancer, producing an epigenetic field defect. Cross-sectional studies show that the degree of the defect may be associated with risk in some types of cancer, especially cancers associated with chronic inflammation.

Objective

To demonstrate, by a multicentre prospective cohort study, that the risk of metachronous gastric cancer after endoscopic resection (ER) can be predicted by assessment of the epigenetic field defect using methylation levels.

Design

Patients with early gastric cancer, aged 40–80 years, who planned to have, or had undergone, ER, were enrolled at least 6 months after Helicobacter pylori infection discontinued. Methylation levels of three preselected genes (miR-124a-3, EMX1 and NKX6-1) were measured by quantitative methylation-specific PCR. Patients were followed up annually by endoscopy, and the primary endpoint was defined as detection of a metachronous gastric cancer. Authentic metachronous gastric cancers were defined as cancers excluding those detected within 1 year after the enrolment.

Results

Among 826 patients enrolled, 782 patients had at least one follow-up, with a median follow-up of 2.97 years. Authentic metachronous gastric cancers developed in 66 patients: 29, 16 and 21 patients at 1–2, 2–3 and ≥3 years after the enrolment, respectively. The highest quartile of the miR-124a-3 methylation level had a significant univariate HR (95% CI) (2.17 (1.07 to 4.41); p=0.032) and a multivariate-adjusted HR (2.30 (1.03 to 5.10); p=0.042) of developing authentic metachronous gastric cancers. Similar trends were seen for EMX1 and NKX6-1.

Conclusions

Assessment of the degree of an epigenetic field defect is a promising cancer risk marker that takes account of life history.


Objective

To clarify the effectiveness of second-look endoscopy (SLE) at preventing bleeding after gastric endoscopic submucosal dissection (ESD).

Design

A multicentre prospective randomised controlled non-inferiority trial was conducted at five referral institutions across Japan. Patients with a solitary gastric neoplasm were enrolled. Exclusion criteria were previous oesophagogastric surgery or radiation therapy; perforation and the administration of antithrombotics, steroids or non-steroidal anti-inflammatory drugs. Patients were assigned to the SLE group or the non-SLE group by a computer-generated random sequence after ESD and were treated perioperatively with a proton pump inhibitor. SLE was performed one day after ESD. The primary endpoint was post-ESD bleeding, defined as an endoscopically proven haemorrhage. The trial had the power to detect a non-inferiority criterion of 7% between the groups.

Results

From February 2012 to February 2013, 130 and 132 patients were assigned to the SLE and the non-SLE groups, respectively. All patients were included in the intention-to-treat analysis of the primary endpoint. Post-ESD bleeding occurred in seven patients with (5.4%) SLE and five patients with (3.8%) non-SLE (risk difference –1.6% (95% CI –6.7 to 3.5); pnon-inferiority<0.001), meeting the non-inferiority criterion. All 12 patients with post-ESD bleeding and one patient with a delayed perforation were successfully managed with conservative treatment.

Conclusions

SLE after gastric ESD is not routinely recommended because it does not contribute to the prevention of post-ESD bleeding for patients with an average bleeding risk.

Trial registration number

UMIN-CTR000007170.


Objective

Intestinal dysbiosis has been associated with coeliac disease (CD), but whether the alterations are cause or consequence of the disease is unknown. This study investigated whether the human leukocyte antigen (HLA)-DQ2 genotype is an independent factor influencing the early gut microbiota composition of healthy infants at family risk of CD.

Design

As part of a larger prospective study, a subset (n=22) of exclusively breastfed and vaginally delivered infants with either high genetic risk (HLA-DQ2 carriers) or low genetic risk (non-HLA-DQ2/8 carriers) of developing CD were selected from a cohort of healthy infants with at least one first-degree relative with CD. Infant faecal microbiota was analysed by 16S rRNA gene pyrosequencing and real time quantitative PCR.

Results

Infants with a high genetic risk had significantly higher proportions of Firmicutes and Proteobacteria and lower proportions of Actinobacteria compared with low-risk infants. At genus level, high-risk infants had significantly less Bifidobacterium and unclassified Bifidobacteriaceae proportions and more Corynebacterium, Gemella, Clostridium sensu stricto, unclassified Clostridiaceae, unclassified Enterobacteriaceae and Raoultella proportions. Quantitative real time PCR also revealed lower numbers of Bifidobacterium species in infants with high genetic risk than in those with low genetic risk.

In high-risk infants negative correlations were identified between Bifidobacterium species and several genera of Proteobacteria (Escherichia/Shigella) and Firmicutes (Clostridium).

Conclusions

The genotype of infants at family risk of developing CD, carrying the HLA-DQ2 haplotypes, influences the early gut microbiota composition. This finding suggests that a specific disease-biased host genotype may also select for the first gut colonisers and could contribute to determining disease risk.


Objective

Understanding the neural circuitry of placebo analgesia in the context of visceral pain is increasingly important given evidence of clinical benefit of placebo treatment in IBS. This functional MRI study addressed placebo analgesia in IBS, UC and healthy control (HC) volunteers.

Design

Painful rectal distensions were delivered in N=17 patients with IBS , N=15 patients with UC in remission, and sex-matched and age-matched HCs in an adaptation phase followed by intravenous application of saline combined with either positive instructions of pain relief (placebo) or neutral instructions (control). Neural activation during cued-pain anticipation and pain was analysed along with ratings of expected and perceived pain and measures of negative affectivity and salivary cortisol concentrations. Correlational analyses between placebo analgesia responses and negative affect were accomplished.

Results

HC and UC revealed significant pain inhibition during placebo analgesia, as evidenced by reduced neural activation in pain-related brain areas. In contrast, patients with IBS failed to effectively engage neural downregulation of pain, as evidenced by the absence of placebo-induced changes in distension-induced brain activation, resulting in a significant group difference in the cingulate cortex compared with HC. Depression scores correlated with weaker placebo analgesia, whereas state and trait anxiety were not associated.

Conclusions

Patients with IBS failed to effectively engage neural downregulation of rectal distension-induced pain during placebo analgesia, indicating a specific deficit in cognitive pain inhibition, which may in part be mediated by depression.


Objective

Adherent-invasive Escherichia coli (AIEC) are abnormally predominant on Crohn's disease (CD) ileal mucosa. AIEC strains adhere to enterocytes via interaction between type 1 pili and CEACAM6 receptors abnormally expressed on CD ileal mucosa, leading to gut inflammation. We analysed whether epigenetic mechanisms are involved in the upregulation of CEACAM6 expression in intestinal epithelial cells (IECs).

Design

Methylation of CEACAM6 promoter was analysed using bisulfite sequencing and site-specific methylation by SnapShot. pCpGfree reporter system was used to analyse CEACAM6 promoter activity. Transgenic mice expressing human CEACAM6 fed either standard food or a low-methyl diet (LMD) were orally challenged with 109 AIEC LF82. After 3 days, gut-associated AIEC and proinflammatory cytokines were quantified.

Results

Analysis of CEACAM6 gene promoter revealed potentially methylated dinucleotide CpGs within HIF-1-responsive elements (HREs). Methylation levels of CpG within CEACAM6 promoter were inversely correlated with CEACAM6 expression in IEC expressing various levels of CEACAM6. We show the critical role of HRE methylation and transcription factor HIF-1 in the regulation of CEACAM6 gene in IEC. This was confirmed in transgenic mice expressing human CEACAM6 fed a LMD. LMD-dependent HRE demethylation led to abnormal gut expression of CEACAM6, favouring AIEC colonisation and subsequent inflammation.

Conclusions

HRE hypomethylation in CEACAM6 promoter correlates with high expression in IEC. Our findings suggest that abnormal DNA methylation leading to CEACAM6 increased expression and AIEC-mediated gut inflammation can be related to changes in nutritional habits, such as low intake in methyl donor molecules, leading to abnormal epigenetic marks in mouse model mimicking CD susceptibility.


Objective

Although paediatric-onset IBD is becoming more common, few medications have a registered paediatric indication. There are multiple hurdles to performing clinical trials in children, emphasising the importance of choosing an appropriate outcome measure, which can facilitate enrolment, and thereby also drug approval. The aim of this consensus statement is to highlight paediatric specific issues and key factors critical for the optimal conduct of paediatric IBD trials.

Design

The Paediatric European Crohn's and Colitis Organisation (ECCO) committee has established an international expert panel to determine the best outcome measures in paediatric IBD, following a literature search and a modified Delphi process. All recommendations were endorsed by at least 80% agreement.

Results

Recognising the importance of mucosal healing (MH), the panel defined steroid-free MH as primary outcome measure for all drugs of new category with one or two postintervention endoscopies per trial (at 8–12 weeks and/or 54 weeks). Since endoscopic evaluation is a barrier for recruitment in children, trials with medications already shown to induce MH in children or adults, could use paediatric-specific disease activity scores as primary outcome, including a modified Paediatric Crohn's Disease Activity Index in Crohn's disease and the Paediatric Ulcerative Colitis Activity Index in UC. Secondary outcomes should include safety issues, MR enterography-based damage and inflammatory scores (in Crohn's disease), faecal calprotectin, quality of life scales, and a patient-reported outcome.

Conclusions

It is crucial to perform paediatric trials early in the development of new drugs in order to reduce off-label use of IBD medication in children. The thoughtful choice of feasible and standardised outcome measures can help move us towards this goal.


Background

Bacteria play a role in the onset and perpetuation of intestinal inflammation in IBD. Compositional alterations may also change the metabolic capacities of the gut bacteria.

Objective

To examine the metabolic activity of the microbiota of patients with Crohn's disease (CD), UC or pouchitis compared with healthy controls (HC) and determine whether eventual differences might be related to the pathogenesis of the disease.

Methods

Faecal samples were obtained from 40 HC, 83 patients with CD, 68 with UC and 13 with pouchitis. Disease activity was assessed in CD using the Harvey–Bradshaw Index, in UC using the UC Disease Activity Index and in pouchitis using the Pouchitis Disease Activity Index. Metabolite profiles were analysed using gas chromatography–mass spectrometry.

Results

The number of metabolites identified in HC (54) was significantly higher than in patients with CD (44, p<0.001), UC (47, p=0.042) and pouchitis (43, p=0.036). Multivariate discriminant analysis predicted HC, CD, UC and pouchitis group membership with high sensitivity and specificity. The levels of medium-chain fatty acids (MCFAs: pentanoate, hexanoate, heptanoate, octanoate and nonanoate), and of some protein fermentation metabolites, were significantly decreased in patients with CD, UC and pouchitis. Hexanoate levels were inversely correlated to disease activity in CD (correlation coefficient=–0.157, p=0.046), whereas a significant positive correlation was found between styrene levels and disease activity in UC (correlation coefficient=0.338, p=0.001).

Conclusions

Faecal metabolic profiling in patients with IBD relative to healthy controls identified MCFAs as important metabolic biomarkers of disease-related changes.

Trial Registration No:

NCT 01666717.


Clinical presentation

An 81-year-old man underwent percutaneous mitral valve repair (MitraClip) due to severe symptomatic mitral valve regurgitation. Coronary heart disease was excluded prior to mitral valve repair. Approximately 8 h after the uneventful and successful intervention, the patient presented with progressive abdominal pain, in particular tenderness in the right upper quadrant with guarding. Laboratory tests did not reveal any acute alterations; serum lactate was 2.4 mmol/L. Bedside ultrasonography showed a distended ascending colon with a pronounced hyperechoic large bowel wall (figure 1A). Native CT imaging was performed (figure 1B). The patient subsequently underwent emergency laparotomy.

Question

What is the correct imaging diagnosis and the underlying condition?

See page 494 for answer

See page 458 for question

Answer

Ultrasonography and CT imaging revealed pneumatosis intestinalis (PI) of the ascending colon (figure 1A, B); however, no hepatic portal venous gas was...


Objective

Commensal bacteria and innate immunity play a major role in the development of colorectal cancer (CRC). We propose that selected commensals polarise colon macrophages to produce endogenous mutagens that initiate chromosomal instability (CIN), lead to expression of progenitor and tumour stem cell markers, and drive CRC through a bystander effect.

Design

Primary murine colon epithelial cells were repetitively exposed to Enterococcus faecalis-infected macrophages, or purified trans-4-hydroxy-2-nonenal (4-HNE)—an endogenous mutagen and spindle poison produced by macrophages. CIN, gene expression, growth as allografts in immunodeficient mice were examined for clones and expression of markers confirmed using interleukin (IL) 10 knockout mice colonised by E. faecalis.

Results

Primary colon epithelial cells exposed to polarised macrophages or 4-hydroxy-2-nonenal developed CIN and were transformed after 10 weekly treatments. In immunodeficient mice, 8 of 25 transformed clones grew as poorly differentiated carcinomas with 3 tumours invading skin and/or muscle. All tumours stained for cytokeratins confirming their epithelial cell origin. Gene expression profiling of clones showed alterations in 3 to 7 cancer driver genes per clone. Clones also strongly expressed stem/progenitor cell markers Ly6A and Ly6E. Although not differentially expressed in clones, murine allografts positively stained for the tumour stem cell marker doublecortin-like kinase 1. Doublecortin-like kinase 1 and Ly6A/E were expressed by epithelial cells in colon biopsies for areas of inflamed and dysplastic tissue from E. faecalis-colonised IL-10 knockout mice.

Conclusions

These results validate a novel mechanism for CRC that involves endogenous CIN and cellular transformation arising through a microbiome-driven bystander effect.


Objective

Although hepatitis delta is considered an immune-mediated disease, adaptive immune responses to hepatitis delta virus (HDV) are hardly detectable. Thus, the role of other immune responses, including those mediated by natural killer (NK) cells, must be considered in HDV pathogenesis and in treatments with immune-stimulating agents such as interferon (IFN)α. However, the phenotype and function of NK cells in chronic HDV infection, or in HDV-infected individuals undergoing IFNα treatment, have not been extensively studied.

Design

We performed an extensive analysis of NK cells in chronically HDV-infected patients before and during treatment with IFNα, and compared the results with those for patients with HBV mono-infection as well as healthy controls.

Results

In untreated HDV-infected patients, a higher than normal frequency of NK cells was observed in peripheral blood with unaltered phenotypic NK cell differentiation status. In contrast, long-term IFNα treatment of HDV-infected patients caused a significant change in NK cell differentiation status, with selective loss of terminally differentiated NK cells and, in parallel, a relative enrichment in immature NK cell subsets. Treatment was associated with marked functional impairment of the NK cells, which was independent of the changes in NK cell differentiation status. Furthermore, treatment polarised NK cell IFN signalling from STAT4 towards STAT1 dependency. Strikingly, a high frequency of CD56dim NK cells at baseline was positively associated with IFNα treatment outcome in the patients.

Conclusions

We describe in detail how HDV infection, and IFNα treatment of this infection, affects the NK cell compartment and what consequences this has for the functional capacity of NK cells.


Objective

Although direct-acting antiviral agents (DAAs) have markedly improved the outcome of treatment in chronic HCV infection, there continues to be an unmet medical need for improved therapies in difficult-to-treat patients as well as liver graft infection. Viral entry is a promising target for antiviral therapy.

Design

Aiming to explore the role of entry inhibitors for future clinical development, we investigated the antiviral efficacy and toxicity of entry inhibitors in combination with DAAs or other host-targeting agents (HTAs). Screening a large series of combinations of entry inhibitors with DAAs or other HTAs, we uncovered novel combinations of antivirals for prevention and treatment of HCV infection.

Results

Combinations of DAAs or HTAs and entry inhibitors including CD81-, scavenger receptor class B type I (SR-BI)- or claudin-1 (CLDN1)-specific antibodies or small-molecule inhibitors erlotinib and dasatinib were characterised by a marked and synergistic inhibition of HCV infection over a broad range of concentrations with undetectable toxicity in experimental designs for prevention and treatment both in cell culture models and in human liver-chimeric uPA/SCID mice.

Conclusions

Our results provide a rationale for the development of antiviral strategies combining entry inhibitors with DAAs or HTAs by taking advantage of synergy. The uncovered combinations provide perspectives for efficient strategies to prevent liver graft infection and novel interferon-free regimens.


Objective

To elucidate the association between antiviral therapy and extrahepatic outcomes in individuals infected with HCV.

Methods

This nationwide cohort study screened 293 480 Taiwanese residents with HCV infection and excluded those with substantial comorbidity. A total of 12 384 eligible patients who had received pegylated interferon plus ribavirin between 1 October 2003 and 31 December 2010 were enrolled in the treated cohort; they were matched 1 : 2 with 24 768 untreated controls in the propensity score and post-diagnosis treatment-free period. The incidences of end-stage renal disease (ESRD), acute coronary syndrome (ACS), ischaemic stroke and catastrophic autoimmune diseases were calculated after adjustment for competing mortality.

Results

The treated and untreated cohorts were followed up for a mean (±SD) duration of 3.3 (±2.5) and 3.2 (±2.4) years, respectively, until 31 December 2011. The calculated 8-year cumulative incidences of ESRD, ACS, ischaemic stroke and autoimmune catastrophes between treated and untreated patients were 0.15% vs 1.32% (p<0.001), 2.21% vs 2.96% (p=0.027), 1.31% vs 1.76% (p=0.001) and 0.57% vs 0.49% (p=0.816), respectively. Multivariate-adjusted Cox regression revealed that antiviral treatment was associated with lower risks of ESRD (HR 0.15; 95% CI 0.07 to 0.31; p<0.001), ACS (HR 0.77; 95% CI 0.62 to 0.97; p=0.026) and ischaemic stroke (HR 0.62; 95% CI 0.46 to 0.83; p=0.001), but unrelated to autoimmune catastrophes. These favourable associations were invalid in incompletely treated patients with duration <16 weeks.

Conclusions

Antiviral treatment for HCV is associated with improved renal and circulatory outcomes, but unrelated to catastrophic autoimmune diseases.


MicroRNAs (miRNAs) are small non-coding RNAs, 18–23 nucleotides long, which act as post-transcriptional regulators of gene expression. miRNAs are strongly implicated in the pathogenesis of many common diseases, including IBDs. This review aims to outline the history, biogenesis and regulation of miRNAs. The role of miRNAs in the development and regulation of the innate and adaptive immune system is discussed, with a particular focus on mechanisms pertinent to IBD and the potential translational applications.


Basic ScienceThe interplay between the gut microbiome and host genetics

Goodrich JK, Waters JL, Poole AC, et al. Human genetics shape the gut microbiome. Cell 2014;159:789–99.

Perturbations in the gut microbiota have been linked to a variety of health problems, from obesity, heart disease, autism and metabolic disorders. Interestingly most of these disorders also have a genetic component, yet the link between genetics and the gut microbiome remains elusive. The gut microbiome differs markedly between individuals and there is support for a host genetic effect on the microbiome. Of the two, the microbiome is distinctly more modifiable than host genetics, making it a potential target for manipulation in the effort to improve health. This study by Goodrich and colleagues assessed whether specific bacterial taxa within the gut microbiome were heritable and could be related to host body mass index (BMI). They also looked at whether predicted...


Dear Sir,

We read with interest the article by Habegger et al1 who demonstrated that duodenal nutrient exclusion using duodenal endoluminal sleeve (DES) improves metabolic syndrome and stimulates intestinal villus hyperplasia, especially the bypassed duodenum, in a rodent model of type 2 diabetes mellitus. There were three intriguing results. First, with regard to DES improving glucose homeostasis, the area under curve analysis showed that both sham-operated and the DES group had statistically significant improvements in glucose homeostasis. Nevertheless, since the pair-fed group had received the same sham operation, it is interesting that the sham-operated group rather than the pair-fed group showed better glucose homeostasis than the naive controls after oral but not intraperitoneal glucose challenge. We doubt whether the anaesthesia and surgery can affect oral glucose challenge in Zucker diabetic fatty rats beyond 2 weeks, in contrast to the authors’ statement that the animals already reached the...


Dear Sir,

I read with interest the study by Steenholdt et al1 which concluded that individualised infliximab therapy was more cost effective compared with empirical dose escalation in Crohn's disease (CD) patients who developed secondary non-response to infliximab.

The study methodology has a number of questions that require attention.

First, 80% of the patients recruited for the study had non-fistulising disease, and the study entry criterion for them was having a Crohn's Disease Activity Index (CDAI) score of ≥220. Furthermore, the endpoint for clinical response for them was defined as CDAI reduction of ≥70 points. CDAI scores are largely driven by symptom reporting2 and the lack of more objective markers for the patients with non-fistulising disease makes interpretation problematic. This leads to the second point below, as some of these patients were later found out not to have a flare of CD.

Second, among the...


Dear Editor,

With interest we read the paper by Juste et al1 proposing the amount of zymogen-granule membrane glycoprotein 2 (GP2) on the surface of intestinal bacteria as a Crohn's disease (CD) marker. Indeed, a decreased GP2 level was found on microbes in patients with CD as compared to those of healthy controls. GP2 is a homologue to the urinary Tamm–Horsefall protein demonstrating an antimicrobial function by binding type 1-fimbriated uropathogenic Escherichia coli (UPEC). Likewise, GP2 seems to interact with intestinal bacteria as a specific receptor of bacterial type-1 fimbriae (FimH) on intestinal microfold cells that are partaking in immune responses against such microbes.2 GP2 is overexpressed in the inflamed intestine of patients with CD and has an immunomodulating role in innate and acquired immune responses.3 4 Interestingly, GP2 was identified as autoantigen of pancreatic antibodies in CD.4...


We have read with great interest the study by Clarke et al1 who in a very elegant and sophisticated manner documented the increase in gut microbial diversity in association with exercise and dietary extremes in professional rugby players. The observed microbial shifts were accompanied by lower inflammatory and healthier metabolic profiles among athletes. Significantly higher proportions of the genus Akkermansia muciniphila in athletes as well as in low Body Mass Index control group were found. As previously shown, the presence of these bacteria in the human GI tract has been associated with improved metabolic profiles, possibly due to enhanced barrier function. However, from the study of Clarke et al it is difficult to draw the conclusion and assess the impact of exercise per se from dietary influences in groups studied for their gut microbial diversity. As the alterations of the microbial diversity have already been linked...


Marlicz and Loniewski1 offer complementary comments regarding the design and execution of our study of exercise and associated dietary extremes on gut microbial diversity.2 They expand on some of the caveats already raised by us. First, we were careful not to transmute correlation into causation. As implied in the title of our study and explicit in our report, we acknowledged and recorded the dietary changes that accompany exercise, particularly in professional athletes. A further study has been designed to control for and examine the separate contributions of diet and exercise in a prospective manner in non-professional athletes. We are pleased to report that such study is already underway. Second, Marlicz and Loniewski refer to the multitude of effects that exercise may have on host physiology, many of which were outside the scope of our study but which collectively support our conclusion that the relationship between...


Sir,

We read with great interest the leading article by Bruix et al1 published in Gut. This article recommended palliative treatments for patients with hepatocellular carcinoma (HCC) involving macrovascular invasion, multiple tumours, or portal hypertension.

With better patient selection and improvement of perioperative care, liver resection (LR) offers the most consistent and clinically meaningful long-term survival in HCC over the past 20 years, which has been documented by both Eastern and Western centres.2 3 However, Western official guidelines do not recommend LR for treating intermediate and advanced stage HCC.4 5 Here, we systematically searched PubMed database for studies investigating the safety and efficacy of LR for treating patients with HCC involving macrovascular invasion, multiple tumours (≥2) or portal hypertension. We only included studies which were published in English on or after January 2000. In the case of multiple studies based...


We appreciate the opportunity to comment on the controversial issues surrounding treatment options for patients with hepatocellular carcinoma. In the field of surgery or interventional radiology it is common to emphasise technical feasibility and early morbidity/mortality rather than medium/long-term survival. Expanding life expectancy of the patients in comparison with that offered by other treatments, or even no treatment, is the goal of therapy. In our review1 and in practice guidelines2 3 the recommendations were based on robust data from prospective studies, preferably randomised, in the target population that had the option of being investigated. In the setting of surgical resection there are now several studies showing that presence of vascular invasion, multifocal disease and portal hypertension are associated with a worse survival when compared against patients without these adverse characteristics. Zhong et al4 expose these outcome differences in their letter and...