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The origin of gastric gland stem cells in gastric malignancy
Leuschacke M, Tan SH, Wong A, et al. Lgr5-expressing chief cells drive epithelial regeneration and cancer in the oxyntic stomach. Nat Cell Biol 2017 Jun. doi: 10.1038/ncb3541. (Epub ahead of print).
Stem cell architecture of the mammalian corpus gland has been hotly debated. Current dogma states that the corpus gland stem cell resides in the gland neck (isthmus) and their progeny migrate in a bidirectional fashion to the top and bottom. In addition, recent evidence suggests a reserve population of stem cells reside at the gland base that are relatively quiescent until damage occurs where they are then capable of rapid expansion. Leushacke and colleagues have shown that Lgr5, expressed on intestinal crypt and pyloric gland stem cells, is also expressed on corpus gland stem cells. In a model that expresses the transgene in all targeted cells, Lgr5 is expressed on a subpopulation of basal chief cells. A previous study showed that chief cells express a stem cell marker called Mist1 that can act as a stem cell from the isthmus but not the base. Understanding the relationship between these two markers will be an important advance for gastric stem cell biology. Here, Lgr5-expressing chief cells did not appear to play a role in normal gland homeostasis. However, ablation of all Lgr5+ cells in the gland resulted in gland base atrophy. On high-dose tamoxifen-induced damage, Lgr5+ chief cells were able to display lineage tracing resulting in monoclonal conversion in a Wnt-dependent mechanism. The authors questioned whether Lgr5+ chief cells could act as a cell of origin for gastric cancer. Kras-dependent metaplasia originated from Lgr5+ chief cells. However, this model does not progress and is histologically metaplastic. The authors do describe the relationship of Lgr5 and other stem cell markers in human cancer and while this is convincing, nearly all cancer cells express Lgr5 and are likely to have arisen from intestinal metaplasia. Nevertheless, this study has contributed significantly to the gastric gland stem cell debate.
Genetic risk of NAFLD
Stender S, Kozlitiner J, Nordestgaard BG, et al. Adiposity amplifies the genetic risk of fatty liver disease conferred by multiple loci. Nat Genet 2017;49(6):842–9.
Non-alcoholic fatty liver disease (NAFLD) is increasingly prevalent leading to advanced cirrhosis in a sizeable minority. Genetic loci associated with NAFLD have been identified, in particular polymorphisms in PNPLA3, TM6FS2 and GCKR genes. This study examines the interaction between adiposity and gene expression in the context of NAFLD. The Dallas Heart Study is a large (approximately 3000 participants in total) observational study used previously to provide new information about NAFLD where MR spectroscopy defined hepatic steatosis in relation to hepatic triglyceride content (HTGC). The investigators first considered PNPLA3. The effect of homozygosity for the I148M polymorphism on HTGC becomes progressively more pronounced with increasing BMI: in lean individuals (BMI <25 kg/m2), a modest increase in median HTGC was observed: 2.8% versus 1.8% in II homozygotes. When BMI was greater than 35 kg/m2, the difference was much bigger: 14.2% versus 4.7%. Interactions between BMI and HTGC were also observed for TM6FS2 and GCKR polymorphisms, although these were slightly less pronounced. The investigators then examined the effect of the I148M polymorphism in PNPLA3 on serum transaminase (ALT) levels in the Dallas Heart Study cohort and also cohorts derived from the Dallas biobank and a Danish cohort. A similar interaction was observed, with MM homozygosity having the greatest effect on ALT concentration at higher levels of BMI. Finally, the prevalence of cirrhosis was much greater in MM homozygosity and obesity. These data suggest that adiposity augments the genetic risk of NAFLD. Stratification of patients is vital if we are to manage the burgeoning epidemic of NAFLD, and this new information provides more evidence that genetic testing could play a role in conjunction with clinical data.
Gut microbiota influences platelet function—risk factor for thrombosis?
Jackel S, Kiouptsi K, Lillich M, et al. Gut microbiota regulate hepatic von Willebrand Factor synthesis and arterial thrombus formation via Toll-like receptor 2. Blood 2017 Jun. pii: blood-2016-11-754416. doi: 10.1182/blood-2016-11-754416. (Epub ahead of print).
The gut microbiota plays a pivotal role in host physiology both within and outside the gastrointestinal tract. The metabolic functioning of the gut microbiota has been linked to cardiovascular diseases, the leading cause of morbidity and mortality in industrialised countries. Pathogen-associated molecular patterns derived from gut microbial communities including lipopolysaccharide and peptidoglycan can translocate across the gut epithelial barrier into tissues and the portal blood network driving activation of the innate immune system. This impacts not only on inflammation but also on cellular pathways relevant to haemostasis and thrombosis. This study by Jackel and colleagues has identified a novel connection in which microbes influence platelet function by indirect effects on hepatic Toll-like receptor 2 (TLR2) signalling. The gut microbiota was shown to modulate hepatic von Willebrand Factor (VWF) expression and platelet VWF levels. These are major risk factors of arterial thrombosis and stroke, by promoting arterial thrombus formation through TLR2-dependent regulation of endothelial VWF synthesis in the liver endothelium. Through careful investigation using TLR2 knockout mice, they showed that TLR2 acts as a key sensor for gut microbial ligands within the liver, inducing remote endothelial signalling and leading to adaptive changes in plasma clotting factors. The study demonstrates that hepatic microvasculature is not only the site for the control of acute infection in immunothrombosis but also a homeostatic regulator of plasma components that affect the reactivity of platelets. The study further highlights the impact of the gut microbiota on host physiology.
Cured? defining endpoints to surveillance after ablation of Barrett's oesophagus
Cotton CC, Wolf WA, Overholt BF, et al. Late recurrence of Barrett's oesophagus after complete eradication of intestinal metaplasia is rare: final report from ablation in intestinal metaplasia containing dysplasia trial. Gastroenterology. 2017 Jun. pii: S0016-5085(17)35686-X. doi: 10.1053/j.gastro.2017.05.044. (Epub ahead of print).
The advent of ablation therapy for all grades of oesophageal dysplasia and early adenocarcinoma is one of the great successes of upper gastrointestinal medicine. There remains an appreciable recurrence rate necessitating postablation endoscopic surveillance. Given the increasing volume of patients undergoing ablation, the timing of potential recurrence needs to be clarified to determine the duration of postablation endoscopic follow-up. The authors have carried out an analysis of an important trial (Ablation of Intestinal Metaplasia Containing Dysplasia (AIM)) in which patients had been randomised to either radiofrequency ablation (RFA) or a sham procedure and then followed up for 5 years with recurrence being defined as at least intestinal metaplasia in the tubular oesophagus. Of 119 patients, 92% achieved complete Barrett's eradication and 32% had a recurrence of Barrett's related pathology, with 17% being dysplastic. The risk of dysplasia recurrence was higher in those with higher initial dysplasia grades. Most recurrences occurred within the first year with no recurrence occurring after 4 years. This recurrence rate is striking, although now that endoscopic mucosal resection prior to RFA is the norm, this is likely to decrease. Even so, the message for the need for postablation surveillance is clear. The lack of recurrence after a 4-year interval is also striking and should help to at least achieve the boundaries of postablation surveillance. The next question should focus on the endoscopic surveillance intervals postablation.
Predicting the disease behaviour in paediatric crohn's disease
Kugathasan S, Denson LA, Walters TD, et al. Prediction of complicated disease course for children newly diagnosed with Crohn's disease: a multicentre inception cohort study. Lancet 2017;389:1710–8.
Crohn's disease can progress towards penetrating complications, namely, stricture, fistula and abscess formation. The ability to predict those at highest risk of this progression at diagnosis would be of great clinical utility in terms of patient counselling and planning more aggressive medical therapies. Investigators in Canada and the USA undertook a large prospective study to identify host and treatment factors at diagnosis in a paediatric Crohn's disease cohort to predict disease behaviour. Nine hundred and thirteen patients were recruited from 28 sites with a diagnosis of Crohn's disease and completed follow-up of 36 months. Patients were managed as per the clinicians’ prerogative at the base centre. Data were collected on genotype, ileal gene expression, antimicrobial serologies, mucosal and faecal microbiota and anti-TNF biologic exposure. The gene signature factors associated with complicated disease (ASCA/CBir1 positivity, older age, race, disease location) were utilised to form a stratification score for complicated disease with an excellent negative predictive value (sensitivity 66% (95% CI 51% to 82%), specificity 63% (95% CI 55% to 71%), NPV 95% (95% CI 94% to 97%) and PPV 14% (95% CI 12% to 17%)). Patients who received anti-TNF therapy were less likely to develop penetrating but not stricturing complications. Also ileal genes with a profibrotic signature at diagnosis predicted stricturing disease behaviour in this cohort. This large and challenging prospective study is more likely to assist with new avenues of drug discovery in the short term and perhaps for selecting patients who do not require a biological agent. Independent validation of the dataset is required.
The ‘ultimate pill’ to treat Hepatitis C?
Bourlière M, Gordon SC, Flamm SL, et al. Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection. N Engl J Med. 2017;376(22):2134–46.
Treatment of hepatitis C has undergone a paradigm shift in the last decade wherein the minimum expectation of success of any new treatment regime is a sustained viral response (SVR) over 90%. In this era of excellent direct acting antiviral (DAA) drug efficacy, there is an ever-growing lack of clarity in dealing with the small cohort of subjects who do not respond to these drug regimes. The POLARIS-1 and POLARIS-4 study have addressed this by recruiting subjects with HCV genotype 1 who had previously failed on a regimen containing an NS5A inhibitor and those with HCV genotype 1, 2 or 3 infection who had previously received a DAA regimen but not an NS5A inhibitor. POLARIS-1 subjects were randomly assigned to receive the nucleotide polymerase inhibitor Sofosbuvir, the NS5A inhibitor Velpatasvir and the protease inhibitor Voxilaprevir (150 patients) with a fixed dose combination tablet or matching placebo (150 patients) once daily for 12 weeks. In the POLARIS-4 study, subjects received combination tablet Sofosbuvir–Velpatasvir–Voxilaprevir (163 patients) or Sofosbuvir–Velpatasvir (151 patients) for 12 weeks. In this difficult to treat group, the SVR achieved in POLARIS-1 was 96% as opposed to 0% with placebo and in the POLARIS-4 study the rate of response was 98% with Sofosbuvir–Velpatasvir–Voxilaprevir and 90% with Sofosbuvir–Velpatasvir combination. Only 1% of patients discontinued therapy due to side effects. Forty-six per cent of the subjects recruited were cirrhotic on entry. The number of patients with genotype 3 was under-represented in this study; this group will likely determine the ‘final frontier’ for this exciting drug combination.
Dr Stuart McDonald, Dr Richard Parker, Dr Georgina Hold, Dr Sebastian Zeki, Dr Dan Gaya, Dr Ashis Mukhopadhya.
Nature Cell Biology, Nature Genetics, Blood, Gastroenterology, The Lancet, New England Journal of Medicine.
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed.
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