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The role of interleukin-22 in epithelial barrier integrity
▸ Lindemans CA, Calafiore M, Mertelsmann AM, et al. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature 2015;528:560–4.
Maintenance and regeneration of the epithelial barrier is critical in preventing infection and inflammation in the GI tract. Innate lymphoid cells (group 3, ILC3s) have immunoregulatory capacity in Crohn's disease by killing commensal stimulated pro-inflammatory T cells, but the role of ILC3s in barrier regeneration is unknown. ILC3s produce interleukin (IL) 17 and IL-22 in mucosal tissues. IL-22 is known to be an inflammatory suppressor. Lindemans and colleagues assessed the effect of IL-22 on intestinal stem cells using mouse small intestinal organoids. They showed that exposure to recombinant IL-22 induced cell proliferation and an increased size of organoids. Coculturing organoids with lymphocytes extracted from the lamina propria (LPLs) also increased organoid size, but not when cocultured with LPLs from IL-22 knock-out mice. Investigation of IL-22 receptor signalling in organoids showed a STAT3-dependent mechanism. Furthermore, Cre-induced STAT3−/− crypts failed to generate organoids. The effect of loss of STAT3 on the Lgr5+ stem cell population showed there was a significantly reduced stem cell-specific gene expression in STAT3−/− mice that were exposed to inflammation. Adding IL-22 to Lgr5-sorted stem cells also produced larger organoids. Together, these data shows that ILC3 cells exert a potent growth effect on crypt stem cells. To test this effect of IL-22 on in vivo inflammation, the authors used a model of graft-versus-host disease (GVHD) treated with IL-22 or saline. The mice that received IL-22 showed a significant reduction in GVHD pathology scores, with a significant recovery in the Lgr5+ stem cell population with IL-22 treatment. Paneth cells are thought to act as niche cells within the small intestine crypt supporting the Lgr5+ stem cell population. The authors showed that IL-22 had no effect on Paneth cell numbers and depletion of the Paneth cells (using Atoh−/− mice) showed no effect on STAT3 activation when Atoh−/− organoids were exposed to IL-22. In conclusion this manuscript shows for the first time a role for innate lymphoid cells in stimulating a regenerative response in the intestinal epithelium. This may have profound implications for treating patients with Crohn's disease and potentially other chronic conditions of the intestine.
STK4: the missing link between liver inflammation and hepatocellular carcinoma?
▸ Li W, Xiao J, Zhou X, et al. STK4 regulates TLR pathways and protects against chronic inflammation-related hepatocellular carcinoma. J Clin Invest 2015;125:4239–54.
The development of hepatocellular carcinoma (HCC) is closely linked to chronic liver inflammation. However, the precise molecular mechanisms linking inflammation and carcinogenesis in the liver have not been fully elucidated. In this article, Li and colleagues identified reduced expression of the tumour suppressor gene serine/threonine-protein kinase 4 (STK4) in liver macrophages, as being critical for both liver inflammation and HCC development. In murine HCC models, reduced macrophage STK4 expression was found, with a corresponding reduction in pro-inflammatory cytokine expression. Furthermore, in two models of chronic liver injury, macrophage-specific knockout of STK4 resulted in increased pro-inflammatory cytokine production and exacerbated liver inflammation, fibrosis and HCC development. Indeed, in human patients with HCC both circulating monocytes and tumour-associated macrophages show reduced STK4 expression. A series of mechanistic experiments demonstrated that the anti-inflammatory effect of macrophage STK4 is mediated via phosphorylation of IRAK1 (IL-1 receptor-associated kinase 1), to promote IRAK1 degradation. The authors proceeded to use this mechanistic data to manipulate the STK4 pathway by administering IRAK1 inhibitors to mice, which abrogated the effect of STK4 deletion on HCC growth. Hence, reduced expression of STK4 in liver macrophages can promote hepatic inflammation and carcinogenesis. Novel therapies to increase the activity of STK4, such as IRAK1 inhibition, may be useful as anti-inflammatory and anti-HCC agents.
Gut microbial signatures—cause of disease or treatment effect?
▸ Forslund K, Hildebrand F, Nielsen T, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 2015;528:262–6.
The association between metabolic diseases, including obesity and type 2 diabetes (T2D) and the gut microbiota has been reported frequently in recent times. However, little consideration has been given to treatment regimens and the impact that these have on microbial signatures. Therefore findings reported to date may obscure microbial causes, protective factors or diagnostically relevant signals that could advance our understanding. Metformin, an oral blood-glucose lowering non-metabolisable compound, whose primary metabolic effect is the inhibition of liver glucose production is frequently used to manage T2D. A significant proportion of patients who use metformin report GI disturbances, although the mechanistic explanation is currently lacking and the effect of metformin on the gut microbiota is unknown. This study by Forslund and colleagues looked at disease and drug signatures in the human gut microbiome of T2D from 2 previously published metagenomics studies that were not stratified by treatment and had yielded divergent conclusions regarding associated gut microbial changes. By considering treatment within the analysis approach they showed increases in Escherichia coli and lower abundance of Intestinibacter species, as well as an increase in short chain fatty acid levels which has been shown in animal models to trigger intestinal gluconeogenesis. When metformin treatment was controlled in the analysis, a unified signature of gut microbiome shifts was apparent within T2D. The study once again illustrates the impact of the microbiota on extraintestinal pathology, and the need to disentangle disease-specific microbial signatures from treatment effects. Future studies should be designed to consider treatment regimens.
Stratifying risk of colorectal cancer in UC
▸ Choi C-hR, Ignjatovic-Wilson A, Askari A, et al. Low-Grade Dysplasia in Ulcerative colitis: risk factors for developing high-grade dysplasia or colorectal cancer. Am J Gastroenterol 2015;110:1461–71.
Patients with UC are at increased risk of colonic dysplasia and colorectal cancer (CRC). Surveillance colonoscopy programmes are designed to identify precancerous dysplasia in the colon. Lesions demonstrating low-grade dysplasia (LGD) are most commonly encountered, but they exhibit morphological and behavioural heterogeneity and the factors influencing progression to CRC are poorly understood. In this paper Choi et al have identified several characteristics of LGD that were significantly associated with later diagnosis of HGD (high-grade dysplasia) or CRC. Patients with histologically confirmed extensive UC, diagnosed with LGD between 1993 and 2012, were identified. Demographics and histological data were collected and correlated with the development of CRC or HGD. One hundred and seventy-two patients were included and followed over a median of 48 months from initial diagnosis of LGD. Median values for number of colonoscopies, surveillance interval and number of biopsies per colonoscopy were 3, 12 months and 12 respectively. Thirty-three patients were subsequently diagnosed with CRC (n=20) or HGD (n=13). Multivariate analysis using a Cox proportional hazard model found that macroscopically non-polypoid lesions, endoscopically invisible dysplasia, dysplastic lesions ≥1 cm and a previous pathological diagnosis of ‘indefinite for dysplasia’ were all statistically significant risk factors for the development of HGD or CRC. There was a significant positive correlation between the number of risk factors present and the cumulative risk for developing HGD or CRC. The authors propose that patients with one or more of the above risk factors should be counselled closely about treatment options including colectomy. These results support the continued use of surveillance colonoscopy programmes. As colonoscopy technologies advance, we will undoubtedly improve our ability to identify and risk-stratify dysplastic lesions in the colon.
Should we react early to Crohn's disease?
▸ Khanna R, Bressler B, Levesque BG, et al. Early combined immunosuppression for the management of Crohn's disease (REACT): a cluster randomised trial. Lancet 2015;386: 1825–34.
The best time point and best strategy to intervene medically in Crohn's disease have been a matter of heated debate in recent years. Proponents of early aggressive therapy argue that the disease's natural history can be altered and morbidity reduced. However, this inevitably comes at a cost of overtreatment of a cohort of patients being exposed to potent medical therapies that they would otherwise not have required. Khanna and colleagues recently published the largest randomised trial in Crohn's disease ever undertaken with an open label cluster randomisation methodology. Patients with Crohn's disease with varying disease activities and on a variety of therapies were recruited from both Belgium and Canada and randomly assigned to either conventional management or early combined immunosuppression with adalimumab and either azathioprine or methotrexate. The primary outcome measure was remission as defined by the Harvey Bradshaw Index. Approximately 1000 patients were recruited to each arm. The data revealed that the 12-month remission rates were not significantly different between the two groups. There was also no difference in drug-related adverse outcomes between the groups. However, the composite rates of surgery, admission to hospital and Crohn's related complications were significantly lower in the early combined therapy group. This was a large well conducted trial but one cannot help thinking that an alternative non-symptom-based primary outcome could have been chosen; an objective faecal marker or validated endoscopic scoring system may well have shown divergent results between the two groups, especially in light of the secondary outcome measures which likely reflect the inflammatory burden of Crohn's disease better. Stratification on the basis of disease severity/behaviour may well have highlighted a treatment effect, as may therapeutic drug monitoring of participants. We await the REACT2 study with interest.
Prevention of rebleeding from oesophageal varices
▸ Sauerbruch T, Mengel M, Dollinger M, et al. German Study Group for Prophylaxis of Variceal Rebleeding. Prevention of Rebleeding From Esophageal Varices in Patients with Cirrhosis Receiving Small-Diameter Stents versus Hemodynamically Controlled Medical Therapy. Gastroenterology 2015;149:660–8.
Variceal bleeding in patients with cirrhosis accounts for mortality rates of up to 20%. A key determinant of survival is the prevention of rebleeding. Recent literature and consensus reports suggest that a combination of endoscopic variceal ligation (EVL) and β blockers is the most favoured treatment option. This randomised multicentric open-labelled trial assessed the efficacy of small covered transjugular intrahepatic portosystemic stent-shunt (TIPS) as a putative option for secondary prophylaxis compared with graded medical therapy. One hundred and eighty-seven from a total of 836 patients (22%), screened in 10 centres from Germany over a period of 6 years, were recruited. The patients were randomised after standard therapy with variceal ligation to either TIPS (group A) or graded medical therapy (group B) of escalating doses of propranolol and nitrate. Hepatic vein pressure gradient (HVPG) was reassessed after 2 weeks in the second group, and non-responders were shifted to EVL. The responders continued on the existing therapy. There was variability in the timing of the TIPS placement, stratified to either within or after 3 weeks of bleeding. The 2-year rebleeding rates were significantly lower in the TIPS (7%) as opposed to the medical group (26%) (HR, 0.28; 95% CI 0.12 to 0.66; p=0.002). A minimally higher proportion of patients in the TIPS group experienced adverse events, including encephalopathy (18% vs 8% for medical treatment; p=0.05). However, there was no difference in the long term survival or quality of life indices between the two groups. There are a few considerations to bear in mind, such as recruitment bias given the small proportion of patients included from the larger screened cohort, the timing of intervention out with the acute scenario, and the medical therapy was not in keeping with the best current medical practice of variceal ligation and β blockers together. Further studies are required to decide best management strategy.
Dr Stuart McDonald, Dr Prakash Ramachandran, Dr Georgina Hold, Dr Jonathan MacDonald, Dr Dan Gaya, Dr Ashis Mukhopadhya
Nature, Journal of Clinical Investigation, American Journal of Gastroenterology, The Lancet, Gastroenterology.
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed.
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