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Access over 400 recorded highlight sessions from UEG Week 2014.

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Julia Kasper


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Homing in on the mechanisms and treatment of inflammation in IBD

α4β7 integrin has recently emerged as a new target for therapy in patients with inflammatory bowel disease (IBD), via the monoclonal antibody vedolizumab. The therapeutic benefit of α4β7 integrin blockade using vedolizimab has been successfully shown for both Crohn’s disease and ulcerative colitis.1,2

The process by which T cells enter the gut mucosa is tightly controlled by a specific homing process involving regulatory molecules on the T-cell surface and their ligands on intestinal endothelial cells. The blockade of T-effector cells (Teff cells) has been demonstrated to be effective in IBD; however, little is known about the mechanisms that control the homing of regulatory T cells (Treg) to the inflamed bowel, although recent research has demonstrated that the G-protein-coupled homing receptor, GPR15, controls the homing of Treg cells to the colon in mice.

In a new study in Gut, Fischer et al.3 studied the in vivo homing of Teff and Treg cells to the inflamed gut via α4β7 integrin and GPR15. The authors looked at expression of homing receptors on T cells from both peripheral blood and inflamed mucosa. They also used a ‘humanised’ mouse model in dextran sodium sulfate (DSS) treated mice to study the migration pattern and homing of Teff and Treg cells to inflamed gut.

Expression of α4β7 integrin and GPR15 on human Treg cells was upregulated in ulcerative colitis, as opposed to Crohn’s disease and controls, and regulated by inflammatory cytokines. In addition, the in vivo homing of Treg cells from patients with ulcerative colitis to the inflamed colon in humanised mice was demonstrated to be augmented when compared with the homing of Treg cells from controls.  Using vedolizumab to block adhesion molecule function did not alter the homing of Treg cells from controls, but showed that α4β7 integrin rather than GPR15 is crucial for controlling homing of Treg cells of patients with ulcerative colitis to the inflamed colon in vivo. By contrast, both molecules were shown to be involved in Teff  cell homing in ulcerative colitis. Finally, the authors demonstrated that vedolizumab therapy results in the accumulation of Treg cells in the peripheral blood of patients with ulcerative colitis.

This is an interesting study because it clearly identifies GPR15 as another potential therapeutic target for the blockade of Teff cell homing in IBD. However, possibly more significantly, via the use of the humanised mouse model, this study offers researchers another method to evaluate the use of anti-adhesion therapies and human T-cell homing in vivo in IBD. 

References 

1. Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013; 369: 699–710.

2. Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2013; 369: 711–721.

3. Fischer A, Zundler A, Atraya R, et al. Differential effects of α4β7 and GPR15 on homing of effector and regulatory T cells from patients with UC to the inflamed gut in vivo. Gut Epub ahead of print 24 July 2015. doi:10.1136/gutjnl-2015-310022.

UEG Basic Science Course 2015

Access lectures from the course on "IBD: models & methods."

Damned if you do and damned if you don’t

How would you manage this polyp in the setting of ulcerative colitis?

The photograph shows a transverse colonic polyp that was found in a 55-year-old man who was under surveillance because of a 15-year history of ulcerative colitis. Analysis of biopsy samples has indicated that the polyp is a tubular adenoma harbouring low-grade dysplasia.

HOW WOULD YOU MANAGE THIS LESION?

a) This is probably a sporadic polyp that can be removed endoscopically.

b) Offer endoscopic resection only if analysis of a full set of random mucosa samples, taken throughout the colon, does not reveal any flat invisible dysplasia.

c) Endoscopically, this is a dysplasia-associated lesion or mass (DALM), but an endoscopic attempt at resection would nevertheless be appropriate.

d) The concept of a DALM is outdated and an attempt at endoscopic resection should be undertaken.

e) This patient should be offered a pan-proctocolectomy with ileo-anal pouch anastomosis.

IBD: Musings on models and methods

A snapshot of current developments!

From July 9–11, the UEG Basic Science Course 'IBD: Models and Methods' took place in the Netherlands. A total of 41 delegates had the opportunity to engage in lectures on models of inflammatory bowel disease (IBD)—mouse, rat and organoid cultures. Delegates also participated in hands-on training in the laboratory, which involved a 2D in vitro barrier function model and a 3D in vitro gut model amongst other things. Here, to follow this up, we highlight a newly published method for 3D-pattern profiling of mouse and human phenotypes of intestinal inflammation and give a snapshot of some of the current developments within gut experimental models.

IBD is a complex of diseases, mainly involving Crohn’s disease and ulcerative colitis, which differ in terms of intestinal involvement and other specific macroscopic and microscopic features. The distinction between macroscopic intestinal disease phenotypes has traditionally relied on macroscopic assessment of lesions by trained pathologists, along with histological characterisation of inflammatory processes using 2D sections from which inflammatory cell counts are calculated by analysis of a very limited amount of tissue.

Rodriguez-Palacios et al. recently took a microscopic approach to comprehensively examining the integrity of the entire intestinal tract, with a view to characterising disease biology based on 3D-structural patterns.1 Realising that the different types of IBD are often histologically indistinguishable on the basis of mucosal biopsy samples and discovering that stereomicroscopy (SM) has great potential as a routine diagnostic tool for real-time topographical analysis of the gastrointestinal tract at the villous level, this team developed a method using SM to rapidly profile the entire intestinal topography (3D-structure patterns) in mouse models of colitis/ileitis and human IBD.

After creating a comprehensive SM catalogue of histologically and scanning electron microscopy (SEM)-validated 3D-intestinal abnormalities (comprising 4,700 mice, 416 inbred strains, and various mouse models of acute/chronic intestinal inflammation and infection), they designed the ‘3D-SM Assessment and Pattern Profiling (3D-SMAPgut)’ system and a registration form to capture qualitative and quantitative data—cm by cm—in order to determine lesion co-occurrence and spatial distribution patterns.

Introducing the concept of ‘stereroenterotypes’, which are subclusters of 3D-structure-patterns of IBD pathology that are histologically indistinguishable, the authors found that spontaneous ileitis led to the ‘cobblestone’ steroenterotype in some mouse lines, while the ‘villous mini-aggregation’ stereoenterotype was identified in others. This finding suggests that host genetics drive unique and divergent inflammatory 3D-structural patterns in the gut. To this end, on the basis of the 3D-stereoenterotype, SM correctly predicted with 100% accuracy whether a mouse ileum belonged to SAMP mice or TNFARE mice (strains that have different genetic backgrounds but that both develop spontaneous ileitis) or to a control (ileitis-free) strain.

The authors believe that the use of SM will improve our understanding of human IBD by facilitating SM-target analysis of intestinal specimens from animals and IBD patients. This analysis is critical to intestinal phenotyping of genetically diverse mouse and human populations and for preclinical drug testing.

The use of animal models has been indispensable in IBD research. These models can be chemically induced, genetically engineered, immunologically mediated or spontaneous. There are also other types of animal models, and the choice of which model to use relies on the specific hypothesis/question that is being addressed.2 The panel of mouse colitis models is vast;3 the oxazolone colitis model in particular appears relevant for studying human ulcerative colitis due to its close resemblance not only with respect to morphology, but also with respect to immunopathogenesis. Another model, the widely applied DSS colitis model, has proven useful for studies on innate immune mechanisms involved in the development of intestinal inflammation. This model has also been used to study the development of colon cancer in relation to colonic inflammation, such as that occurring in patients with long-standing ulcerative colitis.

However, mouse models are intrinsically low throughput and sometimes do not adequately mimic human physiology.3,4 The development of ‘organoids’,4-6 including ‘enteroids’ and ‘colonoids’, by ex vivo culture of intestinal epithelial cells may soon enable a marked reduction in the animals used for experimental purposes and allow for more precise and targeted studies of human intestinal disease phenotypes. Indeed, it appears that there is immense potential for this culture system in gastrointestinal research, particularly to model diseases such as graft-versus-host-disease and IBD.7 As an example, Rodansky et al. have taken advantage of advances in stem-cell-derived human intestinal organoids by developing a new human model of fibrosis in Crohn’s disease.8

To find out more on the use of intestinal and hepatic organoids, please sign in to myUEG and search the UEG Education Library! To learn more about general advances in, and the outlook for, organoid technologies in terms of disease modelling, I’d suggest looking up the 2014 review by Lancaster and Knoblich.9


References

  1. Rodriguez-Palacios A, et al. Stereomicroscopic 3D-pattern profiling of murine and human intestinal inflammation reveals unique structural phenotypes. Nat Commun 2015; 6: 7577 doi: 10.1038/ncomms8577
  2. Pizarro T. Intestinal fibrosis (IBD) including models. Presentation in the "GI organ-specific fibrosis" session at UEGF Teaching Activity on Basic Science 2011. 
  3. Kiesler P, et al. Experimental models of inflammatory bowel diseases. Cell Mol Gastroenterol Hepatol 2015; 1: 154–170. 
  4. Wells JM, and Spence JR. How to make an intestine. Development 2014; 141: 752–760. 
  5. Sato T, et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Battett’s epithelium. Gastroenterology 2011; 141: 1762–1772. 
  6. Watson CL, et al. An in vivo model of human small intestine using pluripotent stem cells. Nat Med 2014; 20: 1310–1314. 
  7. Hartman KG, et al. Modeling inflammation and oxidative stress in gastrointestinal disease development using novel organotypic culture systems. Stem Cell Res Ther 2013; 4 Suppl. 1: S5. 
  8. Rodansky ES, et al. Intestinal organoids: a model of intestinal fibrosis for evaluating anti-fibrotic drugs. Exp Mol Pathol 2015; 98: 346–351. 
  9. Lancaster MA and Knoblich JA. Organogenesis in a dish: modelling development and disease using organoid technologies. Science 2014; 345: 1247125.  

 

 

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Reassure, resect or retreat?

What's the diagnosis and management of this nodule likely to be?

This video clip shows a nodule that was found on the greater curve of the stomach in a 35-year-old man referred for a gastroscopy because of symptoms of reflux oesophagitis.

You take a full set of samples and after the examination the patient asks what the management of the lesion is likely to be.

What do you tell the patient?

a) This is probably a hyperplastic polyp and eradication of any Helicobacter pylori may well induce spontaneous regression. You tell the patient that he will most likely be offered another examination in a year to reassess the stomach after treatment to eradicate Helicobacter pylori.

b) This is probably a gastrointestinal stromal tumour (GIST). You tell the patient that he is likely to be offered an assessment by endoscopic ultrasonography (EUS) and, as the lesion is small, it is likely that surveillance will be offered.

c) This is probably a neuroendocrine tumour (NET). You tell the patient that it is likely to require surgical resection.

d) This is probably an early gastric cancer. You tell the patient that he is likely to be offered an attempt at endoscopic resection.

e) This is probably an advanced gastric cancer. You tell the patient that he is likely to be offered a gastrectomy. 

This was Basic Science Course 2015

41 young clinicians and scientists were in this year's Basic Science Course.

KRAS or BRAF—that is the question

What's causing the altered bowel habits in this elderly patient?

The photograph shows a lesion that was found in the ascending colon of a 75-year-old man who was undergoing colonoscopy because of a change in bowel habit.

WHAT IS YOUR ENDOSCOPIC DIAGNOSIS?

a) Hyperplastic polyp

b) Sessile serrated polyp

c) Traditional serrated adenoma

d) Mixed hyperplastic polyp

e) Tubulovillous adenoma

 

 

 

Irritable Bowel Syndrome

Improve your consultation skills and knowledge of the condition.

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NeuroGASTRO Meeting 2015

37 recorded lectures covering advances in neurogastroenterology .

Get access to 10 recorded lectures from recent Summer School

This intense clinical-based weekend course is perfect for trainees and early career medical professionals and can now be attended from home. 

Let’s get physical: Listen to your liver talk! 

Does exercise benefit NAFLD patients?

Summer is just around the corner and I’ve been hitting the gym more often to get ready for the beach (and by more often I mean I actually started going to the gym)! But there are many more important reasons why you should work out and your liver’s health is a major one, particularly concerning non-alcoholic fatty liver disease (NAFLD).

NAFLD consists of a spectrum of histopathological changes that range in severity from simple steatosis to non-alcoholic steatohepatitis (NASH). Although simple steatosis is characterized by a relatively favourable clinical outcome, NASH can progress to cirrhosis and hepatocellular carcinoma, leading to liver-related morbidity and mortality. Largely considered a manifestation of obesity and the metabolic syndrome, NAFLD is becoming the most common cause of chronic liver disease worldwide. Indeed, NAFLD is found in almost 70% of the adult obese population and in more than 90% of morbidly obese individuals.1 NAFLD is also highly prevalent in children and its incidence appears to be increasing in Europe, with 2–12.5% of children and early adolescents presenting with NAFLD, a number that rises to 36–44% in obese children.2 Of note, the risk factors for paediatric NAFLD mirror those for adult NAFLD and further correlate with an increasingly sedentary lifestyle, coupled with unbalanced dietary habits, where changes in macronutrients, increased calorie intake and decreased physical activity negatively influence NAFLD pathogenesis.

There is no current pharmacological treatment for NAFLD, although several clinical trials are ongoing, with promising results reported so far. As a consequence, lifestyle interventions remain the cornerstone of NAFLD treatment; in parallel with healthier and smarter eating choices, the benefit of physical activity for NAFLD patients has recently been expounded. Originally thought to be effective only when combined with the introduction of a healthy diet in obese patients, it is now apparent that different exercise regimens can benefit NAFLD, even without dietary restriction and/or in the absence of significant weight loss. For instance, aerobic exercise alone has been shown to be able to decrease visceral adipose tissue volume and liver fat content in sedentary obese individuals by 12% and 21%, respectively.3 Similarly, Oh and co-workers showed that increased physical exercise with or without dieting significantly reduced hepatic inflammation and associated oxidative stress in obese men.4

More recently, Oh and colleagues have suggested that at least 250 minutes of moderate to vigorous intensity physical exercise per week was required to reduce liver fat in obese men as part of lifestyle management.5 In other words, this is more or less equivalent to 50 minutes of moderate (dancing, gardening, housework/domestic chores, walking domestic animals) to vigorous (walking, running, fast cycling/swimming, aerobics, competitive sports/games) intensity physical activity, 5 times per week. Not bad at all! But it gets even better. In April 2015, Keating et al. showed that inactive and overweight/obese adults placed under different aerobic exercise regimens reduce their liver fat and visceral adipose tissue, irrespective of exercise volume or intensity and in the absence of clinically significant weight loss!6 In my opinion, these findings suggest that regular exercise may also greatly benefit non-obese NAFLD patients, despite there being no expectation that these patients will lose a significant amount of weight (they are lean!).

Although it might be surprising for some to learn that NAFLD is not solely a disease of the obese population, the prevalence of NAFLD in lean individuals is increasing. This increase in prevalence is particularly noticeable in the Asia-Pacific region, due to diverse environmental and genetic factors.7 As such, if you think you have ‘good genes’ because you look lean and healthy despite not working out much and/or eating junk food all the time, you might want to think twice, listen to your liver talk and get physical! If nothing else, individuals who exercise regularly might be, perhaps unknowingly, actively lowering their risk of developing fatty liver or even cardiometabolic disease, as the latter correlates with excess liver fat, even in the absence of NASH. However, the key word here is ‘regularly’; if you are a seasonal gym member like me, I would encourage you (and myself) to find other parallel and fun exercise activities and to stick to them. This might be difficult for some, but the sustainability of any intervention is the key to success. This is why—despite believing that specialized and personalized exercise prescription, in parallel with dietary advice, should continue to represent the main line of treatment for NAFLD patients—I think that the use of pharmacological agents on their own or as adjunctive therapies to lifestyle modification will remain desirable.

When exercising, the old saying, “Feel good on the inside and look good on the outside,” usually crosses my mind. Now, I can also almost picture my liver shouting “I feel good, na na, na na, na na, na…”

 

References: 

  1. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346: 1221–12231.
  2. Durmaz O. Metabolic liver disease in the adolescent. Presentation in the Non-alcoholic fatty liver disease (NAFLD): any news? session at UEG Week 2014.
  3. Johnson NA, et al. Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without weight loss. Hepatology 2009; 50: 1105–1112.
  4. Oh S, et al. Exercise reduces inflammation and oxidative stress in obesity-related liver diseases. Med Sci Sports Exerc 2013; 45: 2214–2222.
  5. Oh S, et al. Moderate to vigorous physical activity volume is an important factor for managing nonalcoholic fatty liver disease: a retrospective study. Hepatology 2015; 61: 1205–1215.
  6. Keating SE, et al. Effect of aerobic exercise training dose on liver fat and visceral adiposity. J Hepatol Epub ahead of print 1 April 2015. DOI: 10.1016/j.jhep.2015.02.022.
  7. Bugianesi E. Non-obese patients with NAFLD. Presentation in the Non-alcoholic fatty liver disease (NAFLD): any news? session at UEG Week 2014.

 

Further UEG Resources:

Bellentani, S. How frequent is NAFLD in Europe and in the world? Presentation in the Update on non-alcoholic fatty liver disease session at UEG Week 2013

Dufour J-F. Impact of lifestyle and diet on disease progression. Presentation in the Non-alcoholic fatty liver  disease (NAFLD): any news? session at UEG Week 2014.

Ratziu, V.  Medical treatment. Presentation in the Non-alcoholic fatty liver disease (NAFLD): any news? session at UEG Week 2014.

Ratziu, V. Treatment modalities for non-alcoholic steatohepatitis. Presentation in the Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease in 2014 session at UEG Week 2014. 

This was Summer School 2015

164 trainees met for a weekend full of lectures and hands-on training.

9th EDS Postgraduate course

26 surgical lectures from the meeting in Riga are available free of charge. 

Coeliac disease

Based on the ESPGHAN guidelines this course was developed to assist medical professionals with correctly diagnosing the condition.

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