The hot PET
Hot spots in the descending colon. What would you do with the polyps found on subsequent colonoscopy?
A 72-year-old man previously presented with obstructive bowel symptoms. He was diagnosed with mantle cell lymphoma—a type of non-Hodgkin lymphoma—with involvement of the rectosigmoid junction and terminal ileum.He underwent a left hemicolectomy and resection of the terminal ileum followed by chemotherapy (fludarabine, mitoxantrone, dexamethasone and rituximab). After treatment he went into prolonged remission and follow-up colonoscopies 5 years and 7 years later were both unremarkable. The findings of a gastroscopy and capsule endoscopy were also normal 7 years after treatment, at which time the patient was asymptomatic with normal blood results. His haematologist requested a surveillance FDG PET-CT scan, which demonstrated a hot spot in the descending colon (figure 1). A further colonoscopy was carried out and showed 2 polyps in the descending colon (figure 2; DC1 [15mm] and DC2 [50 mm]). The ileocolonic anastomosis and neoterminal ileum were both unremarkable. WHAT WOULD YOU DO WITH THESE POLYPS? a) Ignore them, as they are inflammatory. b) Take biopsy samples only. c) Perform standard snare polypectomy. d) Organise an endoscopic mucosal resection (EMR). e) Organise an endoscopic submucosal dissection (ESD).
E-learning adventures at UEG Week 2015
Getting ready for a busy few days in Barcelona!
UEG Week 2015 is just around the corner and the UEG E-learning team is getting ready for a busy few days in Barcelona! As well as meeting to plan future UEG Education online courses and content, we’ll be spending time at the UEG Booth and the Young GI Lounge in Hall 8.0 during many of the session breaks on Monday, Tuesday and Wednesday. We’ll also be attending the “Young GI Network—Let’s Meet” reception on Sunday evening. If you’d like to meet the team to find out more about what we do, discuss how we can best serve you and how you might be able to get involved, then please do come and say hello!Tomer, Rui and Bjorn will also be chairing sessions and, as one of this year’s UEG Rising Stars, Rui will be presenting his work on microRNAs in NASH in Room E1 during the first session on Wednesday morning. The team will also be attending many of the sessions to get their annual updates across the breadth of the field, and below are a few highlights that everyone is looking forward to. Charlie’s choice: As usual there is so much excellent content that the problem will be fitting it all in. I'll certainly be attending the Rising Stars session, highlighting the best of our researchers from Europe and the USA—this is always an inspiring session. I'll also be playing close attention to the IBD free paper sessions. Like Rune, I'm looking forward to attending the microbiota-focused sessions. And for all the rest there is UEG Week Live! Bjorn’s choice: My pick of the sessions would be “Endoscopic management of benign oesophageal strictures.” I am convinced that in treatment-resistant cases a “stricturoplasty”—whereby the stricture is cut with an endoscopic knife—can turn failure into victory. I would like to discuss this option with the presenters! Tomer’s choice: There are many attractive learning options at the upcoming UEG Week, ranging from basic science to practical patient management. I am looking forward to “Introducing the omics: A guide for clinicians” on Monday morning, as part of the Today’s Science; Tomorrow’s Medicine lectures. This field has evolved greatly and I am looking to hear an update on the implications for clinicians. I am also glad the Postgraduate Teaching Programme has a session dedicated to lower GI bleeding, a topic that applies to our everyday practice. Rui’s choice: I am particularly interested in the hepatobiliary pathway, featuring different session formats on liver cirrhosis and cholestasis. And I always love the Today’s Science; Tomorrow’s Medicine sessions, showing just how much can be achieved from a well-sustained and rational basic-to-translational/clinical research plan. And speaking of research, I am also looking forward to a great panel discussion at the “How to do research?” Hotspot Symposia! Rune’s choice: The impact of the intestinal microbiota on human health and disease is something that never ceases to fascinate me, and of course, I’ll be giving priority to the gut microbiota pathway. I’m especially looking forward to the session chaired by my colleague Mirjana Rajilic-Stojanovic and Giovanni Barbara on evolving microbiota concepts in GI disorders on Tuesday. Here, Paul O'Toole will deliver a talk with the title “Microbiota: What gastroenterologists should know.” Natalie’s choice: I love a bit of controversy, so I’m really looking forward to visiting the UEG Week Hotspot to see some of the new session formats—Abstracts on Fire, Clinical Trials Revisited and Hotspot Symposia—in action! Coming from a basic research background, I’m also particularly interested in the sessions on the ‘omics’ and learning more about what difference they are making to practical patient care and what they might allow us to achieve in the future. Don’t forget to look out for tweets from all of the team (@CharlieMuz, @Bjorn_Rembacken, @Eukaryotes, @RuiCastroHD, @adartom and @nataliewood06) during UEG Week (#uegweek)! Why not join the dialogue and tell us what’s got your attention? And if you like twitter debates then make sure you’re online for the #WeekChat on Sunday with Mark Hull (@mark_tbh; Diet, microbiota and colonic disease) and on Tuesday with Chris Hawkey (@chrishawkey; Updates on stem cell research in gastroenterology). There will also be three Decide on the Spot cases published in the UEG Week News and online during UEG Week (on Saturday, Monday and Tuesday)—the answer and explanation for each case will be posted online the following day. Those of you who view the case online, sign in to myUEG and post a comment or answer in the comments section will qualify for a complimentary UEG Education Power Bank, which is perfect for charging your mobile devices on the go! To receive your UEG Education Power Bank, simply come and show us your post on the laptop at the UEG booth in Hall 8.0. Please note that comments on social media don’t count, participants are entitled to a maximum of one Power Bank and the number of Power Banks available each day is limited! Wishing you all an enjoyable and productive time in Barcelona!
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Quick or Quincke's thinking?
What next for a patient who's recently been feeling unwell & passing black stools?
A 40-year-old male patient went to his local A&E department with a short history of feeling unwell and passing black stools. He had a past history of chronic pancreatitis that was attributable to alcohol and a bleeding peptic ulcer some 15 years earlier. He was not taking any medication. On admission, the patient was pale with a heart rate of 75 BPM and his blood pressure was 125/80 mm Hg. The patient’s Hb level was 36 g/L, with a mean corpuscular volume of 8.93, iron 1.253 mmol/L and ferritin 0.27 pmol/L. On endoscopy, the oesophagus and stomach were unremarkable and the photographs show the appearance of the duodenal ampulla (figure 1a–c).WHAT WOULD YOU DO NEXT? a) Endoscopic retrograde cholangiopancreatography (ERCP) b) Percutaenous transhepatic cholangiogram c) Abdominal computed tomography (CT) d) Angiogram e) Abdominal ultrasound
Time to change a treatment paradigm
Models of care and malnourished patients
In the past 10 years we have seen the expansion of a cadre of gastroenterologists who have a sub-specialty interest in nutrition. As a result, we have seen nutrition rightfully taking centre stage in our hospitals. Indeed, in the UK hospital mealtimes are now ‘protected’ and malnourished patients have their food served on red trays.Our nutrition experts have more directly been involved in a transformation of the care of patients who have short bowels. This group of patients is a complex mix, in which every patient is different depending on how much small bowel is left, what type of anastomosis was constructed and the underlying disease. Such patients may suffer high morbidity and mortality because the malabsorption of macronutrients, micronutrients, electrolytes and water can result in impaired growth, premature aging, sudden hypotension, renal failure, arrhythmias, fits, infections, liver failure and impaired healing. The increased survival of these desperately ill patients has been achieved by meticulous attention to detail. A tiny shift in a patient’s serum magnesium level triggers an adjustment. As the 2003 AGA review put it: “Vitamin and mineral status should be monitored regularly, and supplementation should be customized for each patient.”1 Of course, it takes a particular type of meticulous doctor to tirelessly manage a patient’s micronutrient intake. I am not sure that I could manage to pay such careful daily attention to every patient’s zinc, copper, magnesium and selenium levels. Luckily, gastroenterologists with a specialist interest in nutrition are self-selected, thorough doctors and their patients with intestinal failure benefit greatly. Most UK hospitals now have a nutrition team, which is headed up by a gastroenterologist with a specialist interest in nutrition. Initially these teams only cared for patients with intestinal failure. Subsequently their remit enlarged to include patients with malabsorption and more recently came to include all those who are malnourished. The most severely malnourished patients in our hospitals are those with anorexia nervosa. The nutrition of these patients is now often looked after by gastroenterologists with an expertise in intestinal failure. Just as intestinal failure is at the sharp end of gastroenterology, anorexia nervosa is at the sharp end of psychiatry. Not only does the condition have the highest mortality rate of any mental illness,2 the management is complicated by a lack of reliably successful treatments. The National Institute for Health and Care Excellence (NICE) has reviewed the therapies available and awarded only “grade C level evidence” for 74 of the 75 therapies for eating disorders.3 As we start to see severely malnourished patients who have eating disorders on our gastroenterology wards, it is becoming apparent that simply focusing on a patient’s nutritional needs does not work. Care may be reduced to a battle of wills in which patients pull out their feeding tubes as quickly as doctors put them back down. Furthermore, in spite of opiates, botox injections, naso-gastric feeding, venting PEGs, gastric pacemakers and parenteral nutrition, many patients remain just as debilitated. Personally, I believe that the key to understanding why many patients with the most severe eating disorders do not seem to be greatly improved by pipes and pills is because we practise the “Medical Model” of care. This model focuses on ‘curing’ patients, whereby ‘cure’ is defined by the absence of symptoms and a return to normal, pre-morbid health.4 Of course, such a model is entirely appropriate for treating reflux oesophagitis, a peptic ulcer or an exacerbation of colitis. However, when managing patients who have functional bowel disease, alcohol addiction or eating disorders this model of care may be less helpful. In all areas of psychiatry, the Medical Model of care is being superseded by the “Recovery Model”. Indeed, the Recovery Model of care has been integrated into public mental health policy in many countries, including Australia, New Zealand, USA, Canada, Ireland and the UK.5 The Recovery Model emphasises the personal experience of recovery, involving hope, rebuilding connections with family, friends and supporting patients in rebuilding a fulfilling life in spite of ongoing illness. In contrast to the Medical Model, this model aims for ‘recovery’, defined as enabling a return of hope, personal responsibility, control and empowerment.6 Supporting patients with functional bowel disease, alcohol addiction and eating disorders on their journey towards recovery involves understanding their agenda, active listening, empathy and the setting of realistic goals in equal partnership with patients and their families. Unfortunately, this model of care is unfamiliar to many gastroenterologists, and perhaps particularly to those with a sub-speciality interest in intestinal failure. For this reason we may have to train a new cadre of gastroenterologists with particular expertise in functional disease. This new gastroenterological subspeciality would protect vulnerable patients against repeated cycles of inappropriate investigations and increasingly invasive interventions and instead focus on supporting them on a road towards recovery and a living a fulfilling life. References
- Buchman AL, Scolapio J and Fryer J. AGA technical review on short bowel syndrome and intestinal transplantation. Gastroenterology 2003; 124: 1111–1134.
- Beumont PJ and Touyz SW. What kind of illness is anorexia nervosa? European Child and Adolescent Psychiatry 2003; 12: i20–i24.
- National Institute for Health and Clinical Excellence. Eating disorders. NICE clinical guideline 9. January 2004.
- Roberts G and Wolfson P. The rediscovery of recovery: open to all. Advances in Psychiatric Treatment 2004; 10: 37–49.
- Andresen R, Oades LG and Caputi P. Psychological Recovery: Beyond Mental Illness. Chichester, UK: Wiley-Blackwell 2011
- Schrank B and Slade M. Recovery in psychiatry. Psychiatric Bulletin 2007; 31: 321–325.
Ruminations on gut fermentation—any link to IBS?
Diet, gut microbiota, fermentation and IBS
The aetiology of irritable bowel syndrome (IBS), a disease that may affect at least 10% of the general population, continues to puzzle gastroenterologists and other scientists. While there is some evidence of perturbed gut microbiota in patients with IBS, microbiota profiles reliably linked to IBS remain to be identified. Meanwhile, studies of intestinal fermentation might hold the key to expanding our knowledge on the aetiology and management of IBS.In a recent article in the American Journal of Gastroenterology, Rajilić-Stojanović et al. reviewed data on the impact of diet and the intestinal microbiota on IBS symptoms.1 One of their important conclusions was that powerful interactions between distinct dietary patterns and intestinal microbial communities may—at least in part—be responsible for the fact that IBS has not yet been shown to be defined by certain microbiota profiles. As a lot of data going into studies exploring associations between microbiota profiles and disease conditions are cross-sectional, what we need to know much more about is how, including how quickly, changes in diet influences our gut microbiota, and therefore how resilient gut microbiota are to dietary changes. A study that appeared in Gut earlier in 2015 was looking into just that issue. In their study, Halmos et al. considered whether differences in dietary FODMAP (fermentable oligo-, di-, monosaccharides and polyols) content reflect differences in the colonic luminal microenvironment.2 Study participants (IBS patients and healthy controls) consumed their habitual diets for 1 week, but were subsequently switched to one of two challenge diets for 3 weeks (i.e. either a diet low in FODMAPs or a typical Australian diet). They were then allowed a wash-out period of 5 days, during which they consumed their habitual diets, and then later allocated to the alternative challenge diet for a further 3 weeks. Halmos et al. found that the higher FODMAP content of the Australian diet compared with that of the low FODMAP or habitual diets was associated with specific stimulation of the growth of bacterial groups with putative health benefits, including butyrate-producers and mucus-associated Akkermansia muciniphila. This finding made the team speculate that long-term use of low-FODMAP diets should be used with caution, at least until the long-term effects of such diets on intestinal microbiota have been fully elucidated. To this end, a recent randomized controlled trial by Böhn et al. compared the effects of a diet low in FODMAPs with traditional dietary advice in patients with IBS. The findings of this study suggest that traditional IBS dietary advice is just as effective in terms of reducing IBS symptoms as adhering to a diet low in FODMAPs.3 In the study by Halmos et al., the concentration of short-chain fatty acids (SCFAs) in stool, which was used as a colonic health index, was independent of diet type.2 The SCFAs acetate, propionate, and butyrate are produced primarily by bacterial fermentation of undigested carbohydrates (primarily dietary fibre aka ‘resistant starch’). The relevance of using the faecal SCFA concentration as a biomarker has, however, been questioned. Ringel–Kulka et al. looked into altered intestinal bacterial fermentation in the setting of IBS with regard to bowel characteristics and gastrointestinal symptoms.4 In their study, the primary aim was not merely to look at the distribution and composition of the microbiota, but to look at what the bacteria were actually doing. For this purpose, they looked at surrogate markers of gut bacterial fermentation, namely intestinal intraluminal pH and faecal SCFAs. Faecal SCFAs are naturally acidic and therefore cause a drop in the pH of the intestinal lumen. Compared with healthy controls, patients with IBS—independent of subtype—exhibited a significantly lower mean total colonic pH level, which could indicate higher intraluminal bacterial fermentation in this cohort. Of note, small-intestine pH levels did not differ between IBS patients and healthy controls, which suggests that bacterial fermentation is not increased in the small intestine of IBS patients. This finding may have important implications for understanding the contribution of small intestinal bacterial overgrowth (SIBO) in the pathophysiology of IBS. The SCFA levels in stool from IBS patients and healthy controls did not differ. Although this could be due to a number of circumstances, including differences in the absorption of SCFAs and colonic transit time, the authors do not recommend using faecal SCFAs as a marker for estimating intraluminal bacterial fermentation. There seems to be an emerging focus on the role of SCFAs in intestinal health and disease. While the low-FODMAP diet used by some IBS patients is associated with reduced SCFA production, these fermented substances appear to have a central role in the prevention of colon cancer and possibly other diseases. The use of surrogate markers of fermentation may have taken us some way already in our search for aetiological factors, but we need to know more about the direct impact of changes in intestinal fermentation and the various molecules generated by these processes on the development and course of IBS. I look forward to discussing the impact on SCFAs on intestinal homeostasis specifically and public health in general in one or more future blog posts. References
- Rajilić-Stojanović M, Jonkers DM, Salonen A, et al. Intestinal microbiota and diet in IBS: causes, consequences, or epiphenomena? Am J Gastroenterol 2015; 110: 278–287.
- Halmos EP, Christophersen CT, Bird AR, et al. Diets that differ in their FODMAP content alter the colonic lumincal microenvironment. Gut Epub ahead of print 12 July 2015 doi: 10.1136/gutjnl-2014-307264.
- Böhn L, Störsrud S, Liljebo T, et al. Diet low in FODMAPs reduces symptoms of irritable bowel syndrome as well as traditional dietary advice: A randomized controlled trial. Gastroenterology Epub ahead of print 5 August 2015. DOI: 10.1053/j.gastro.2015.07.054.
- Ringel-Kulka T, Choi CH, Temas D, et al. Altered colonic bacterial fermentation as a potential pathophysiological factor in irritable bowel syndrome. Am J Gastroenterol 2015; 110: 1339–1346.
A curious case of colitis
What type of colitis would you diagnose?
A 45-year-old Chinese woman presented with a 2-year history of intermittent loose stools, occasional PR bleeding and abdominal pain. The mucosal patches seen on the photograph were found in the left side of the colon. A full set of mucosal biopsy samples were taken and a representative histology slide, stained with H&E, is also shown.WHAT IS THE MOST LIKELY DIAGNOSIS? a) Schistosomal colitis b) Crohn’s colitis c) Ulcerative colitis d) Ischaemic colitis e) Amoebic colitis
On gut microbiota profiles and obesity
Can we prevent obesity by controlling our intestinal flora?
- OECD. Obesity update. June 2014.
- Hu H-J, Park S-G, Jang HB, et al. Obesity alters the microbial community profile in Korean adolescents. PLoS ONE 2015 10: e0134333.
Gastric balloons join the fight against obesity
How can we tackle obesity?
Obesity is one of today’s most worrying public health problems; it strongly correlates with cardiovascular disease, diabetes, cancer and non-alcoholic fatty liver disease, among other pathologies associated with metabolic syndrome.According to the World Health Organization (WHO),1 the worldwide prevalence of obesity has more than doubled since 1980; in 2014, a whopping 39% of adults aged 18 years and older were overweight and 13% were obese. The culprits? Ever-increasing sedentary lifestyles and overconsumption of high-fat/high-sugar foods. Which means that the solution should be very easy—to move more and eat less of the wrong foods—right? Unfortunately, there is no simple solution/easy answer. Obesity encompasses many social and psychological layers, which are difficult to get past. Children and adults are constantly exposed to advertisements on how tasty and delicious sugary drinks or high-fat/high-sugar foods are, not to mention the fun and approval associated with sharing them with friends. At the same time, kids will play on their videogame consoles or chat with friends online, rather than going outside and doing the exact same things… for real. Not that I am against any of those things, but a knowledge-based balance is essential. Healthy lifestyles are now being heavily promoted at the societal level, starting from a very early age; as an example, the WHO has created a commission on ending childhood obesity, taking into account the different economic and cultural contexts of each region of the world. The medical community itself has been changing gears in the fight against obesity. Several recent clinical guidelines advise doctors to think of obesity as a disease and to have a more active role in treating obese patients to help them achieve weight loss.2 As a result, most medical practitioners now require that their patients engage in healthy lifestyles before any medical or surgical procedure is considered. In particular, gastroenterologists are stepping up their game. As stated by Professor Mathus-Vliegen, Gastroenterologist and Professor in Clinical Nutrition at the Academic Medical Centre, University of Amsterdam, there are several natural reasons why gastroenterologists should take care of obese patients: many obesity-associated diseases develop in the gastrointestinal tract; patients with complications arising from bariatric surgery can be managed using minimally invasive endoscopic techniques; and the gastrointestinal tract is also the target for other forms of treatment, like endoscopic therapy.3 Indeed, endoscopic bariatric treatment of obesity has recently jumped into the spotlight since the US Food and Drug Administration (FDA) approved the use of two different inflatable medical devices, which are delivered to the stomach via a quick and minimally invasive endoscopic procedure and that trigger a feeling of fullness to help with weight loss. The ReShape™ Integrated Dual Balloon System consists of two attached balloons that are filled and sealed separately in the stomach of the patient during an endoscopic procedure. 326 obese patients (BMI 30–40 kg/m2), who had at least one obesity-related health condition, participated in the clinical study that led to the FDA approval.4 Individuals who received the device lost an average of 6.8% of their total body weight at the time of removal (6 months after placement) compared with an average of 3.3% in the control group. The ORBERA™ Intragastric Balloon System uses a single balloon that can be filled with different amounts of saline. In the pivotal ORBERA™ clinical trial in the US, 255 obese patients (BMI 30–40 kg/m2) were randomly allocated to the treatment and control groups.5 The treatment group lost 3.1 times as much weight as the control group at 6 months. Gastric balloons have been around for years outside the US and are not without controversy. Both of the obesity devices approved by the FDA are temporary and should be removed after 6 months. As such, are they effective in the long term? The clinical trials showed that patients were able to keep off most of the weight they had lost 6 months after removal of the device. But whether the same is true for longer periods of time is not clear. It is also important to note that both trials used obesity devices as adjuncts to lifestyle modification and it would be interesting to see their effect in isolation, for patients unable to diet and exercise. Whatever the case might be, it is clear that gastroenterologists are on the look out for obesity, which is also reflected by the increasing discussion of this topic at speciality meetings. At UEG Week 2015, for instance, you can expect to hear all about potential novel solutions for obesity, new developments in our knowledge on the gut-brain axis and cancer as they relate to obesity, as well as a dedicated symposium on its epidemiology, treatment and management. I am curious to see what gastroenterologists will bring to the table this time around! References
- World Health Organization. Obesity and overweight. Fact Sheet No 311 (January 2015) http://www.who.int/mediacentre/factsheets/fs311/en/.
- Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol 2014; 63: 2985–3023.
- Mathus-Vliegen EM. Endoscopic treatment: the past, the present and the future. Best Pract Res Clin Gastroenterol 2014; 28: 685–702.
- Ponce J, Woodman G, Swain J, et al. The REDUCE pivotal trial: a prospective, randomized controlled pivotal trial of a dual intragastric balloon for the treatment of obesity. Surg Obes Relat Dis 2015; 11: 874–881.
- Abu Dayyeh BK, Eaton LL, Woodman G, et al. 444. A randomized, multi-center study to evaluate the safety and effectiveness of an intragastric balloon as an adjunct to a behavioral modification program, in comparison with a behavioral modification program alone in the weight management of obese subjects. Gastrointest Endosc 2015; 81: Supplement, Page AB147.
An incidental gastric finding
What would you diagnose in this elderly, overweight man with diabetes and iron deficiency anaemia?
The lesion in the photographs was noted in the stomach of an overweight 70-year-old man with diabetes who was undergoing gastroscopy because of iron deficiency anaemia.WHAT IS YOUR ENDOSCOPIC DIAGNOSIS? a) Lymphangiectatic cyst b) Small gastrointestinal stromal tumour (GIST) c) Small leiomyoma d) Xanthelasma e) Small signet ring cell carcinoma
Summer School on Nutrition
Get practical, up-to-date information on the management of healthy children or those with specific illnesses.
A scary looking polyp
What would you do if you found this polyp in the high rectum of an elderly patient?
These four photographs show a polyp that was found in the high rectum of an elderly patient.WHAT WOULD YOU DO NEXT? a) Take a full set of samples and wait for histology findings b) Take samples and request an endoscopic ultrasound (EUS) c) Take samples and request staging X-rays d) Resect the polyp endoscopically e) Refer the polyp for transanal resection
Endoscopy Symposium 2015
16 recordings cover recent advances and new endoscopic techniques presented at this symposium.
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.1,2The 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?
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
- 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
- Pizarro T. Intestinal fibrosis (IBD) including models. Presentation in the "GI organ-specific fibrosis" session at UEGF Teaching Activity on Basic Science 2011.
- Kiesler P, et al. Experimental models of inflammatory bowel diseases. Cell Mol Gastroenterol Hepatol 2015; 1: 154–170.
- Wells JM, and Spence JR. How to make an intestine. Development 2014; 141: 752–760.
- Sato T, et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Battett’s epithelium. Gastroenterology 2011; 141: 1762–1772.
- Watson CL, et al. An in vivo model of human small intestine using pluripotent stem cells. Nat Med 2014; 20: 1310–1314.
- 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.
- Rodansky ES, et al. Intestinal organoids: a model of intestinal fibrosis for evaluating anti-fibrotic drugs. Exp Mol Pathol 2015; 98: 346–351.
- Lancaster MA and Knoblich JA. Organogenesis in a dish: modelling development and disease using organoid technologies. Science 2014; 345: 1247125.
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?