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Access over 400 recorded highlight sessions from UEG Week 2014.

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Julia Kasper


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E  j.kasper@remove-this.medadvice.co.at

 

 

On gut microbiota profiles and obesity

Can we prevent obesity by controlling our intestinal flora?

According to a recent report from the Organisation for Economic Co-operation and Development (OECD), over half of all adults in the OECD area are overweight, and 18% of adults are obese.1 Environmental factors may be a major factor underlying the obesity ‘epidemic’, prompting researchers to harness the potential of metagenomics to comprehensively examine the communities of microorganisms inhabiting the human gut (known as the microbiota) as a novel environmental factor associated with obesity. Metagenomics is the genomic analysis of microbial DNA that enables culture-independent investigation of microbial communities in complex sample material, and the rationale is primarily that differences in the structure and function of the microbiota are key to individual differences in energy harvest and storage.

Recently, Hu et al. carried out an in-depth analysis of the gut microbiota from 67 obese and 67 normal-weight  Korean adolescents.2 The researchers sequenced bacterial ribosomal genes (16S) obtained from stool samples in order to obtain data on the gut bacterial composition of the two groups according to taxonomic rank. Operational taxonomic units were identified using the much-used software QIIME, and taxonomic abundance was calculated using the RDP Classifier.

Firmicutes/Bacteroidetes (F/B) ratios have often been calculated and used to identify potential differences in the microbiota of obese and non-obese individuals. The authors of the present study were not able to identify differences in F/B ratios among obese and non-obese adolescents; to this end, no differences could be detected between the two groups at the phylum level. Meanwhile, significant differences were noticed at the family and genus levels: the proportion of Bacteroides in normal-weight and obese adolescents was 45% and 25%, respectively. Conversely, the proportion of Prevotella in normal-weight adolescents was 16%, but in obese adolescents it was 35%. The authors developed an algorithm that enabled prediction of obesity versus non-obesity based on the relative composition of the genera Bacteroides, Alistipes, Prevotella, Faecalibacterium, and Oscillibacter.

While the title of the article appears to imply that the development of obesity drives gut microbiota in a particular direction, the team does not actually show this. The data presented here are cross-sectional, and no longitudinal data are presented. This means that we do not know whether certain changes in the microbiota lead to obesity or obesity leads to certain changes in the microbiota. Safe to say, however, is that in this particular study cohort, obesity was associated with a certain microbiota profile at the family and genus level.

Regardless of any shortcomings, the work is fascinating. In the event that methods (e.g. sampling methods, DNA extraction from stool, and taxonomic analysis) can be standardized, it may prove useful to simply look at the distribution of bacteria in stool samples in order to identify microbiota differences between disease phenotypes—in this case obesity versus non-obesity—with a view to manipulating the gut flora towards a healthy microbiota. However, there is still a need to identify to which extent the composition of bacterial communities present in stool in fact reflects the relative distribution of these bacteria in the digestive system. Probably even more importantly, it should be investigated to which extent different bacteria share functional properties. Hence, we need to know whether the function of one type of microbiota can be more or less the same as a different type of microbiota due to the potential ability of bacteria to adapt to various ecological and physiological situations.  Furthermore, variation in the structure and function of the microbiota due to differences in genetic factors (age, gender, ethnicity, etc.) should be investigated.

While studies aiming to link microbiota profiles to obesity are booming, we still need large amounts of standardized data in order to answer the question as to if and how we may be able to prevent obesity and metabolic disorder by manipulating gut microbial communities (for instance by prebiotics and/or probiotics), or—potentially—more bespoke cocktails of bacteria. We also need to develop a deeper understanding of the potential short-term and long-term effects of changes in diet on our gut flora. The article by Hu et al. cites a good many papers that have been central to the research linking the gut microbiota with diet and metabolism, so if you’re new to the area, this is a good place to start!

 

References

  1. OECD. Obesity update. June 2014.
  2. 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 [https://www.ueg.eu/week/], 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

  1. World Health Organization. Obesity and overweight. Fact Sheet No 311 (January 2015) http://www.who.int/mediacentre/factsheets/fs311/en/.
  2. 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. 
  3. Mathus-Vliegen EM. Endoscopic treatment: the past, the present and the future. Best Pract Res Clin Gastroenterol 2014; 28: 685–702. 
  4. 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. 
  5. 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.

 

Further UEG Resources

Invasive management of obesity Session at UEG Week 2014.

Obesity and the digestive tract Session at EAGEN Obesity Conference 2013.

Obesity: Causes and consequences for the digestive system Session at EAGEN Obesity Conference 2013.

 

 

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.1,2

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.  

 

 

Your last chance to join

Get in-depth information on Evidence Based Medicine and apply for this unique opportunity by July 26, 2015!

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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