Thomas Klag

Defective Antibacterial Barrier in Inflammatory Bowel Disease

The pathogenesis of inflammatory bowel disease (IBD) is very complex, including a variety of genetic and environmental contributing factors. In this context, over the past few years, a picture of IBD as a primary defect of the innate immune system rather than the adaptive immune system has evolved. The intestinal antimicrobial barrier morphologically consists of a single layer of epithelial cells and the mucus and constitutes the first defense mechanism against the microbial burden of the gut. From a more mechanistic point of view, this barrier additionally depends on a crucial interplay between the mucus and antimicrobial peptides like for instance defensins. Disturbances in this system are in the pathophysiological center stage of IBD genesis and progression. In this article we will give a short overview about some of the key mechanisms in this context with special attention on defensins and the mucus layer.

High Demand for Psychotherapy in Patients with Inflammatory Bowel Disease

Background: The relative contribution of psychological factors to the onset and course of inflammatory bowel diseases (IBD) is a matter of constant debate since its beginning, as is the clinical need and the efficacy of psychotherapeutic interventions. However, the perspective of patients with IBD has largely been ignored in this debate. Methods: Psychometric tests including the Short-Form IBD Questionnaire (SIBDQ), the ADAP test measuring demand for psychotherapy, and the Fear-of-Progression Questionnaire Short Form as well as disease-related questions were positioned on the internet between December 2014 and January 2016. The study was advertised through DCCV (German branch of the European Federation of Crohns and Ulcerative Colitis Associations). Results: n = 631 patients responded, and complete data from n = 578 (356 Crohns disease, 219 ulcerative colitis, 3 unclear) were available for analysis. n = 296 had previous experiences with psychotherapy, whereas n = 282 had not. This distribution clearly determined the factor “demand for psychotherapy” (chi-square = 23.7, P < 0.001). When all available data were entered into a (stepwise-forward) regression model, psychotherapy demand was dependent on previous experience (P < 0.001), fear of progression (P < 0.001), quality of life (P = 0.001), smoking (P = 0.003), and previous surgery (P = 0.005) with the total model explaining 29.7% of the variance. The total explained variance of this model was higher in ulcerative colitis (37.6%) than in Crohns disease alone (25.4%). Conclusions: The demand for psychotherapy as additional therapy in IBD depends on previous experience with psychotherapy, fear for disease progression but also other disease or social characteristics and quality of life.

Endoscopic Balloon Dilation for Crohn’s Disease-Associated Strictures

Management of intestinal strictures associated with Crohn’s disease (CD) is clinically challenging despite advanced medical therapy directed toward mucosal healing to positively influence the natural course of CD-associated complications. Although medical therapy is available for inflammatory strictures, therapy of fibrostenotic strictures is the domain of surgery and endoscopy. Endoscopic balloon dilation (EBD) has been recognized as a well-established first-line procedure in terms of safety and efficacy. Although surgery is a valuable treatment modality for the management of CD-related strictures, EBD can help prevent multiple surgical interventions, which might in the long-term lead to a risk of short bowel syndrome. In this review we discuss requirements, techniques, safety, short- and long-term outcomes, as well as combinations of this procedure with surgical and medical treatment in CD-associated intestinal strictures.

Practical guidance for the management of iron deficiency in patients with inflammatory bowel disease

Iron deficiency or iron deficiency anemia (IDA) are some of the most common systemic complications of inflammatory bowel diseases (IBD). Symptoms such as fatigue, reduced ability to concentrate and reduced exercise tolerance can mimic common symptoms of IBD and can therefore easily be overseen. Furthermore, clinicians tend to see mild to moderate anemia as an inevitable accompaniment of IBD that is sufficiently explained by the underlying disease and does not require further workup. But in contrast to these clinical routines, current guidelines recommend that any degree of anemia in patients with IBD should be further evaluated and treated. Multiple studies have shown that anemia is a main factor for decreased quality of life (QoL) in patients with IBD. Correction of anemia, however, can significantly improve the QoL of patients with IBD. It is therefore recommended that every patient with IBD is regularly screened for iron deficiency and anemia. If detected, appropriate workup and treatment should be initiated. Over the last years, a number of new diagnostic tools and treatment options have been developed. Multiple studies have demonstrated the safety of newer formulations of intravenous iron in patients with IBD and have compared oral and intravenous iron in various situations. Treatment recommendations have changed and new evidence-based guidelines were developed. However, to date these guidelines are still not widely implemented in clinical practice. The aim of this review is to draw attention to the need for treatment for every level of anemia in patients with IBD and to provide some practical guidance for screening, diagnostics, treatment and follow up of IDA in patients with IBD following current international guidelines.

GLP-2 analog teduglutide significantly reduces need for parenteral nutrition and stool frequency in a real-life setting

Background: To evaluate the benefits of teduglutide in a real-life setting, we analyzed the data of 14 patients with short bowel syndrome treated with teduglutide. Additionally, we studied glucagon-like peptide 2 (GLP-2) receptor expression in samples of small intestinal and colonic tissue to provide explanations for clinical observations. Methods: Stool frequency and consistency, sensation of thirst, parental calorie or fluid uptake and the number of days on parenteral support per week were collected for up to 2 years. Quantitative real-time polymerase chain reaction of the GLP-2 receptor in healthy controls was performed to better understand clinical response in different patient subgroups. Results: There was a significant reduction in parenteral support after 24 and 48 weeks (by 11.0 and 36.6%, respectively; p < 0.05). Further major improvements were made in several patients after over 1 year (reduction by 79.3%, p < 0.05). The proportion of patients who reduced parenteral support by at least 20% was 33.3%, 54.5% and 71.3% after 24 weeks, 48 weeks and beyond 1 year, respectively. Patients on daily parenteral support showed late but strong amelioration. The reduction of thirst was the earliest marker for response. While stool consistency increased (p < 0.01), stool frequency decreased (p < 0.05) significantly after 12 weeks. This reduction was even more pronounced in patients with colon in continuity. Supporting these clinical observations, we found a stronger physiological expression of the GLP-2 receptor in the colon than in the small intestine. Conclusions: Patients benefit from teduglutide in a real-life setting, but in contrast to randomized, controlled studies reduction of parenteral support took longer. We identified early clinical markers of response, such as stool consistency and frequency as well as sensation of thirst. Clinical and molecular observations support the role of the colon as an important target organ of teduglutide.

β-Defensin 1 Is Prominent in the Liver and Induced During Cholestasis by Bilirubin and Bile Acids via Farnesoid X Receptor and Constitutive Androstane Receptor

Background & aims Knowledge about innate antimicrobial defense of the liver is limited. We investigated hepatic expression and regulation of antimicrobial peptides with focus on the human beta defensin-1 (hBD-1). Methods Radial diffusion assay was used to analyze antimicrobial activity of liver tissue. Different defensins including hBD-1 and its activator thioredoxin-1 (TXN) were analyzed in healthy and cholestatic liver samples by qPCR and immunostaining. Regulation of hBD-1 expression was studied in vitro and in vivo using bile duct-ligated mice. Regulation of hBD-1 via bilirubin and bile acids (BAs) was studied using siRNA. Results We found strong antimicrobial activity of liver tissue against Escherichia coli. As a potential mediator of this antimicrobial activity we detected high expression of hBD-1 and TXN in hepatocytes, whereas other defensins were minimally expressed. Using a specific antibody for the reduced, antimicrobially active form of hBD-1 we found hBD-1 in co-localization with TXN within hepatocytes. hBD-1 was upregulated in cholestasis in a graded fashion. In cholestatic mice hepatic AMP expression (Defb-1 and Hamp) was enhanced. Bilirubin and BAs were able to induce hBD-1 in hepatic cell cultures in vitro. Treatment with siRNA and/or agonists demonstrated that the farnesoid X receptor (FXR) mediates basal expression of hBD-1, whereas both constitutive androstane receptor (CAR) and FXR seem to be responsible for the induction of hBD-1 by bilirubin. Conclusion hBD-1 is prominently expressed in hepatocytes. It is induced during cholestasis through bilirubin and BAs, mediated by CAR and especially FXR. Reduction by TXN activates hBD-1 to a potential key player in innate antimicrobial defense of the liver.

Low-grade appendiceal mucinous neoplasm (LAMN) – 3-year endoscopic follow-up underlines benign course of LAMN type 1

Low-grade appendiceal mucinous neoplasms (LAMNs) are neoplastic lesions with potential progression to pseudomyxoma peritonei (PMP). In most cases, diagnosis is made because of suspected acute appendicitis or incidentally by computed tomography (CT). However, incidental diagnosis during colonoscopy is rare. We present the case of a 63-year-old man with a LAMN type 1 lesion, diagnosed at routine colonoscopy for surveillance of ulcerative colitis. Because in earlier surveillance colonoscopies, this lesion was misinterpreted as fecal polution, for the first time, this case describes retrospectively a 3-year endoscopic follow-up of LAMN type 1, underlining the benign course of these kind of lesions compared to type 2 lesions with submucosal infiltration. Even though endoscopy and sonography are not accepted as method of choice to detect LAMN lesions, our case highlights their role regarding diagnosis of small lesions, as CT scan was not able to detect the lesion in our case. Even though LAMNs are rare, awareness of LAMN lesions in routine colonoscopy is favorable as potential progression to PMP can not be ruled out.

Colitis ulcerosa und Morbus Crohn – Chronisch entzündliche Darmerkrankungen

Morbus Crohn und Colitis ulcerosa sind inzwischen relativ gut medikamentos beherrschbar. Trotzdem ist bei etwa 16% (Colitis ulcerosa) bzw. 47% (Morbus Crohn) der Patienten innerhalb von 10 Jahren nach Diagnosestellung eine Operation notig. Prioritat sollte dabei sein, die Lebensqualitat zu verbessern. Da diese jeder unterschiedlich bewertet, ist die Kommunikation mit dem Patienten essenziell.