Specific T-cell receptor beta-rearrangements of gluten-triggered CD8+ T-cells are enriched in celiac disease patients' duodenal mucosa.

Celiac disease (CeD) is an autoimmune disorder affecting the small intestine with gluten as disease trigger. Infections including Influenza A, increase the CeD risk. While gluten-specific CD4+ T-cells, recognizing HLA-DQ2/DQ8 presented gluten-peptides, initiate and sustain the celiac immune response, CD8+ α/ß intraepithelial T-cells elicit mucosal damage. Here, we subjected TCRs from a cohort of 56 CeD patients and 22 controls to an analysis employing 749 published CeD-related TCRß-rearrangements derived from gluten-specific CD4+ T-cells and gluten-triggered peripheral blood CD8+ T-cells. We show, that in addition to TCRs from gluten-specific CD4+ T-cells, TCRs of gluten-triggered CD8+ T-cells are significantly enriched in CeD duodenal tissue samples. TCRß-rearrangements of gluten-triggered CD8+ T-cells were even more expanded in patients than TCRs from gluten-specific CD4+ T-cells (p < 0.0002) and highest in refractory CeD. Sequence alignments with TCR-antigen databases suggest that a subgroup of these most likely indirectly gluten-triggered TCRs recognize microbial, viral, and autoantigens.

Effects of high-intensity interval training on functional performance and maximal oxygen uptake in comparison with moderate intensity continuous training in cancer patients: a systematic review and meta-analysis.

INTRODUCTION: High-intensity interval training (HIIT) is an appropriate training modality to improve endurance and therefore contributes to physical performance. This review investigates the effect of HIIT on functional performance in cancer patients. We reviewed the relative peak oxygen uptake (relV̇O2PEAK) and meta-analytical compared HIIT with moderate intensity continuous training (MICT). Furthermore, we took various training parameters under consideration. METHODS: A systematic literature search was conducted in Scopus, PubMed, and Cochrane Library databases. For the review, we included randomized controlled trials containing HIIT with cancer patients. From this, we filtered interventions with additional MICT for the meta-analysis. Outcomes of interest were various functional performance assessments and V̇O2MAX. RESULTS: The research yielded 584 records which fit the inclusion criteria, of which 31 studies with n=1555 patients (57.4±8.6 years) could be included in the overall review and 8 studies in the meta-analysis (n=268, 59.11±5.11 years) regarding relV̇O2PEAK. Different functional outcomes were found, of which walking distance (+8.63±6.91% meters in 6-min walk test) and mobility (+2.7cm in sit and reach test) improved significantly due to HIIT. In terms of relV̇O2PEAK, the performance of cancer patients was improved by HIIT (10.68±6.48%) and MICT (7.4±4.29%). HIIT can be favored to increase relV̇O2PEAK (SMD 0.37; 95% CI 0.09-0.65; I2=0%; p=0.009). Effect sizes for relV̇O2PEAK improvements correlate moderately with total training volume (Spearman's ρ=0.49; p=0.03), whereas percentage increases do not (Spearman's ρ=0.24; p=0.14). CONCLUSION: Functional and physical outcomes were positively altered by different HIIT protocols and forms of implementation, whereas a tendency toward more effectiveness of HIIT vs. MICT was found for relV̇O2PEAK. Future studies should include functional parameters more often, to finally allow a comparison between both training protocols in this regard.

Effects of physical exercise on breast cancer-related secondary lymphedema: a systematic review.

PURPOSE: The aim of this systematic review is to assess the effect of different types of exercise on breast cancer-related lymphedema (BCRL) in order to elucidate the role of exercise in this patient group. METHODS: A systematic data search was performed using PubMed (December 2016). The review is focused on the rehabilitative aspect of BCRL and undertaken according to the PRISMA statement with Levels of Evidence (LoE) assessed. RESULTS: 11 randomized controlled trials (9 with LoE 1a and 2 with LoE 1b) that included 458 women with breast cancer in aftercare were included. The different types of exercise consisted of aqua lymph training, swimming, resistance exercise, yoga, aerobic, and gravity-resistive exercise. Four of the studies measured a significant reduction in BCRL status based on arm volume and seven studies reported significant subjective improvements. No study showed adverse effects of exercise on BCRL. CONCLUSION: The evidence indicates that exercise can improve subjective and objective parameters in BCRL patients, with dynamic, moderate, and high-frequency exercise appearing to provide the most positive effects.

Combined aerobic and resistance training decreases inflammation markers in healthy men.

Our primary aim was to study the effects of 24 weeks of combined aerobic and resistance training performed on the same day or on different days on inflammation markers. Physically active, healthy young men were randomly divided into three groups that performed: aerobic and resistance training consecutively in the same training session (SS) 2-3 days wk-1 or on alternating days (AD) 4-6 days wk-1 as well as control (C). The total training volume was matched in the training groups. The control group was asked to maintain their habitual physical activity and exercise level. Maximal leg press strength (1RM) and peak oxygen uptake (VO2peak ) were measured. Abdominal fat mass was estimated with dual-energy absorptiometry (DXA). High-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor alpha (TNF-α), and adipocytokines resistin, adiponectin, and leptin were analyzed from plasma samples. Training significantly reduced circulating hs-CRP, leptin, and resistin in both training groups (P<.05), whereas MCP-1 and TNF-α decreased only in AD (P<.05). Significant correlations were observed between changes in abdominal fat mass and corresponding changes in MCP-1, leptin, adiponectin, and resistin. Long-term combined aerobic and resistance training reduced markers of subclinical inflammation in healthy young men. The results indicate that a higher frequency of individual exercise sessions might be more beneficial with respect to the anti-inflammatory effects of physical activity. The decreases in inflammation markers seem to be related to decreases in abdominal fat mass.

Neuromuscular Adaptations to Same-Session Combined Endurance and Strength Training in Recreational Endurance Runners.

This study examined neuromuscular adaptations in recreational endurance runners during 24 weeks of same-session combined endurance and strength training (E+S, n=13) vs. endurance training only (E, n=14). Endurance training was similar in the 2 groups (4-6x/week). Additional maximal and explosive strength training was performed in E+S always after incremental endurance running sessions (35-45 min, 65-85% HRmax). Maximal dynamic leg press strength remained statistically unaltered in E+S but decreased in E at week 24 (-5±5%, p=0.014, btw-groups at week 12 and 24, p=0.014 and 0.011). Isometric leg press and unilateral knee extension force, EMG of knee extensors and voluntary activation remained statistically unaltered in E+S and E. The changes in muscle cross-sectional (CSA) differed between the 2 groups after 12 (E+S+6±8%, E -5±6%, p<0.001) and 24 (E+S+7±7%, E -6±5%, p<0.001) weeks. 1 000 m running time determined during an incremental field test decreased in E+S and E after 12 (-7±3%, p<0.001 and -8±5%, p=0.001) and 24 (-9±5%, p=0.001 and -13±5%, p<0.001) weeks. Strength training performed always after an endurance running session did not lead to increased maximal strength, CSA, EMG or voluntary activation. This possibly contributed to the finding of no endurance performance benefits in E+S compared to E.

Neuromuscular adaptations to different modes of combined strength and endurance training.

The present study investigated neuromuscular adaptations between same-session combined strength and endurance training with 2 loading orders and different day combined training over 24 weeks. 56 subjects were divided into different day (DD) combined strength and endurance training (4-6 d·wk(-1)) and same-session combined training: endurance preceding strength (E+S) or vice versa (S+E) (2-3 d·wk(-1)). Dynamic and isometric strength, EMG, voluntary activation, muscle cross-sectional area and endurance performance were measured. All groups increased dynamic one-repetition maximum (p<0.001; DD 13±7%, E+S 12±9% and S+E 17±12%) and isometric force (p<0.05-0.01), muscle cross-sectional area (p<0.001) and maximal power output during cycling (p<0.001). DD and S+E increased voluntary activation during training (p<0.05-0.01). In E+S no increase in voluntary activation was detected after 12 or 24 weeks. E+S also showed unchanged and S+E increased maximum EMG after 24 weeks during maximal isometric muscle actions. A high correlation (p<0.001, r=0.83) between the individual changes in voluntary activation and maximal knee extension force was found for E+S during weeks 13-24. Neural adaptations showed indications of being compromised and highly individual relating to changes in isometric strength when E+S-training was performed, while gains in one-repetition maximum, endurance performance and hypertrophy did not differ between the training modes.

[Jejunal ulcerations - a diagnostic challenge in a patient with coeliac disease]. / Jejunale Ulzerationen - eine diagnostische Herausforderung bei einem Patienten mit Zöliakie.

A subset of patients with coeliac disease (CD) suffers persistent or recurrent complaints despite a strict adherence to a gluten-free diet (GFD) that can be caused by refractory coeliac disease (RCD). We present a patient with weight loss and signs of malassimilation secondary to villous atrophy and jejunal ulcerations complicating known CD. We demonstrate a stepwise approach to the diagnosis and subtyping of RCD and to rule out important alternative causes of jejunal ulcerations. RCD can be classified as type I based on the absence or as type II based on the presence of an aberrant intestinal mucosal lymphocyte population. RCD type I shows a more benign course as these patients usually improve on a treatment consisting of nutritional support and immunosuppressive therapies such as budesonide or azathioprine. In contrast, clinical response to standard therapies in RCD type II is less certain and the prognosis is poor. Several groups suggest that RCD type II should be regarded as low-grade intraepithelial lymphoma which frequently transforms into an aggressive enteropathy associated T-cell lymphoma with a high mortality rate. Therefore, a rapid differentiation of RCD type I and RCD type II is a major clinical challenge to early initiate appropriate treatment modalities.

The mitochondrial protein TCAIM regulates activation of T cells and thereby promotes tolerance induction of allogeneic transplants.

Primary T cell activation and effector cell differentiation is required for rejection of allogeneic grafts in naïve recipients. It has become evident, that mitochondria play an important role for T cell activation. Expression of several mitochondrial proteins such as TCAIM (T cell activation inhibitor, mitochondrial) is down-regulated upon T cell receptor triggering. Here we report that TCAIM inhibited spontaneous development of memory and effector T cells. CD4(+) T cells from Tcaim knock-in (KI) mice showed reduced activation, cytokine secretion and proliferation in vitro. Tcaim KI T cells tolerated allogeneic skin grafts upon transfer into Rag-1 KO mice. CD4(+) and CD8(+) T cells from these mice did not infiltrate skin grafts and kept a naïve or central memory phenotype, respectively. They were unable to acquire effector phenotype and functions. TCAIM altered T cell activation-induced mitochondrial distribution and reduced mitochondrial reactive oxygen species (mROS) production. Thus, TCAIM controls T cell activation and promotes tolerance induction probably by regulating TCR-mediated mitochondrial distribution and mROS production.

Tracheal intubation in patients with odentogenous abscesses and reduced mouth opening.

BACKGROUND: Odentogenous abscesses with involvement of the facial or cervical spaces can be life-threatening and often have to be drained under general anaesthesia. Trismus and swelling can make intubation with a Macintosh laryngoscope difficult or even impossible. However, indirect laryngoscopy has been successful when conventional direct laryngoscopy has failed. Therefore, we evaluated the efficacy of the Glidescope laryngoscope in patients with odentogenous abscesses and the improvement in mouth opening after neuromuscular block. METHODS: After approval of the ethics committee, 100 patients with odentogenous abscesses were randomized to undergo tracheal intubation with the Glidescope or Macintosh laryngoscope. Success rate, visualization of the glottis, intubation duration, and need for supporting manoeuvres were evaluated. RESULTS: Intubation with the Glidescope was always successful, while conventional intubation failed in 17 out of 50 patients (P<0.0001). In all patients in whom conventional tracheal intubation failed, a subsequent attempt with the Glidescope was successful. The view at the glottis (according to Cormack and Lehane; P<0.0001), intubation duration [34 s (CI 27-41) vs 67 s (CI 52-82), mean (95% confidence interval); P=0.0001], and need for supporting manoeuvres (P<0.0001) were significantly different. The inter-incisor distance improved overall with induction of anaesthesia from 2.0 cm (CI 1.8-2.2) to 2.6 cm (CI 2.3-2.9; P<0.0001) and was correlated with the duration of symptoms. CONCLUSIONS: In patients with odentogenous abscesses, the use of a Glidescope laryngoscope was associated with significantly faster tracheal intubation, with a better view, fewer supporting manoeuvres, and a higher success rate than with a conventional laryngoscope. Improvement of the inter-incisor distance after induction of anaesthesia correlated with the duration of symptoms.

Soil application of an encapsulated CO2 source and its potential for management of western corn rootworm larvae.

Western corn rootworm (Diabrotica virgifera virgifera LeConte) larvae use carbon dioxide (CO2) to locate the roots of their hosts. This study investigated whether an encapsulated CO2 source (CO2-emitting capsules) is able to outcompete CO2 gradients established by corn root respiration in the soil. Furthermore, the following two management options with the capsules were tested in semifield experiments (0.5- to 1-m2 greenhouse plots): the disruption of host location and an "attract-and-kill" strategy in which larvae were lured to a soil insecticide (Tefluthrin) between the corn rows. The attract-and-kill strategy was compared with an application of Tefluthrin in the corn rows (conventional treatment) at 33 and 18% of the standard field application rate. Application of the CO2-emitting capsules 30 cm from the plant base increased CO2 levels near the application point for up to 20 d with a peak at day 10. Both the disruption of host location and an attract-and-kill strategy caused a slight but nonsignificant reduction in larval densities. The disruption of host location caused a 17% reduction in larval densities, whereas an attract-and-kill strategy with Tefluthrin added at 33 and 18% of the standard application rate caused a 24 and 27% reduction in larval densities, respectively. As presently formulated, the CO2-emitting capsules, either with or without insecticide, do not provide adequate control of western corn rootworm.

Determination of the weak axial vector coupling λ = gA/gV from a measurement of the ß-asymmetry parameter A in neutron beta decay.

We report on a new measurement of the neutron ß-asymmetry parameter A with the instrument Perkeo II. The main enhancements are the high neutron polarization of P = 99.7(1)% from a novel arrangement of supermirror polarizers and reduced background from improvements in beam line and shielding. The leading corrections were thus reduced by a factor of 4, pushing them below the level of statistical error and resulting in a significant reduction of systematic uncertainty compared to our previous experiments. We derive the ß-asymmetry parameter A0 = -0.11972(45)(stat)((-44)(+32))(sys) = -0.11972((-65)(+53)) and the ratio of the axial vector to the vector coupling constant λ = gA/gV = -1.2761(12)(stat)((-12)(+9))(sys) = -1.2761((-17)(+14)).

Treatment of metastatic colorectal cancer with cetuximab: influence on the quality of life.

BACKGROUND: Epidermal Growth Factor Receptor (EGFR) antibodies are innovative anti-cancer drugs prolonging survival in metastatic colocrectal cancer. However, due to adverse drug reactions, patients develop acneform skin toxicities. We hypothesized that the skin reaction leads to a decline in general (QOL) and dermatological health related quality of life (HQOL). Furthermore, we aimed at evaluating predictors for QOL and HQOL to improve individual adjustment of therapy. METHODS: 40 outpatients with metastatic colocrectal cancer were involved in this study. According to their KRAS status, patients were allocated to 2 groups: The CTCX group (n = 20; KRAS wild-type) was treated with the EGFR-antibody Cetuximab plus chemotherapy, the CT group (n = 20; KRAS mutation) was receiving chemotherapy only. Psychological assessment consisted of questionaires to evaluate QOL and HQOL, depression, coping-styles, health beliefs and the patient´s personality. RESULTS: Between the two groups, no significanct difference in QOL was found, QOL remained stable over the course of treatment. Yet, the severity of the skin reactions had a significant influence on HQOL. Internal health beliefs and high compliance were found to be protective factors, while passive coping strategies, depression and the personality trait neuroticism were identified as risk factors. DISCUSSION: Interdisciplinary cooperation between medical professionals and psycho-oncologists is strongly recommended to encourage patients to embark on and to retain EGFR-antibody therapy. If risk factors are present, psycho-oncological therapy should focus on the minimization of depression and on the development of active coping strategies.

The effects of menstrual cycle phases on immune function and inflammation at rest and after acute exercise: A systematic review and meta-analysis.

The immune system plays an important role in mediating exercise responses and adaptations. However, whether fluctuating hormone concentrations across the menstrual cycle may impact these processes remains unknown. The aim of this systematic review with meta-analysis was to compare baseline concentrations as well as exercise-induced changes in immune and inflammatory parameters between menstrual cycle phases. A systematic literature search was conducted according to the PRISMA guidelines using Pubmed/MEDLINE, ISI Web of Science, and SPORTDiscus. Of the 159 studies included in the qualitative synthesis, 110 studies were used for meta-analysis. Due to the designs of the included studies, only the follicular and luteal phase could be compared. The estimated standardized mean differences based on the random-effects model revealed higher numbers of leukocytes (-0.48 [-0.73; -0.23], p < 0.001), monocytes (-0.73 [-1.37; -0.10], p = 0.023), granulocytes (-0.85 [-0.1.48; -0.21], p = 0.009), neutrophils (-0.32 [-0.52; -0.12], p = 0.001), and leptin concentrations (-0.37 [-0.5; -0.23], p = 0.003) in the luteal compared to the follicular phase at rest. Other parameters (adaptive immune cells, cytokines, chemokines, and cell adhesion molecules) showed no systematic baseline differences. Seventeen studies investigated the exercise-induced response of these parameters, providing some indications for a higher pro-inflammatory response in the luteal phase. In conclusion, parameters of innate immunity showed cycle-dependent regulation at rest, while little is known on the exercise responses. Due to a large heterogeneity and a lack of cycle phase standardization among the included studies, future research should focus on comparing at least three distinct hormonal profiles to derive more specific recommendations for exercise prescription.

RF positivity has substantial influence on the peripheral memory B-cell compartment and its modulation by TNF inhibition.

OBJECTIVES: The role of B cells in rheumatoid arthritis (RA) has been well established with the advent of B-cell targeted therapies. Alterations of peripheral B-cell subsets in RA and heterogeneous modulations of the B-cell compartment under tumour necrosis factor (TNF) inhibition have been described. In this study we examined the influence of rheumatoid factor (RF) positivity on the peripheral B-cell compartment and its modulation under TNF blockade. METHODS: Consecutive patients with RA and inadequate response to methotrexate (MTX) were stratified according to RF status and a subset of them was included in a prospective study of weekly etanercept treatment. RESULTS: At baseline, RF-negative patients had a significant higher percentage of overall CD27+ B cells compared to healthy controls (HC) and RF-positive patients. In detail, RF-negative patients had 46.6% (range 15.7-86.8%) CD27+ B cells compared to 31.3% (12.9-56.9%, p = 0.026) in HC and 29.8% (19-73.3%, p = 0.04) in RF-positive patients. Within the CD27+ compartment, CD27+/immunoglobulin (Ig)D+ memory B cells were significantly increased to 26.4% (range 5.9-54.7%) in RF-negative patients compared to 14.9% (4.1-27.3%, p = 0.006) in HC and 10.5% (3.4-41.1%, p = 0.003) in RF-positive patients. During anti-TNF therapy, memory B cells increased significantly in relative and absolute numbers only in RF-negative patients. CONCLUSIONS: In RF-negative patients, we observed an enhanced frequency of peripheral memory B cells and an accumulation of pre-switch memory B cells. During anti-TNF therapy, memory B cells increased significantly only in RF-negative patients, suggesting that the peripheral memory B-cell compartment is more amenable to TNF inhibition in these patients.

Microbial community shifts induced by plastic and zinc as substitutes of tire abrasion.

Aquatic environments serve as a sink for anthropogenic discharges. A significant part of the discharge is tire wear, which is increasingly being released into the environment, causing environmental disasters due to their longevity and the large number of pollutants they contain. Main components of tires are plastic and zinc, which therefore can be used as substitutes for tire abrasion to study the effect on microbial life. We investigate environmentally realistic concentrations of plastic and zinc on a freshwater microeukaryotic community using high-throughput sequencing of the 18S V9 region over a 14-day exposure period. Apart from a generally unchanged diversity upon exposure to zinc and nanoplastics, a change in community structure due to zinc is evident, but not due to nanoplastics. Evidently, nanoplastic particles hardly affect the community, but zinc exposure results in drastic functional abundance shifts concerning the trophic mode. Phototrophic microorganisms were almost completely diminished initially, but photosynthesis recovered. However, the dominant taxa performing photosynthesis changed from bacillariophytes to chlorophytes. While phototrophic organisms are decreasing in the presence of zinc, the mixotrophic fraction initially benefitted and the heterotrophic fraction were benefitting throughout the exposure period. In contrast to lasting changes in taxon composition, the functional community composition is initially strongly imbalanced after application of zinc but returns to the original state.

Dark matter results from 100 live days of XENON100 data.

We present results from the direct search for dark matter with the XENON100 detector, installed underground at the Laboratori Nazionali del Gran Sasso of INFN, Italy. XENON100 is a two-phase time-projection chamber with a 62 kg liquid xenon target. Interaction vertex reconstruction in three dimensions with millimeter precision allows the selection of only the innermost 48 kg as the ultralow background fiducial target. In 100.9 live days of data, acquired between January and June 2010, no evidence for dark matter is found. Three candidate events were observed in the signal region with an expected background of (1.8 ± 0.6) events. This leads to the most stringent limit on dark matter interactions today, excluding spin-independent elastic weakly interacting massive particle (WIMP) nucleon scattering cross sections above 7.0 × 10(-45) cm(2) for a WIMP mass of 50 GeV/c(2) at 90% confidence level.

First dark matter results from the XENON100 experiment.

The XENON100 experiment, in operation at the Laboratori Nazionali del Gran Sasso in Italy, is designed to search for dark matter weakly interacting massive particles (WIMPs) scattering off 62 kg of liquid xenon in an ultralow background dual-phase time projection chamber. In this Letter, we present first dark matter results from the analysis of 11.17 live days of nonblind data, acquired in October and November 2009. In the selected fiducial target of 40 kg, and within the predefined signal region, we observe no events and hence exclude spin-independent WIMP-nucleon elastic scattering cross sections above 3.4 × 10⁻44 cm² for 55 GeV/c² WIMPs at 90% confidence level. Below 20 GeV/c², this result constrains the interpretation of the CoGeNT and DAMA signals as being due to spin-independent, elastic, light mass WIMP interactions.

Diagnostic value of confocal endomicroscopy in celiac disease.

BACKGROUND: Improved endoscopic screening with targeted biopsies might enhance diagnostic yield in celiac disease. Confocal endomicroscopy (CEM) allows high-resolution in vivo histological analysis. We compared the endomicroscopic findings during ongoing endoscopy with the histological findings graded according to the Marsh classification. METHODS: Twenty-four patients with celiac disease and six patients with celiac disease that was refractory on a gluten-free diet were examined using CEM. The duodenal mucosa was evaluated by CEM and by conventional histological analysis in respect of villous atrophy, crypt hyperplasia, and increased numbers of intraepithelial lymphocytes (IELs > 40 / 100 enterocytes). The CEM results were assessed as to sensitivity, specificity, and interobserver variability. A Marsh classification score determined by CEM was compared to that obtained by histology. Thirty patients undergoing routine upper gastrointestinal endoscopy were used as controls. RESULTS: Conventional histology showed villous atrophy and crypt hyperplasia in 23 and increased numbers of IELs in 27 of the 30 patients with celiac disease. With CEM, villous atrophy, crypt hyperplasia, and increased IELs were respectively identified in 17, 12, and 22 of the 30 patients. The agreement of the findings on CEM with those of conventional histology was good in relation to villous atrophy (sensitivity 74 %) and increased numbers of IELs (sensitivity 81 %), but inadequate in relation to crypt hyperplasia (sensitivity 52 %). The kappa values for determination of interobserver variability were 0.90 for villous atrophy, 1.00 for crypt hyperplasia, and 0.84 for IEL detection. In the 30 control patients, normal duodenal architecture was found by both histology and endomicroscopy, indicating an overall specificity of 100 %. CONCLUSION: The assessment of duodenal histology by CEM in patients with celiac disease is sensitive and specific in determining increased numbers of IELs and villous atrophy, but insufficient in respect of crypt hyperplasia. For routine use of CEM in patients with celiac disease, the technique would need to be improved.

[New therapeutic approaches to special diseases of the small intestine]. / Neue therapeutische Ansätze bei speziellen Erkrankungen des Dünndarms.

Numerous reports on fundamental research and clinical studies have appeared in the past 1-2 decades which have contributed decisively to understanding inflammatory diseases of the small intestine. Illustrated by the examples of Crohn's disease, celiac disease, refractory sprue, and Whipple's disease, the rationale and evidence for treatment approaches are presented that are based on these pathophysiological findings. Emphasis is placed on modulation of the intestinal flora with antibiotics and probiotics as well as immunomodulatory/immunosuppressive measures with so-called biological agents. Future treatment options that directly intervene in the disease process are discussed.