The Interplay of Biopsychosocial Factors and Quality of Life in Inflammatory Bowel Diseases: A Network Analysis.

GOAL: The aim of this study was to investigate the network of biopsychosocial factors and quality of life (QoL) in persons with inflammatory bowel diseases (IBDs) and explore the influence of psychological factors on the course of the disease. BACKGROUND: QoL of persons with IBD depends on disease activity but also on numerous interacting psychosocial factors. The influence of psychosocial factors on the disease course in controversially discussed. MATERIALS AND METHODS: In 2 independent IBD samples (sample 1: n=209, anonymous internet survey; sample 2: n=84, outpatients with active disease), we measured QoL, anxiety, depression, illness identity, self-esteem, loneliness, childhood trauma, and visceral sensitivity with questionnaires. In addition, fatigue, hemoglobin levels, and response to therapy were assessed in sample 2. We estimated multiple regularized partial correlation networks and conducted accuracy and stability tests of the networks. RESULTS: In both samples, QoL had the strongest relationships with visceral sensitivity and the illness identity engulfment. Depression was the most central factor in the networks. Baseline depression scores, visceral sensitivity, and engulfment were associated with response to therapy in sample 2. CONCLUSIONS: This first network study to assess the interplay between biopsychosocial factors and QoL in IBD reveals a comparable network structure in 2 samples. Results partly replicate findings from previous studies with regard to the importance of depression and yield information on the central role of the newly introduced concepts of illness identity and visceral sensitivity. Preliminary findings point to an influence of these parameters on the disease course, which indicates their role as a possible target in individualized therapy.

Questions to consider when caring for patients with ulcerative colitis.

Although the management of patients with ulcerative colitis (UC) is well defined by national and international guidelines, there are many debates and open questions related to daily care of UC patients. Here, we aimed to review topics with high clinical relevance including therapy algorithms, potential biomarkers for disease prognosis and response to therapy, the role of interventions targeting the gut microbiota, insights from head-to-head trials, novel UC medications, exit strategies, the impact of COVID19 on UC, care of patients with acute severe disease, cancer screening, and the role of surgery.

Validation of the German version of the Short Health Scale - a brief, valid and reliable instrument to assess health-related quality of life in German-speaking patients with inflammatory bowel diseases.

BACKGROUND: Health-related quality of life (hrQoL) may be the most important patient-reported outcome for patients with chronic disorders. The Short Health Scale (SHS) is a brief four-item instrument to assess hrQoL in patients with bowel disorders. This study examined the validity, reliability and sensitivity of the German translation of the SHS in a cohort of outpatients with inflammatory bowel diseases (IBD). METHODS: The study was preregistered in April 2021 (https://doi.org/10.17605/OSF.IO/S82D9). Outpatients with IBD (n=225) in different stages of disease activity (as determined by the Harvey-Bradshaw index or partial Mayo score) completed the German SHS and the short Inflammatory Bowel Disease Questionnaire (sIBDQ) as an established measure of hrQoL to examine the convergent validity. To assess reliability, a subset of patients (n=30) in remission completed the same questionnaires after 4-8 weeks. Sensitivity to change was established from questionnaires of patients with either decreased (n=15) or increased (n=16) disease activity after 3-6 months. RESULTS: The internal consistency of the German SHS was high (Cronbach's α=0.860). SHS total scores correlated strongly with sIBDQ scores (ρ=-0.760, p<0.001) and disease activity (ρ=0.590, p<0.001). Retest reliability was high (ρ=0.695, p<0.001). Sensitivity to change was statistically significant for patients with decreased (p=0.013) but not increased (p=0.134) disease activity. CONCLUSION: The German version of the SHS is a valid and reliable tool to measure hrQoL in persons with IBD.

Depression and fatigue in active IBD from a microbiome perspective-a Bayesian approach to faecal metagenomics.

BACKGROUND: Extraintestinal symptoms are common in inflammatory bowel diseases (IBD) and include depression and fatigue. These are highly prevalent especially in active disease, potentially due to inflammation-mediated changes in the microbiota-gut-brain axis. The aim of this study was to investigate the associations between structural and functional microbiota characteristics and severity of fatigue and depressive symptoms in patients with active IBD. METHODS: We included clinical data of 62 prospectively enrolled patients with IBD in an active disease state. Patients supplied stool samples and completed the questionnaires regarding depression and fatigue symptoms. Based on taxonomic and functional metagenomic profiles of faecal gut microbiota, we used Bayesian statistics to investigate the associative networks and triangle motifs between bacterial genera, functional modules and symptom severity of self-reported fatigue and depression. RESULTS: Associations with moderate to strong evidence were found for 3 genera (Odoribacter, Anaerotruncus and Alistipes) and 3 functional modules (pectin, glycosaminoglycan and central carbohydrate metabolism) with regard to depression and for 4 genera (Intestinimonas, Anaerotruncus, Eubacterium and Clostridiales g.i.s) and 2 functional modules implicating amino acid and central carbohydrate metabolism with regard to fatigue. CONCLUSIONS: This study provides the first evidence of association triplets between microbiota composition, function and extraintestinal symptoms in active IBD. Depression and fatigue were associated with lower abundances of short-chain fatty acid producers and distinct pathways implicating glycan, carbohydrate and amino acid metabolism. Our results suggest that microbiota-directed therapeutic approaches may reduce fatigue and depression in IBD and should be investigated in future research.

A case series of severe breakthrough infections observed in nine patients with COVID-19 in a southwestern German university hospital.

PURPOSE: Vaccination is the key element for protection against COVID-19. Increased vaccination breakthroughs raise the question of whether additional prevention is necessary in case of individual risk factors for a severe course with hospitalization or death despite vaccination. METHODS: Since July 13, 2021, there is an extended reporting requirement by German law. We analyzed our hospitalized patients with vaccine breakthrough infection during the first 8 weeks. RESULTS: Nine of 67 patients (13.4%) hospitalized for COVID-19 (median age 75 years) were fully vaccinated. Five of these patients received intensive care; two patients died. All had received two doses of BNT162b2 vaccines (Pfizer-BioNTech). There was a median of 99 days between complete immunization and symptom onset. All patients suffered from ≥ three comorbidities. Six patients (66.7%) showed a negative Anti-SARS-CoV-2-N titer at the time of vaccine breakthrough, five of these also had Anti-SARS-CoV-2-S titers < 100 U/ml. All determinable cases were Delta variant B.1.617.2. CONCLUSION: Advanced age, underlying cardiorespiratory disease, and the Delta variant of SARS-CoV-2 were associated with hospitalization of our patients, suffering from vaccine breakthrough infection. Avoidance of face masks, lack of immunization of close contacts, and travel to high-risk areas have been observed as modifiable behavioural circumstances. Consistent personal protective measures, vaccination of close caregivers, and increased awareness might be effective measures in addition to COVID-19 booster vaccination for patients at a high risk to suffer a severe course of infection.

Association of ileocolic pedicle division with postoperative complications after restorative proctocolectomy and ileal pouch-anal anastomosis for ulcerative colitis.

BACKGROUND: When performing a restorative proctocolectomy (RPC) with an ileal pouch-anal anastomosis (IPAA), it is common practice to divide the ileocolic artery (ICA) if the patient has a tumor or dysplasia, or in order to gain sufficient length to secure a tension-free anastomosis. However, it is unclear whether there is an association between division of the ICA and the rate of postoperative complications. METHODS: We retrospectively analysed all patients with ulcerative colitis who underwent RPC and IPAA in our department between January 2010 and December 2016. These were divided in two groups, with regard to the ICA being preserved (PRE group) or divided (DIV group). Complications such as stenosis or leakage of the IPAA, perianal fistulas, abscess formation within the lesser pelvis and pouchitis were analysed and compared between both groups. RESULTS: We identified 130 patients meeting the study inclusion criteria, 49 patients in the PRE and 81 patients in the DIV group. No statistical significance was observed in IPAA leakages (p = 0.71), anastomotic strictures (p = 0.33), fistulas (p = 0.19) and pouchitis (p = 0.72). Abscess formation frequency was similar in both groups (p > 0.99). Moreover, short-term (p = 0.53) and long-term complications (p = 0.11) were similar in both groups. A higher conversion rate was observed in obese (p = 0.006) and male (p = 0.02) patients. Within the entire study population, fistulas and IPAA leakages were associated with a higher rate of anastomotic strictures (p = 0.008 and p = 0.02 respectively). CONCLUSION: Our data suggest similar IPAA related complications after either division or preservation of the ICA. Further trials are required in order to examine the trends observed in this study.

Ultrahigh-Throughput ESI-MS: Sampling Pushed to Six Samples per Second by Acoustic Ejection Mass Spectrometry.

We present an acoustic ejection mass spectrometry (AEMS) setup for contactless electrospray ionization mass spectrometry (ESI-MS)-based sample injection at a sampling rate faster than current ESI and matrix-assisted laser desorption ionization (MALDI) techniques. For the direct transfer of samples out of 384-well plates into a modified ESI source, an open port interface (OPI) was combined with a modified acoustic droplet ejection (ADE) system. AEMS has the potential to eliminate bottlenecks known from classical MS approaches, such as speed, reproducibility, carryover, ion suppression, as well as sample preparation and consumption. This setup provided a drastically reduced transfer distance between OPI and ESI electrode for optimum throughput performance and broadens the scope of applications for this emerging technique. To simulate label-free applications of drug metabolism and pharmacokinetics (DMPK) analysis and high-throughput screening (HTS) campaigns, two stress tests were performed regarding ion suppression and system endurance in combination with minor sample preparation. The maximum sampling rate was 6 Hz for dextromethorphan and d3-dextrorphan (each 100 nM) for 1152 injections in 63 s at full width at half-maximum (FWHM) of 105 ms and a relative standard deviation (%RSD) of 7.7/7.5% without internal standard correction. Enzyme assay buffer and crude dog plasma caused signal suppression of 51/73% at %RSD of 5.7/6.7% (n = 120). An HTS endurance buffer was used for >25 000 injections with minor OPI pollution and constant signals (%RSD = 8.5%, FWHM of 177 ms ± 8.5%, n = 10 557). The optimized hardware and method setup resulted in high-throughput performance and enables further implementation in a fully automated platform for ESI-MS-based high-throughput screening.

High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity.

Several features common to a Western lifestyle, including obesity and low levels of physical activity, are known risk factors for gastrointestinal cancers. There is substantial evidence suggesting that diet markedly affects the composition of the intestinal microbiota. Moreover, there is now unequivocal evidence linking dysbiosis to cancer development. However, the mechanisms by which high-fat diet (HFD)-mediated changes in the microbial community affect the severity of tumorigenesis in the gut remain to be determined. Here we demonstrate that an HFD promotes tumour progression in the small intestine of genetically susceptible, K-ras(G12Dint), mice independently of obesity. HFD consumption, in conjunction with K-ras mutation, mediated a shift in the composition of the gut microbiota, and this shift was associated with a decrease in Paneth-cell-mediated antimicrobial host defence that compromised dendritic cell recruitment and MHC class II molecule presentation in the gut-associated lymphoid tissues. When butyrate was administered to HFD-fed K-ras(G12Dint) mice, dendritic cell recruitment in the gut-associated lymphoid tissues was normalized, and tumour progression was attenuated. Importantly, deficiency in MYD88, a signalling adaptor for pattern recognition receptors and Toll-like receptors, blocked tumour progression. The transfer of faecal samples from HFD-fed mice with intestinal tumours to healthy adult K-ras(G12Dint) mice was sufficient to transmit disease in the absence of an HFD. Furthermore, treatment with antibiotics completely blocked HFD-induced tumour progression, suggesting that distinct shifts in the microbiota have a pivotal role in aggravating disease. Collectively, these data underscore the importance of the reciprocal interaction between host and environmental factors in selecting a microbiota that favours carcinogenesis, and they suggest that tumorigenesis is transmissible among genetically predisposed individuals.

Ustekinumab serum concentrations are associated with clinical outcomes in Crohn's disease - a regional multi-center pilot study.

BACKGROUND AND AIM: The role of therapeutic drug monitoring (TDM) in ustekinumab (UST) therapy for Crohn's disease (CD) has not been established, as only few studies have analyzed the relationship between UST serum concentrations and clinical outcome. In this pilot study, we retrospectively examined the potential of UST-concentrations (cUST) 8 weeks after induction (cUSTw8) to predict clinical response at week 16. METHODS: Serum samples and clinical data from patients (n = 72) with moderate to severely active CD who received intravenous induction with UST were retrospectively analyzed. cUST were quantitated using liquid chromatography-tandem mass spectrometry (LC-MSMS). A receiver-operating characteristic (ROC) curve and area under ROC curve (AUROC) was computed to analyze the predictive potential of cUSTw8 for clinical response at week 16 and to determine the minimal therapeutic UST trough concentration. RESULTS: Forty-four patients (61 %) achieved clinical response to UST therapy at week 16. cUSTw8 was moderately effective to predict clinical response with a minimal therapeutic cUSTw8 of 2.0 mg/l (AUC 0.72, p = 0.001). CONCLUSION: Trough concentrations of UST 8 weeks after induction predict clinical response to therapy in week 16 with moderate sensitivity and specificity. TDM using LC-MSMS could prove beneficial in personalized UST therapy of patients with CD by identifying individuals with subtherapeutic concentrations who might benefit from dose escalation.

Clinical and Histopathologic Features of Colorectal Adenocarcinoma in Crohn's Disease.

GOALS: The aim of this study was to assess the histopathologic characteristics of colorectal carcinomas (CRC) in patients with Crohn's disease (CD). BACKGROUND: A higher frequency of microsatellite instability (MSI) is seen in mucinous compared with nonmucinous CRC which suggests that its pathogenesis involves distinct molecular pathways. Several publications reported a higher percentage of mucinous adenocarcinoma in CD patients with CRC. So far, there has been no investigation of MSI in CD patients with mucinous CRC. STUDY: The medical records of patients who underwent surgery for CRC were reviewed and those with a history of CD identified. The data of histologic classification and MSI status of the tumor were investigated. RESULTS: Fourteen patients with CD-associated CRC were identified (5 female, 9 male) resulting in 20 CRC in total. Histologic investigation revealed 7 adenocarcinomas without a mucinous or signet ring cell component. All other CRCs harbored a mucinous (n=11) and/or signet ring cell (n=6) component. All tumors assessed for MSI were found to be microsatellite stable. CONCLUSIONS: Our data indicate that CRCs with signet ring cell and mucinous components were much more common in patients with CD than in patients with sporadic CRC. This observation suggests that CRC in CD represent an own entity with distinct histopathologic and molecular features. This may implicate potential consequences for diagnosis and therapy of CRC in CD in the future as well as new factors to identify patients with an increased risk for developing CRC in CD.

Infection and Predictors of Outcome of Cirrhotic Patients after Emergency Care Hospital Admission.

INTRODUCTION AND AIMS: We aimed to explore the impact of infection diagnosed upon admission and of other clinical baseline parameters on mortality of cirrhotic patients with emergency admissions. MATERIAL AND METHODS: We performed a prospective observational monocentric study in a tertiary care center. The association of clinical parameters and established scoring systems with short-term mortality up to 90 days was assessed by univariate and multivariable Cox regression analysis. Akaike's Information Criterion (AIC) was used for automated variable selection. Statistical interaction effects with infection were also taken into account. RESULTS: 218 patients were included. 71.2% were male, mean age was 61.1 ± 10.5 years. Mean MELD score was 16.2 ± 6.5, CLIF-consortium Acute on Chronic Liver Failure-score was 34 ± 11. At 28, 90 and 365 days, 9.6%, 26.0% and 40.6% of patients had died, respectively. In multivariable analysis, respiratory organ failure [Hazard Ratio (HR) = 0.15], albumin substitution (HR = 2.48), non-HCC-malignancy (HR = 4.93), CLIF-C-ACLF (HR = 1.10), HCC (HR = 3.70) and first episode of ascites (HR = 0.11) were significantly associated with 90-day mortality. Patients with infection had a significantly higher 90-day mortality (36.3 vs. 20.1%, p = 0.007). Cultures were positive in 32 patients with resistance to cephalosporins or quinolones in 10, to ampicillin/sulbactam in 14 and carbapenems in 6 patients. CONCLUSION: Infection is common in cirrhotic ED admissions and increases mortality. The proportion of resistant microorganisms is high. The predictive capacity of established scoring systems in this setting was low to moderate.

Prevalence of inflammatory bowel disease in alcoholic, non-alcoholic and autoimmune pancreatitis.

OBJECTIVES: Patients with inflammatory bowel disease (IBD) frequently reveal features of pancreatic inflammation. However, the prevalence of IBD in patients with alcoholic pancreatitis (AP) and nonalcoholic pancreatitis (NAP) has not yet been determined, and the prevalence of IBD in patients with autoimmune pancreatitis (AiP) from Germany is unknown. AIMS: Thus, we aimed, first, to determine the prevalence of IBD in AP, NAP, and AiP from a tertiary center in Germany and, second, to characterize patients with AiP and IBD. METHODS: We performed a retrospective cross-sectional study to determine the prevalence of IBD in patients with different forms of pancreatitis presenting to our clinic. RESULTS: Compared to the general population and to a control group with viral hepatitis from our clinic, we observed the most significant increase of IBD in patients with AiP (n = 3/28; p < 0.0001 vs. general population, binomial proportion test; p = 0.0112 vs. hepatitis group, Fisher's exact test), followed by a significant increase in subjects with NAP (n = 11/278; p < 0.0001 vs. general population, binomial proportion test; p = 0.0338 vs. hepatitis group, Fisher's exact test). A review of previous studies on the prevalence of IBD among patients with AiP revealed a combined prevalence of 12 % (n = 43/355). Type 2 AiP is significantly more often associated with IBD than type 1 AiP (n = 28/48, 58 % vs. n = 7/129, 5 %; combined patient cohort, p < 10E - 12; Fisher's exact test). CONCLUSIONS: Immune-mediated mechanisms related to IBD may participate in the development of AiP, especially AiP type 2, and may also increase the risk for the development of other forms of pancreatic inflammation.

IRAK1 Drives Intestinal Inflammation by Promoting the Generation of Effector Th Cells with Optimal Gut-Homing Capacity.

IL-1R-associated kinase (IRAK) 1 is an important component of the IL-1R and TLR signaling pathways, which influence Th cell differentiation. In this study, we show that IRAK1 promotes Th17 development by mediating IL-1ß-induced upregulation of IL-23R and subsequent STAT3 phosphorylation, thus enabling sustained IL-17 production. Moreover, we show that IRAK1 signaling fosters Th1 differentiation by mediating T-bet induction and counteracts regulatory T cell generation. Cotransfer experiments revealed that Irak1-deficient CD4(+) T cells have a cell-intrinsic defect in generating Th1 and Th17 cells under inflammatory conditions in spleen, mesenteric lymph nodes, and colon tissue. Furthermore, IRAK1 expression in T cells was shown to be essential for T cell accumulation in the inflamed intestine and mesenteric lymph nodes. Transcriptome analysis ex vivo revealed that IRAK1 promotes T cell activation and induction of gut-homing molecules in a cell-intrinsic manner. Accordingly, Irak1-deficient T cells failed to upregulate surface expression of α4ß7 integrin after transfer into Rag1(-/-) mice, and their ability to induce colitis was greatly impaired. Lack of IRAK1 in recipient mice provided additional protection from colitis. Therefore, IRAK1 plays an important role in intestinal inflammation by mediating T cell activation, differentiation, and accumulation in the gut. Thus, IRAK1 is a promising novel target for therapy of inflammatory bowel diseases.

Development of Bifunctional Inhibitors of Polo-Like Kinase†1 with Low-Nanomolar Activities Against the Polo-Box Domain.

Polo-like kinase 1 (Plk1), a validated cancer target, harbors a protein-protein interaction domain referred to as the polo-box domain (PBD), in addition to its enzymatic domain. Although functional inhibition either of the enzymatic domain or of the PBD has been shown to inhibit Plk1, so far there have been no reports of bifunctional agents with the potential to target both protein domains. Here we report the development of Plk1 inhibitors that incorporate both an ATP-competitive ligand of the enzymatic domain, derived from BI 2536, and a functional inhibitor of the PBD, based either on the small molecule poloxin-2 or on a PBD-binding peptide. Although these bifunctional agents do not seem to bind both protein domains simultaneously, the most potent compound displays low-nanomolar activity against the Plk1 PBD, with excellent selectivity over the PBDs of Plk2 and Plk3. Our data provide insights into challenges and opportunities relating to the optimization of Plk1 PBD ligands as potent Plk1 inhibitors.

Patient position and hypoxemia during propofol sedation for colonoscopy: a randomized trial.

AIM: To evaluate the benefits of the left lateral position in avoiding hypoxemic events in patients undergoing colonoscopy. METHODS: We conducted a randomized, prospective, controlled trial at two study sites in Germany. Patients undergoing colonoscopy under propofol sedation were randomized to either the supine or left lateral position. The primary outcome was oxygen desaturation (SaO2<90%). Secondary outcome measures were apneic events, hypotension, patient satisfaction, propofol dosage, cecal intubation time, and adenoma detection. RESULTS: A total of 412 patients were randomized 1:1 to undergo colonoscopy in the supine or left lateral position. No severe adverse events were observed in either group. Intention-to-treat analysis revealed no significant difference in the frequency of desaturation in the left lateral arm compared with the supine arm (6.8% vs. 12.1%; P=0.064). Patients in the left lateral arm showed lower apnea rates (9.4% vs. 16.2%; P= .040), but had more episodes of hypotension (12.3% vs. 2.9%; P<0.001). The frequency of repositioning was higher in the left lateral group. No significant differences were observed in patient satisfaction and cooperation, propofol dosage, or adenoma detection rate. Patients who were repositioned to facilitate endoscope passage were excluded from per-protocol analysis. The incidence of hypoxemia was lower for the left lateral than for the supine group in per-protocol analysis (1.8% vs. 11.2%; P=0.003). CONCLUSION: The positioning of patients in the left lateral position during propofol sedation for colonoscopy results in lower desaturation rates provided the position can be maintained throughout endoscopy. ClinicalTrials.gov NCT02001792.

Dose-intensified granulocyte-monocyte apheresis in therapy refractory ulcerative colitis.

Granulocyte-monocyte apheresis (GMA) is an emerging therapeutic option in active course of ulcerative colitis (UC). Appropriate GMA dose, including total number, frequency, and duration of the individual GMA session, is a matter of debate. It was the aim of the present study to evaluate the efficacy of a dose-intensified GMA regimen in patients with moderately to severely active UC. A prospective open-label, single-center study was performed in 10 patients with active UC (Rachmilewitz Clinical Activity Index [CAI] ≥ 8 points; Rachmilewitz Endoscopic Index ≥ 7 points). Patients had failed to improve after treatment with steroids and/or immunomodulators. GMA was performed twice weekly for 2 h to a maximum of 10 sessions. In each GMA session, the adsorber was changed after 1 h of treatment time. Four patients achieved remission with a CAI ≤ 4 points. Three patients had a response with an improvement of CAI of ≥3 points. Three patients showed no benefit from GMA. The quality of life score determined by the inflammatory bowel disease questionnaire-Deutschland increased by 26 points in median. First and second filters had similar efficiency in granulocyte and monocyte adsorption. No major adverse effects were observed. Dose-intensified GMA as reported in this study provided an encouraging short-term response rate of 70% in patients with moderately to severely active UC not responding to standard steroid or immunomodulator therapy. Although all patients relapsed not later than 16 weeks, GMA might be useful to reduce steroid and immunomodulator usage, or to delay surgery in this patient group.

From soil to structure, a novel dimeric ß-glucosidase belonging to glycoside hydrolase family 3 isolated from compost using metagenomic analysis.

A recent metagenomic analysis sequenced a switchgrass-adapted compost community to identify enzymes from microorganisms that were specifically adapted to switchgrass under thermophilic conditions. These enzymes are being examined as part of the pretreatment process for the production of "second-generation" biofuels. Among the enzymes discovered was JMB19063, a novel three-domain ß-glucosidase that belongs to the GH3 (glycoside hydrolase 3) family. Here, we report the structure of JMB19063 in complex with glucose and the catalytic variant D261N crystallized in the presence of cellopentaose. JMB19063 is first structure of a dimeric member of the GH3 family, and we demonstrate that dimerization is required for catalytic activity. Arg-587 and Phe-598 from the C-terminal domain of the opposing monomer are shown to interact with bound ligands in the D261N structure. Enzyme assays confirmed that these residues are absolutely essential for full catalytic activity.

Tissue-specific differentiation of a circulating CCR9- pDC-like common dendritic cell precursor.

The ontogenic relationship between the common dendritic cell (DC) progenitor (CDP), the committed conventional DC precursor (pre-cDC), and cDC subpopulations in lymphoid and nonlymphoid tissues has been largely unraveled. In contrast, the sequential steps of plasmacytoid DC (pDC) development are less defined, and it is unknown at which developmental stage and location final commitment to the pDC lineage occurs. Here we show that CCR9(-) pDCs from murine BM which enter the circulation and peripheral tissues have a common DC precursor function in vivo in the steady state, in contrast to CCR9(+) pDCs which are terminally differentiated. On adoptive transfer, the fate of CCR9(-) pDC-like precursors is governed by the tissues they enter. In the BM and liver, most transferred CCR9(-) pDC-like precursors differentiate into CCR9(+) pDCs, whereas in peripheral lymphoid organs, lung, and intestine, they additionally give rise to cDCs. CCR9(-) pDC-like precursors which are distinct from pre-cDCs can be generated from the CDP. Thus, CCR9(-) pDC-like cells are novel CDP-derived circulating DC precursors with pDC and cDC potential. Their final differentiation into functionally distinct pDCs and cDCs depends on tissue-specific factors allowing adaptation to local requirements under homeostatic conditions.

Associations between brain morphology, inflammatory markers and symptoms of fatigue, depression or anxiety in active and remitted Crohn's disease.

BACKGROUND: Fatigue and psychosocial impairments are highly prevalent in IBD, especially during active disease. Disturbed brain-gut-interactions may contribute to these symptoms. This study examined associations between brain structure, faecal calprotectin and symptoms of fatigue, depression and anxiety in persons with Crohn's Disease (CD) in different disease states. METHODS: In this prospective observational study, n=109 participants (n=67 persons with CD, n=42 healthy controls) underwent cranial magnetic resonance imaging, provided stool samples for analysis of faecal calprotectin and completed questionnaires to assess symptoms of fatigue, depression and anxiety. We analysed differences in grey matter volume (GMV) between patients and controls and associations between regional GMV alterations, neuropsychiatric symptoms and faecal calprotectin. RESULTS: Symptoms of fatigue, depression and anxiety were increased in patients with CD compared to controls, with highest scores in active CD. Patients exhibited regionally reduced GMV in cortical and subcortical sensorimotor regions, occipitotemporal and medial frontal areas. Regional GMV differences showed a significant negative association with fatigue, but not with depression or anxiety. Subgroup analyses revealed symptom-GMV-associations for fatigue in remitted, but not in active CD, while fatigue was positively associated with faecal calprotectin in active, but not remitted disease. CONCLUSION: Our findings support disturbed brain-gut-interactions in CD which may be particularly relevant for fatigue during remitted disease. Reduced GMV in the precentral gyrus and other sensorimotor areas could reflect key contributions to fatigue pathophysiology in CD. A sensorimotor model of fatigue in CD could also pave the way for novel treatment approaches.

CCL17 promotes intestinal inflammation in mice and counteracts regulatory T cell-mediated protection from colitis.

BACKGROUND & AIMS: Priming of T cells by dendritic cells (DCs) in the intestinal mucosa and associated lymphoid tissues helps maintain mucosal tolerance but also contributes to the development of chronic intestinal inflammation. Chemokines regulate the intestinal immune response and can contribute to pathogenesis of inflammatory bowel diseases. We investigated the role of the chemokine CCL17, which is expressed by conventional DCs in the intestine and is up-regulated during colitis. METHODS: Colitis was induced by administration of dextran sodium sulfate (DSS) to mice or transfer of T cells to lymphopenic mice. Colitis activity was monitored by body weight assessment, histologic scoring, and cytokine profile analysis. The direct effects of CCL17 on DCs and the indirect effects on differentiation of T helper (Th) cells were determined in vitro and ex vivo. RESULTS: Mice that lacked CCL17 (Ccl17(E/E) mice) were protected from induction of severe colitis by DSS or T-cell transfer. Colonic mucosa and mesenteric lymph nodes from Ccl17-deficient mice produced lower levels of proinflammatory cytokines. The population of Foxp3(+) regulatory T cells (Tregs) was expanded in Ccl17(E/E) mice and required for long-term protection from colitis. CCR4 expression by transferred T cells was not required for induction of colitis, but CCR4 expression by the recipients was required. CCL17 promoted Toll-like receptor-induced secretion of interleukin-12 and interleukin-23 by DCs in an autocrine manner, promoted differentiation of Th1 and Th17 cells, and reduced induction of Foxp3(+) Treg cells. CONCLUSIONS: The chemokine CCL17 is required for induction of intestinal inflammation in mice. CCL17 has an autocrine effect on DCs that promotes production of inflammatory cytokines and activation of Th1 and Th17 cells and reduces expansion of Treg cells.