Transcriptional regulation of chemokine network by biologic monotherapy in ileum of patients with Crohn's disease.

BACKGROUND: Crohn's disease (CD) exacerbation is marked by an intense cellular trafficking. We set out to determine the specific impact of biologic therapies on regulating chemokine network gene expression in healthy, mildly and severely inflamed tissue of CD patients. METHODS: Twenty CD patients on biologics (adalimumab, ustekinumab, vedolizumab) or untreated undergoing colonoscopy due to clinical symptoms of flare. Healthy, mildly and severely inflamed ileum biopsies from each patient were collected. Chemokines and receptors gene expression was analyzed and a STRING analysis for functional enrichment was performed. RESULTS: The chemokine network exhibited wide transcriptional differences among tissues in active untreated patients, whereas all biologic treatments reduced these differences and homogenized their transcriptional activity. In mildly inflamed tissue, all treatments showed gene upregulation while ustekinumab additionally maintained the downregulation of genes such as CCL2, CCL3, CCL17 or CCL23, involved in T cell chemotaxis, inflammatory monocyte and NK trafficking. In severely inflamed tissue, all treatments shared a downregulatory effect on chemokines controlling T cell response (i.e. CXCL16, CXCR3). Adalimumab and vedolizumab significantly reduced the expression of genes promoting antigen presentation by DCs and the initiation of leukocyte extravasation (i.e. CXCL12, CCL25, CCR7). Ustekinumab significantly reduced genes positively regulating Th1 cytokine production and IL-8 mediated signaling (i.e. IL1B, XCL1, CXCR1, CXCR2). CONCLUSION: Biologic therapies differentially target the chemokine network gene expression profile in the ileal tissue of active CD patients. These results may contribute to better understanding cell homing and to defining future personalized therapeutic strategies for CD patients.

Bacterial Translocation as Inflammatory Driver in Crohn's Disease.

Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract responsible for intestinal lesions. The multifactorial etiology attributed to CD includes a combination of environmental and host susceptibility factors, which result in an impaired host-microbe gut interaction. Bacterial overgrowth and dysbiosis, increased intestinal barrier permeability, and altered inflammatory responses in patients with CD have been described in the past. Those events explain the pathogenesis of luminal translocation of bacteria or its products into the blood, a frequent event in CD, which, in turn, favors a sustained inflammatory response in these patients. In this review, we navigate through the interaction between bacterial antigen translocation, permeability of the intestinal barrier, immunologic response of the host, and genetic predisposition as a combined effect on the inflammatory response observed in CD. Several lines of evidence support that translocation of bacterial products leads to uncontrolled inflammation in CD patients, and as a matter of fact, the presence of gut bacterial genomic fragments at a systemic level constitutes a marker for increased risk of relapse among CD patients. Also, the significant percentage of CD patients who lose response to biologic therapies may be influenced by the translocation of bacterial products, which are well-known drivers of proinflammatory cytokine production by host immune cells. Further mechanistic studies evaluating cellular and humoral immune responses, gut microbiota alterations, and genetic predisposition will help clinicians to better control and personalize the management of CD patients in the future.

Endocrine disruption in Crohn's disease: Bisphenol A enhances systemic inflammatory response in patients with gut barrier translocation of dysbiotic microbiota products.

The relevance of environmental triggers in Crohn's disease remains poorly explored, despite the well-known association between industrialization and disease onset/progression. We have aimed at evaluating the influence of endocrine disrupting chemicals in CD patients. We performed a prospective observational study on consecutive patients diagnosed of CD. Serum levels of endocrine disruptors, short-chain fatty acids, tryptophan and cytokines were measured. Bacterial-DNA and serum endotoxin levels were also evaluated. Gene expression of ER-α, ER-ß and GPER was measured in PBMCs. All patients were genotyped for NOD2 and ATG16L1 polymorphisms. A series of 200 CD patients (140 in remission, 60 with active disease) was included in the study. Bisphenol A was significantly higher in patients with active disease versus remission and in colonic versus ileal disease. GPER was significantly increased in active patients and correlated with BPA levels. BPA was significantly increased in patients with bacterial-DNA and correlated with serum endotoxin levels, (r = 0.417; P = .003). Serum butyrate and tryptophan levels were significantly lower in patients with bacterial-DNA and an inverse relationship was present between them and BPA levels (r = -0.491; P = .001) (r = -0.611; P = .001). Serum BPA levels correlated with IL-23 (r = 0.807; P = .001) and IL-17A (r = 0.743; P = .001). The multivariate analysis revealed an independent significant contribution of BPA and bacterial-DNA to serum levels of IL-23 and IL-17A. In conclusion, bisphenol A significantly affects systemic inflammatory response in CD patients with gut barrier disruption and dysbiotic microbiota secretory products in blood. These results provide evidence of an endocrine disruptor playing an actual pathogenic role on CD.

Impact of COVID-19 Lockdown in Eating Disorders: A Multicentre Collaborative International Study.

BACKGROUND: The COVID-19 lockdown has had a significant impact on mental health. Patients with eating disorders (ED) have been particularly vulnerable. AIMS: (1) To explore changes in eating-related symptoms and general psychopathology during lockdown in patients with an ED from various European and Asian countries; and (2) to assess differences related to diagnostic ED subtypes, age, and geography. METHODS: The sample comprised 829 participants, diagnosed with an ED according to DSM-5 criteria from specialized ED units in Europe and Asia. Participants were assessed using the COVID-19 Isolation Scale (CIES). RESULTS: Patients with binge eating disorder (BED) experienced the highest impact on weight and ED symptoms in comparison with other ED subtypes during lockdown, whereas individuals with other specified feeding and eating disorders (OFSED) had greater deterioration in general psychological functioning than subjects with other ED subtypes. Finally, Asian and younger individuals appeared to be more resilient. CONCLUSIONS: The psychopathological changes in ED patients during the COVID-19 lockdown varied by cultural context and individual variation in age and ED diagnosis. Clinical services may need to target preventive measures and adapt therapeutic approaches for the most vulnerable patients.

COVID Isolation Eating Scale (CIES): Analysis of the impact of confinement in eating disorders and obesity-A collaborative international study.

Confinement during the COVID-19 pandemic is expected to have a serious and complex impact on the mental health of patients with an eating disorder (ED) and of patients with obesity. The present manuscript has the following aims: (1) to analyse the psychometric properties of the COVID Isolation Eating Scale (CIES), (2) to explore changes that occurred due to confinement in eating symptomatology; and (3) to explore the general acceptation of the use of telemedicine during confinement. The sample comprised 121 participants (87 ED patients and 34 patients with obesity) recruited from six different centres. Confirmatory Factor Analyses (CFA) tested the rational-theoretical structure of the CIES. Adequate goodness-of-fit was obtained for the confirmatory factor analysis, and Cronbach alpha values ranged from good to excellent. Regarding the effects of confinement, positive and negative impacts of the confinement depends of the eating disorder subtype. Patients with anorexia nervosa (AN) and with obesity endorsed a positive response to treatment during confinement, no significant changes were found in bulimia nervosa (BN) patients, whereas Other Specified Feeding or Eating Disorder (OSFED) patients endorsed an increase in eating symptomatology and in psychopathology. Furthermore, AN patients expressed the greatest dissatisfaction and accommodation difficulty with remote therapy when compared with the previously provided face-to-face therapy. The present study provides empirical evidence on the psychometric robustness of the CIES tool and shows that a negative confinement impact was associated with ED subtype, whereas OSFED patients showed the highest impairment in eating symptomatology and in psychopathology.

Liver Sinusoidal Endothelial Cells Contribute to Hepatic Antigen-Presenting Cell Function and Th17 Expansion in Cirrhosis.

Hepatic immune function is compromised during cirrhosis. This study investigated the immune features of liver sinusoidal endothelial cells (LSECs) in two experimental models of cirrhosis. Dendritic cells, hepatic macrophages, and LSECs were isolated from carbon tetrachloride and bile duct-ligated rats. Gene expression of innate receptors, bacterial internalization, co-stimulatory molecules induction, and CD4+ T cell activation and differentiation were evaluated. Induced bacterial peritonitis and norfloxacin protocols on cirrhotic rats were also carried out. LSECs demonstrated an active immunosurveillance profile, as shown by transcriptional modulation of different scavenger and cell-adhesion genes, and their contribution to bacterial internalization. LSECs significantly increased their expression of CD40 and CD80 and stimulated CD4+ T cell activation marker CD71 in both models. The pro-inflammatory Th17 subset was expanded in CCl4-derived LSECs co-cultures. In the bile duct ligation (BDL) model, CD4+ T cell differentiation only occurred under induced bacterial peritonitis conditions. Differentiated pro-inflammatory Th cells by LSECs in both experimental models were significantly reduced with norfloxacin treatment, whereas Foxp3 tolerogenic Th CD4+ cells were expanded. Conclusion: LSECs' participation in the innate-adaptive immune progression, their ability to stimulate pro-inflammatory CD4+ T cells expansion during liver damage, and their target role in norfloxacin-induced immunomodulation granted a specific competence to this cell population in cirrhosis.

Actual Anti-TNF Trough Levels Relate to Serum IL-10 in Drug-Responding Patients With Crohn's Disease.

BACKGROUND: Patients with Crohn's disease (CD) responding to anti-tumor necrosis factor (anti-TNF) show great variability in serum drug levels, even within the therapeutic range. We aimed at exploring the role of inflammatory, genetic, and bacterial variables in relation to anti-TNF through levels in CD patients. METHODS: Consecutive CD patients receiving stable doses of infliximab or adalimumab were included. Clinical and analytical parameters were recorded. Cytokine response, bacterial DNA translocation, and several immune-related genes' genotypes were evaluated, along with serum through anti-TNF drug levels. A linear regression analysis controlled by weight and drug regimen was performed. RESULTS: One hundred nineteen patients were initially considered. Five patients on infliximab and 2 on adalimumab showed antidrug antibodies in serum and were excluded. One hundred twelve patients were finally included (62 on infliximab, 50 on adalimumab). Fourteen patients on infliximab and 15 on adalimumab (22.6% vs 30%, P = 0.37) were receiving an intensified drug regimen. C-reactive protein (CRP), fecal calprotectin, Crohn's Disease Activity Index, leukocyte count, and albumin levels in plasma were not significantly associated with infliximab or adalimumab levels in the multivariate analysis. Serum interleukin-10 (IL-10) levels were directly related to infliximab (Beta = 0.097, P < 0.0001) and adalimumab levels (Beta = 0.069, P = 0.0241). The best multivariate regression model explaining the variability of serum infliximab and adalimumab levels included IL-10. Predicted drug levels by this model robustly fitted with actual drug levels (R2 = 0.841 for infliximab, R2 = 0.733 for adalimumab). CONCLUSION: Serum IL-10 is significantly related to serum anti-TNF levels in CD patients, showing how the disposition of anti-TNF drugs is significantly influenced by the degree of immunological activation.