Antibiotic Therapy for Active Crohn's Disease Targeting Pathogens: An Overview and Update.

Crohn's disease (CD) is a multifactorial chronic disorder that involves a combination of factors, including genetics, immune response, and gut microbiota. Therapy includes salicylates, immunosuppressive agents, corticosteroids, and biologic drugs. International guidelines do not recommend the use of antibiotics for CD patients, except in the case of septic complications. Increasing evidence of the involvement of gut bacteria in this chronic disease supports the rationale for using antibiotics as the primary treatment for active CD. In recent decades, several pathogens have been reported to be involved in the development of CD, but only Escherichia coli (E. coli) and Mycobacterium avium paratubercolosis (MAP) have aroused interest due to their strong association with CD pathogenesis. Several meta-analyses have been published concerning antibiotic treatment for CD patients, but randomized trials testing antibiotic treatment against E. coli and MAP have not shown prolonged benefits and have generated conflicting results; several questions are still unresolved regarding trial design, antibiotic dosing, the formulation used, the treatment course, and the outcome measures. In this paper, we provide an overview and update of the trials testing antibiotic treatment for active CD patients, taking into account the role of pathogens, the mechanisms by which different antibiotics act on harmful pathogens, and antibiotic resistance. Finally, we also present new lines of study for the future regarding the use of antibiotics to treat patients with active CD.

Pathogens in Crohn's Disease: The Role of Adherent Invasive Escherichia coli.

In Crohn's disease (CD), gut dysbiosis is marked by the prevalence of pathogenic bacterial species. Although several microbes have been reported as risk factors or causative agents of CD, it is not yet clear which is the real trigger of the disease. Thirty years ago, a new pathovar of Escherichia coli strain was isolated in the ileal mucosa of CD patients. This strain, called adherent invasive E. coli (AIEC), for its ability to invade the intestinal mucosa, could represent the causative agent of the disease. Several authors studied the mechanisms by which the AIEC penetrate and replicate within macrophages, and release inflammatory cytokines sustaining inflammation. In this review we will discuss about the role of AIEC in the pathogenesis of CD, the virulence factors mediating adhesion and invasion of AIEC in mucosal tissue, the environmental conditions improving AIEC survival and replication within macrophages. Finally, we will also give an overview of the new strategies developed to limit AIEC overgrowth.

Real-Life Effectiveness and Safety of Golimumab and Its Predictors of Response in Patients with Ulcerative Colitis.

BACKGROUND: Golimumab is a new anti-TNF-alpha monoclonal antibody for patients with ulcerative colitis. AIMS: To assess the short- and long-term effectiveness and safety of golimumab in daily clinical practice and to identify predictors of response. METHODS: Consecutive patients treated with golimumab in 22 Italian centers were enrolled. Clinical, laboratory, and endoscopic data were prospectively collected before and during treatment. A subgroup of patients completed a questionnaire to assess personal satisfaction with a golimumab autoinjector system. RESULTS: A total of 196 patients were included. After 3 months, 130 patients were responders (66.3%) and showed significant reductions in mean partial, total, and endoscopic Mayo scores and in mean ESR, C-reactive protein, and fecal calprotectin levels (p < 0.001). Multivariate analysis revealed that a higher total Mayo score (p < 0.001, OR 1.5, 95% CI 1.2-1.8) and naïve status to anti-TNF-alpha (p = 0.015, OR 3.0, 95% CI 1.2-7.5) were predictive of a favorable response. Seventy-seven (39.3%) of the 130 responders maintained a response at month 12 of therapy. There were 17 adverse events, 28 patients needed hospitalization, and 15 patients underwent surgery. Self-administration of the drug was appreciated by most patients. CONCLUSIONS: The efficacy and safety of golimumab in daily clinical practice were confirmed for the short- and long-term treatment of patients with active ulcerative colitis. Patients naïve to the anti-TNF-alpha monoclonal antibody and those with a higher total Mayo score were more likely to respond to golimumab.

IBD: Role of intestinal compartments in the mucosal immune response.

BACKGROUND AND AIMS: Laser capture microdissection (LCM) is a powerful tool for the isolation of specific tissue compartments. We aimed to investigate the mucosal immune response that takes place in different intestinal compartments of IBD patients, dissected by LCM, analyzing cytokines expression profile and endoplasmic reticulum (ER) stress markers. METHODS: Frozen sections of gut were obtained from patients with Crohn's disease (CD), ulcerative colitis (UC) and from controls. Using LCM, surface epithelium (SE) and lamina propria (LP) compartments were isolated and total RNA extracted. The relative expression of Th1, Th17 and Treg cytokines was evaluated by quantitative reverse transcriptase real-time PCR (qRT-PCR), in addition to the assessment of mRNA splicing of the transcription factor X-box binding protein-1 (XBP1). Human neutrophil elastase (HNE) and the transcription factor forkhead box P3 (Foxp3) were also analyzed by immunohistochemistry. RESULTS: The increased expression of IL-17 was observed in both intestinal compartments of IBD patients when compared to controls. IFN- γ, TNF-α , IL-10, HNE and Foxp3 were overexpressed in the LP compartment of both IBD patients as compared to controls. An upregulation of IFN-γ and an infiltration of HNE+ cells was found in the SE of patients with UC. Splicing of XBP1 mRNA was recognized in both intestinal compartments of IBD patients when compared to controls. CONCLUSIONS: In IBD patients, both intestinal compartments are involved in Th17 response, whereas, LP compartment plays a prominent role in Th1 and Treg immune responses. Nevertheless, high level of IFN- γ was found in the SE of UC patients, suggesting that this compartment is involved in the Th1 immune response. Our data also suggested that ER stress signalling is active in both LP and SE compartment of IBD patients, thus advocating that ER stress and immunity are intertwined.

Pathogenic Role of Associated Adherent-Invasive Escherichia coli in Crohn's Disease.

Several lines of evidence suggest that adherent-invasive Escherichia coli (AIEC) strains play an important role in Crohn's disease (CD). The objective of this study was to investigate the pathogenic role of two AIEC strains, LF82 and O83:H1, in CD patients. Organ cultures of colonic biopsies from patients were set up to assess the effects of LF82 and O83:H1 on the expression of CEACAM6, LAMP1, HLA-DR, ICAM1 by immunohistochemistry and of IL-8, IFNʏ, and TNF-α genes by RT-PCR. Moreover, on Caco2 cells, we analyzed the cell cycle, the expression of MGMT and DNMT1 genes, and DNA damage induced by LF82 and O83:H1, by FACS, RT-PCR, and DAPI staining, respectively. Epithelial and lamina propria mononuclear cells (LPMNC) expression of CEACAM6 and LAMP1 were higher in biopsies cultured in the presence of both O83:H1 and LF82 than in biopsies cultured with non-pathogenic E. coli. Both AIEC strains induced increased expression of ICAM-1 on blood vessels and HLA-DR on LPMNC. We observed higher levels of TNF-α, IFN-γ, and IL-8 transcripts in biopsies cultured with both AIEC strains than in those cultured with NP. Both LF82 and O83:H1, block the cell cycle into S phase, inducing DNA damage, and modulate the expression of DNMT1 and MGMT genes. Our data suggest that LF82 and 083:H1 strains of E. coli are able to increase in CD colonic biopsies the expression of all the pro-inflammatory cytokines and all the mucosal immune markers investigated. J. Cell. Physiol. 232: 2860-2868, 2017. © 2016 Wiley Periodicals, Inc.

Interobserver agreement in describing video capsule endoscopy findings: a multicentre prospective study.

BACKGROUND AND AIM: Few studies have specifically addressed interobserver agreement in describing lesions identified during capsule endoscopy. The aim of our study is to evaluate interobserver agreement in the description of capsule endoscopy findings. MATERIALS AND METHODS: Consecutive short segments of capsule endoscopy were prospectively observed by 8 investigators. Seventy-five videos were prepared by an external investigator (gold standard). The description of the findings was reported by the investigators using the same validated and standardized capsule endoscopy structured terminology. The agreement was assessed using Cohen's kappa statistic. RESULTS: As concerns the ability to detect a lesion, the agreement with the gold standard was moderate (kappa 0.48), as well as the agreement relating to the final diagnosis (κ 0.45). The best agreement was observed in identifying the presence of active bleeding (κ 0.72), whereas the poorest agreement concerned the lesion size (κ 0.32). The agreement with the GS was significantly better in endoscopists with higher case/volume of capsule endoscopy per year. Diagnostic concordance was better in the presence of angiectasia than in the presence of polyps or ulcers/erosions. CONCLUSIONS: Correct lesion identification and diagnosis seem more likely to occur in presence of angiectasia, and for readers with more experience in capsule endoscopy reading.