G.L. de'Angelis

Exploring the Diversity of the Bifidobacterial Population in the Human Intestinal Tract

ABSTRACT Although the health-promoting roles of bifidobacteria are widely accepted, the diversity of bifidobacteria among the human intestinal microbiota is still poorly understood. We performed a census of bifidobacterial populations from human intestinal mucosal and fecal samples by plating them on selective medium, coupled with molecular analysis of selected rRNA gene sequences (16S rRNA gene and internally transcribed spacer [ITS] 16S-23S spacer sequences) of isolated colonies. A total of 900 isolates were collected, of which 704 were shown to belong to bifidobacteria. Analyses showed that the culturable bifidobacterial population from intestinal and fecal samples include six main phylogenetic taxa, i.e., Bifidobacterium longum, Bifidobacterium pseudocatenulatum, Bifidobacterium adolescentis, Bifidobacterium pseudolongum, Bifidobacterium breve, and Bifidobacterium bifidum, and two species mostly detected in fecal samples, i.e., Bifidobacterium dentium and Bifidobacterium animalis subp. lactis. Analysis of bifidobacterial distribution based on age of the subject revealed that certain identified bifidobacterial species were exclusively present in the adult human gut microbiota whereas others were found to be widely distributed. We encountered significant intersubject variability and composition differences between fecal and mucosa-adherent bifidobacterial communities. In contrast, a modest diversification of bifidobacterial populations was noticed between different intestinal regions within the same individual (intrasubject variability). Notably, a small number of bifidobacterial isolates were shown to display a wide ecological distribution, thus suggesting that they possess a broad colonization capacity.

Polymorphisms of tumor necrosis factor-α but not MDR1 influence response to medical therapy in pediatric-onset inflammatory bowel disease

Aim:We investigated the contribution of variants of tumour necrosis factor (TNF)-α and MDR1 genes in the predisposition and response to medical therapy in a large pediatric cohort of patients with Crohn disease (CD) and ulcerative colitis (UC). Patients and Methods:In this study, 200 patients with CD, 186 patients with UC, 434 parents (217 trios), and 347 healthy unrelated controls were investigated. Single-nucleotide polymorphisms −G308A and −C857T of the TNF-α gene and C3435T of the MDR1 gene were investigated and correlated with clinical subphenotypes and efficacy of medical therapy. Results:The frequency of the −308A allele of the TNF-α gene was significantly increased in both patients with CD (15%; odds ratio [OR] = 2.79; P < 0.01) and patients with UC (11%; OR = 1.96; P < 0.003) compared with controls (6%). Carriers of this allele were 27% in CD (OR = 2.94; P < 0.01) and 19% in UC (OR = 1.86; P = 0.015) compared with 11% in healthy controls. No significant difference was found for both the −C857T and C3435T single-nucleotide polymorphisms. With the genotype/phenotype analysis, no correlation in patients with UC with the MDR1 gene was found. CD carriers of the −308A allele had a higher frequency of surgical resection (35% vs 20%; OR = 2.1; P = 0.035) and more frequent resistance to steroids (22% vs 8%; OR = 0.29; P = 0.032) compared with noncarriers. These findings were confirmed by stepwise logistic regression. Conclusions:In our pediatric cohort, the promoter −308A polymorphism of TNF-α but not the MDR1 gene is significantly involved in the predisposition to both CD and UC. This polymorphism carries a significant reduction in response to steroid therapy, probably leading to a more frequent need for surgical resection.

Dual vs. Triple Therapy for Childhood Helicobacter pylori Gastritis: a Double-Blind Randomized Multicentre Trial

Background.  Data on the efficacy of eradication treatment for Helicobacter pylori gastritis in children are scarce.

Infliximab for pediatric ulcerative colitis: a retrospective Italian multicenter study.

BACKGROUND Infliximab (IFX), the chimeric anti TNFalpha antibody, an established treatment for Crohns disease in adults and in children, is used less frequently in ulcerative colitis (UC). AIM OF THE STUDY To report the clinical course of pediatric patients with active UC receiving IFX. PATIENTS AND METHODS Charts of 22 patients were reviewed (13 male, 9 female): 4 with a severe UC attack refractory to systemic corticosteroids (CS); 18 with a protracted course, of which 16 CS-dependent and 2 CS-resistant. The baseline therapeutic program consisted of 3 consecutive intravenous infusions (0, 2, 6 weeks) of IFX (5 mg/kg), followed by a retreatment schedule (infusion every 8 weeks); azathioprine (AZA) was administered chronically in all. Clinical evaluation was done with the Lichtiger Colitis Activity Index (LCAI). Follow-up was performed until week 54. LCAI >/= 9 was considered treatment failure; a LCAI </= 2 was consistent with remission. RESULTS All 22 patients began the study with a LCAI > 9: 12 had a full response and were on remission at week 54 and did not receive CS (8 on IFX re-treatment and AZA, 4 on AZA alone); 6 had a partial response; 4 were non responders. Colectomy was performed in 7 patients, beyond the period of the acute attack in all but one. CONCLUSIONS In children with severe ulcerative colitis IFX is a valuable treatment for inducing remission, avoiding emergency colectomy; retreatment may be offered to maintain remission.

Elucidating the gut microbiome of ulcerative colitis: bifidobacteria as novel microbial biomarkers

Ulcerative colitis (UC) is associated with a substantial alteration of specific gut commensals, some of which may be involved in microbiota-mediated protection. In this study, microbiota cataloging of UC patients by 16S rRNA microbial profiling revealed a marked reduction of bifidobacteria, in particular the Bifidobacterium bifidum species, thus suggesting that this taxon plays a biological role in the aetiology of UC. We investigated this further through an in vivo trial by testing the effects of oral treatment with B. bifidum PRL2010 in a wild-type murine colitis model. TNBS-treated mice receiving 10(9) cells of B. bifidum PRL2010 showed a marked reduction of all colitis-associated histological indices as well as maintenance of mucosal integrity as it was shown by the increase in the expression of many tight junction-encoding genes. The protective role of B. bifidum PRL2010, as well as its sortase-dependent pili, appears to be established through the induction of an innate immune response of the host. These results highlight the importance of B. bifidum as a microbial biomarker for UC, revealing its role in protection against experimentally induced colitis.

Confocal Laser Endomicroscopy in Gastrointestinal and Pancreatobiliary Diseases: A Systematic Review and Meta-Analysis

Confocal laser endomicroscopy (CLE) is an endoscopic-assisted technique developed to obtain histopathological diagnoses of gastrointestinal and pancreatobiliary diseases in real time. The objective of this systematic review is to analyze the current literature on CLE and to evaluate the applicability and diagnostic yield of CLE in patients with gastrointestinal and pancreatobiliary diseases. A literature search was performed on MEDLINE, EMBASE, Scopus, and Cochrane Oral Health Group Specialized Register, using pertinent keywords without time limitations. Both prospective and retrospective clinical studies that evaluated the sensitivity, specificity, or accuracy of CLE were eligible for inclusion. Of 662 articles identified, 102 studies were included in the systematic review. The studies were conducted between 2004 and 2015 in 16 different countries. CLE demonstrated high sensitivity and specificity in the detection of dysplasia in Barretts esophagus, gastric neoplasms and polyps, colorectal cancers in inflammatory bowel disease, malignant pancreatobiliary strictures, and pancreatic cysts. Although CLE has several promising applications, its use has been limited by its low availability, high cost, and need of specific operator training. Further clinical trials with a particular focus on cost-effectiveness and medicoeconomic analyses, as well as standardized institutional training, are advocated to implement CLE in routine clinical practice.

Management of duodenal-jejunal polyps in children with peutz-jeghers syndrome with single-balloon enteroscopy.

Objectives: Children with Peutz-Jeghers syndrome (PJS) have increased risk of polyp-related complications and emergency laparotomies. The aim of the present study was to assess the efficacy and the safety of endoscopic therapy of small bowel polyps using single-balloon enteroscopy (SBE) in children affected by PJS. Methods: Between January 2010 and December 2011, prospectively consecutive PJS children with polyps >15 mm or polyps actively bleeding previously identified using video capsule endoscopy and magnetic resonance imaging underwent therapeutic SBE. The main outcome measurements were the feasibility, the technical performance, and the safety. Results: A total of 10 children (6 boys; median age 13.7 years, range 5.6–15.6) underwent 23 SBE procedures. Four patients had a history of abdominal surgery. A total of 53 polyps were removed, and 23 of them were >15 mm. The majority of polyps were found in jejunum (85%). The mean insertion depths for antegrade and retrograde approach were 200 ± 80 and 100 ± 50 cm beyond the ileal valve, respectively. The mean procedure time was 75 ± 25 minutes. Mild abdominal pain was reported after 3 procedures. In 1 patient a postpolypectomy perforation occurred. Conclusions: In conclusion, SBE is an effective endoscopic tool for treating small bowel polyps in children with PJS, and well-timed polypectomy may optimize patients’ care, preventing polyp-related complications and emergency laparotomy. Further larger multicenter studies are warranted to accurately determine the safety of therapeutic SBE in children.

Gluten peptides drive healthy and celiac monocytes toward an M2-like polarization

Celiac disease (CD) is an immune-mediated enteropathy triggered by ingested gluten in genetically susceptible individuals and sustained by both adaptive and innate immune responses. Recent studies in murine macrophages demonstrated that the activation of arginase (ARG) metabolic pathway by gluten peptides contributes to the modulation of intestinal permeability in vitro. Here we characterize the effects of gluten on arginine metabolism and cell polarization in human monocytes from both healthy and CD subjects; both a simplified enzymatic digestion of gliadin and a physiological digestion of whole wheat have been tested. Results indicate that gluten digests induce the onset of an M2-like phenotype in activated macrophages; more precisely, both isoforms of arginase, ARG1 and ARG2, are induced likely due to the inhibition of mTOR and the consequent induction of C/EBPβ transcription factor. These effects are independent from the origin of gluten as well as from the digestive protocol employed; moreover, no statistical difference can be evidenced between healthy and CD patients, excluding a diverse predisposition of CD monocytes to gluten-triggered polarization with respect to healthy immune cells. Overall, the present findings sustain a role for arginase pathway in the immune response elicited by human monocytes toward ingested gluten that, hence, deserves particular attention when addressing the pathogenesis of CD.

Widespread Nivolumab-induced Enteropathy in a Long Responder Non–Small-cell Lung Cancer Patient

The outcomes of patients with advanced nonesmallcell lung cancer will be dramatically improved in a significant proportion of cases by administration of immune checkpoint blockers (ICBs) and further disruption of the programmed cell death 1 (PD-1)/ programmed cell death ligand 1 (PD-L1) axis. AntiePD-1 (nivolumab, pembrolizumab) and antiePDL1 (atezolizumab) agents have resulted in better and more durable disease responses compared with standard chemotherapy in the pretreatment setting. ICBs are generally well tolerated; nevertheless, immune-related toxicities can be severe and require special clinical attention given their potential to emerge at any time during or even after treatment. We report the case of a young woman with advanced lung adenocarcinoma who had continued to maintain a remarkable and sustained response to nivolumab for more than 2 years, which was administered as thirdline treatment. In our patient, nivolumab administration caused enteral toxicity several months after achieving a disease response. The enteral toxicity involved all portions of the upper and lower intestines at differential time points and led to definitive drug discontinuation. Considering the late-occurring, extensive involvement of the enteric tract by nivolumab immune-related toxicity, treatment with ICBs requires effective management.