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Background Fecal metabolomic profiles differ between pediatric inflammatory bowel disease (IBD) patients and controls and may provide new insights in the pathophysiology of IBD. The role of amino acids, however, is not fully elucidated. We aimed to assess fecal amino acid profiles in pediatric IBD. Methods In this case-control study, treatment-naïve, newly diagnosed pediatric IBD patients and a non-IBD control group, matched based on sex and age, were included in 2 tertiary centres. Fecal amino acid profiles were assessed using a targeted high-performance liquid chromatography technique. A random forest classifier method was used to develop a prediction model differentiating IBD from controls and predicting IBD phenotype. The association between IBD localization and amino acid concentrations was tested with ordinal regression models. Results We included 78 newly diagnosed IBD patients (40 Crohn’s disease [CD], 38 ulcerative colitis [UC]) and 105 controls. Patients with IBD could be differentiated from controls with an accuracy of 82% (sensitivity 63%, specificity 97%). Twenty-nine out of the 42 measured unique amino acids were included in the prediction model. Increased levels of tryptophan, taurine, alanine, ornithine, valine, histidine, and leucine were the most differentiating features. Children with CD and UC could be differentiated from the controls with an accuracy of 80% and 90%, respectively. Inflammatory bowel disease phenotype could not be predicted. Tryptophan, valine, and histidine levels were positively associated with more extended disease in UC patients (P < .05). Conclusions Fecal amino acids may enhance understanding of the role of host-microbial interactions in the pathophysiology of IBD and may evolve into biomarkers for pediatric IBD diagnostic and personalized medicine.

BACKGROUND: Antibodies to infliximab (ATI) are associated with secondary loss of response and increased risk for drug reactions. Limited studies have associated ATI with increased infliximab clearance. AIMS: We assessed the impact of ATI on infliximab clearance and loss of response in an inception paediatric Crohn’s disease cohort with 1-year follow-up. METHODS: This multi-centre prospective cohort study collected peak and trough serum infliximab/ATI concentrations from 660 infusions (78 patients) during the first year of therapy. Clinicians were blinded to these research labs. The primary outcome was the difference in infliximab clearance between ATI-positive (ATI) and ATI-negative (no-ATI) patients. Secondary outcomes included pre-treatment predictors of ATI (including HLA-DQA1 genotyping). Clinical remission, loss of response and infliximab clearance were compared between pre-ATI, during ATI and following ATI resolution with MANOVA. Time to ATI was calculated by Cox proportional Hazards model. RESULTS: ATI were detected in 68% (53/78) patients with a median concentration of 76 ng/mL (range 23–1828). Maximum ATI concentration was 6 and starting dose

ObjectiveWe aimed to provide an evidence-supported update of the ECCO-ESPGHAN guideline on the medical management of paediatric Crohn’s disease [CD].MethodsWe formed 10 working groups and formulated 17 PICO-structured clinical questions [Patients, Intervention, Comparator, and Outcome]. A systematic literature search from January 1, 1991 to March 19, 2019 was conducted by a medical librarian using MEDLINE, EMBASE, and Cochrane Central databases. A shortlist of 30 provisional statements were further refined during a consensus meeting in Barcelona in October 2019 and subjected to a vote. In total 22 statements reached ≥ 80% agreement and were retained.ResultsWe established that it was key to identify patients at high risk of a complicated disease course at the earliest opportunity, to reduce bowel damage. Patients with perianal disease, stricturing or penetrating behaviour, or severe growth retardation should be considered for up-front anti-tumour necrosis factor [TNF] agents in combination with an immunomodulator. Therapeutic drug monitoring to guide treatment changes is recommended over empirically escalating anti-TNF dose or switching therapies. Patients with low-risk luminal CD should be induced with exclusive enteral nutrition [EEN], or with corticosteroids when EEN is not an option, and require immunomodulator-based maintenance therapy. Favourable outcomes rely on close monitoring of treatment response, with timely adjustments in therapy when treatment targets are not met. Serial faecal calprotectin measurements or small bowel imaging [ultrasound or magnetic resonance enterography] are more reliable markers of treatment response than clinical scores alone.ConclusionsWe present state-of-the-art guidance on the medical treatment and long-term management of children and adolescents with CD.

Inflammatory bowel disease (IBD) is a chronic, autoimmune disorder of the gastrointestinal tract with numerous genetic and environmental risk factors. Patients with Crohn’s disease (CD) or ulcerative colitis (UC) often demonstrate marked disruptions of their gut microbiome. The intestinal microbiota is strongly influenced by diet. The association between the increasing incidence of IBD worldwide and increased consumption of a westernized diet suggests host nutrition may influence the progression or treatment of IBD via the microbiome. Several nutritional therapies have been studied for the treatment of CD and UC. While their mechanisms of action are only partially understood, existing studies do suggest that diet-driven changes in microbial composition and function underlie the diverse mechanisms of nutritional therapy. Despite existing therapies for IBD focusing heavily on immune suppression, nutrition is an important treatment option due to its superior safety profile, potentially low cost, and benefits for growth and development. These benefits are increasingly important to patients. In this review, we will describe the clinical efficacy of the different nutritional therapies that have been described for the treatment of CD and UC. We will also describe the effects of each nutritional therapy on the gut microbiome and summarize the strength of the literature with recommendations for the practicing clinician.

Introduction: Treatment of celiac disease is a strict life-long gluten-free diet (GFD). The GFD is complex, and counseling by a dietitian is essential. The number of new referrals for GFD education has increased. We studied the feasibility of GFD teaching using distributed education. Methods: The IWK Health Center in Halifax is the only tertiary-care pediatric hospital in the 3 Maritime provinces with GFD experienced dietitians. Families travel long distances to attend teaching sessions. Families outside the Halifax area were offered to participate in the 2.5-hour education sessions held once a month via live videoconference link at their regional hospitals. All participants were surveyed with a 10-item questionnaire assessing the content and delivery and usefulness of information. Results: Over a 6-month period, 39 families attended the sessions, 21 locally and 18 at distributed sites across the Maritimes. The survey was completed by 26 participants (67%). All participants at both sites strongly agreed or agreed that their setting was good for learning and the information provided was easy to understand. There were no significant differences between the 2 groups on any individual questions in the 2 domains assessed (all P > 0.06). Conclusions: Distributed education on GFD is feasible and as effective as in person education. It affords convenience and savings to families by reducing travel costs.

Background The gut microbiome is extensively involved in induction of remission in pediatric Crohn’s disease (CD) patients by exclusive enteral nutrition (EEN). In this follow-up study of pediatric CD patients undergoing treatment with EEN, we employ machine learning models trained on baseline gut microbiome data to distinguish patients who achieved and sustained remission (SR) from those who did not achieve remission nor relapse (non-SR) by 24 weeks. Methods A total of 139 fecal samples were obtained from 22 patients (8–15 years of age) for up to 96 weeks. Gut microbiome taxonomy was assessed by 16S rRNA gene sequencing, and functional capacity was assessed by metagenomic sequencing. We used standard metrics of diversity and taxonomy to quantify differences between SR and non-SR patients and to associate gut microbial shifts with fecal calprotectin (FCP), and disease severity as defined by weighted Pediatric Crohn’s Disease Activity Index. We used microbial data sets in addition to clinical metadata in random forests (RFs) models to classify treatment response and predict FCP levels. Results Microbial diversity did not change after EEN, but species richness was lower in low-FCP samples (, Here, authors present a follow-up on a cohort of 22 pediatric CD patients undergoing EEN treatment to induce remission. They leverage machine learning techniques to show that the baseline microbiome with clinical metadata can predict sustained remission.

Multiple studies have identified that complement becomes activated during inflammation of the intestines yet it is unclear what roles the split complement molecules play. The epithelium, in particular, may be impacted and accordingly, we first discovered that colonic cell lines indeed possess the C5aR. Here we examined whether these cells also possess the C3aR. We determined that T84, HT-29 and Caco2 all possess C3aR mRNA and protein; T84 and HT29 were used to further explore the consequence of C3a binding the C3aR. C3a led to increased mRNA for CXCL2, CXCL8 and CXCL11. Polarized T84 monolayers responded to apically applied C3a with increased CXCL8 mRNA more rapidly than if the C3a was applied basolaterally. Polarized monolayers also increased permeability when treated with C3a. ERK1/2 was activated by C3a and the increase in CXCL8 mRNA was ERK-dependent in both T84 and HT-29. C3a resulted in activation of Gαi, determined by the ERK1/2 signal showing sensitivity to pertussis toxin. The transmembrane signal was further mapped to include Ras and c-Raf. Finally, we show that the C3aR is expressed by primary cells in mouse enteroids. We conclude that complement activation will contribute to the epithelial response during inflammation through C3a binding to the C3aR including by priming the cells to upregulate mRNA for selected chemokines.

Background and Aims Exclusive enteral nutrition [EEN] is recommended as a first-line induction therapy for paediatric Crohn's disease [CD] although corticosteroids [CS] are still used commonly. Our aim was to compare short- and long-term disease outcomes of paediatric CD patients initially managed with either EEN or CS. Methods Medical records of newly diagnosed paediatric CD patients treated with EEN or CS as induction therapy were retrospectively reviewed. To minimise selection bias inherent in observational cohort studies, propensity analysis was carried out. Data on anthropometrics, medical history, and presenting phenotype were collected at time of diagnosis [baseline]; outcomes of interest, including medication use, hospitalisation, surgical procedures, and disease progression were assessed up to 6 years following diagnosis. Results Of 127 patients reviewed, a total of 111 propensity-score matched CD patients receiving EEN [n = 76] or CS [n = 35] were analysed. By 4-12 weeks of induction therapy, 86.6% of EEN-treated patients achieved remission (Paediatric Crohn's Disease Activity Index [PCDAI] ≤ 7.5) compared with 58.1% of patients in the CS-treated group [p < 0.01]. Choice of EEN over CS for induction was associated with avoidance of corticosteroids over a 6-year follow-up period. Analysis of long-term linear growth, hospitalisation, need for biologic therapy, or surgical intervention did not reveal any significant differences. Conclusions These findings suggest that EEN induction therapy is more effective in achieving early remission and is associated with long-term steroid avoidance without increased use of biologics or need for surgery.

Background: Clinical remission achieved by exclusive enteral nutrition (EEN) is associated with marked microbiome changes. In this prospective study of exclusive enteral nutrition, we employ a hierarchical model of microbial community structure to distinguish between pediatric Crohn's disease patients who achieved sustained remission (SR) and those who relapsed early (non-SR), after restarting a normal diet. Methods: Fecal samples were obtained from 10 patients (age 10-16) and from 5 healthy controls (age 9-14). The microbiota was assessed via 16S rRNA sequencing. In addition to standard measures of microbial biodiversity, we employed Bayesian methods to characterize the hierarchical community structure. Community structure between patients who sustained remission (wPCDAI

Background: Exclusive enteral nutrition (EEN) is a first-line therapy in pediatric Crohn's disease (CD) thought to induce remission through changes in the gut microbiome. With microbiome assessment largely focused on microbial taxonomy and diversity, it remains unclear to what extent EEN induces functional changes that thereby contribute to its therapeutic effect. Methods: Fecal samples were collected from 15 pediatric CD patients prior to and after EEN treatment, as well as from 5 healthy controls. Metagenomic data were obtained via next-generation sequencing, and nonhuman reads were mapped to KEGG pathways, where possible. Pathway abundance was compared between CD patients and controls, and between CD patients that sustained remission (SR) and those that did not sustain remission (NSR). Results: Of 132 KEGG pathways identified, 8 pathways differed significantly between baseline CD patients and controls. Examination of these eight pathways showed SR patients had greater similarity to controls than NSR patients in all cases. Pathways fell into one of three groups: 1) no prior connection to IBD, 2) previously reported connection to IBD, and 3) known roles in innate immunity and immunoregulation. Conclusions: The microbiota of CD patients and controls represent alternative ecological states that have broad differences in functional capabilities, including xenobiotic and environmental pollutant degradation, succinate metavolism, and bacterial HtpG, all of which can affect barrier integrity and immune regulation. Moreover, our finding that SR patients were more similar to healthy controls suggests that community microbial function, as inferred from fecal microbiomes, could serve as a valuable diagnostic tool.

A. Palotie on työryhmän Int IBD Genetics Consortium jäsen. One goal of human genetics is to understand the genetic basis of disease, a challenge for diseases of complex inheritance because risk alleles are few relative to the vast set of benign variants. Risk variants are often sought by association studies in which allele frequencies in case subjects are contrasted with those from population-based samples used as control subjects. In an ideal world we would know population-level allele frequencies, releasing researchers to focus on case subjects. We argue this ideal is possible, at least theoretically, and we outline a path to achieving it in reality. If such a resource were to exist, it would yield ample savings and would facilitate the effective use of data repositories by removing administrative and technical barriers. We call this concept the Universal Control Repository Network (UNICORN), a means to perform association analyses without necessitating direct access to individual-level control data. Our approach to UNICORN uses existing genetic resources and various statistical tools to analyze these data, including hierarchical clustering with spectral analysis of ancestry; and empirical Bayesian analysis along with Gaussian spatial processes to estimate ancestry-specific allele frequencies. We demonstrate our approach using tens of thousands of control subjects from studies of Crohn disease, showing how it controls false positives, provides power similar to that achieved when all control data are directly accessible, and enhances power when control data are limiting or even imperfectly matched ancestrally. These results highlight how UNICORN can enable reliable, powerful, and convenient genetic association analyses without access to the individual-level data.

Background Newer strategies that target the microbiome may offer an alternative therapeutic approach for Ulcerative Colitis (UC). We developed a novel diet that targets changes in the microbiome and barrier function that have been reported in UC. The goal of the current study was to evaluate the efficacy of two sequential induction of remission strategies that target the microbiota: the novel diet termed the ulcerative colitis diet (UCD) and an antibiotics cocktail combination in dietary non responders. Methods This was a prospective, single arm, open label, pilot study in patients aged 8–19, with a pediatric UC activity index (PUCAI) scores >10 and ≤45 on stable maintenance therapy (5ASA or thiopurines). PUCAI score was assessed at week 3 and 6. Patients failing to enter remission or intolerant to dietary therapy could receive an open label 14-day course of Amoxycillin, Metronidazole and Doxycycline (AMD), and had PUCAI scored at day 21. Response was defined a decline in PUCAI ≥ 10 points, remission as PUCAI< 10. The primary endpoint was intention to treat (ITT) remission at week 6 with diet as the sole intervention. Results Twenty-three children mean age of 15.1±2.9 years were enrolled. Two patients (1 responder, 1 remission) withdrew by 3 weeks, four required additional therapy by week 3, all were considered failures by ITT. Mean PUCAI decreased at week 3 and 6 from 34.5±9.8 to 21.7±14.9 and 17.6±17.2 respectively (P=0.005, P=0.001) at ITT analysis including all patients. Sixteen out of twenty-three patients (69.6%) responded by week 6. Ten of twenty-three (43.5%) achieved remission by week 6, and nine (39.1%) had clinical remission at week 6. The median fecal calprotectin (FC) level decreased in patients (n=5) who achieved remission from 630 (IQR, 332–1586) μg/g at week 0 to 230 (75–1298) μg/g at week 6. Eight patients received treatment with antibiotics after failing diet, 4/8 (50.0%) subsequently entered remission. Conclusion A dietary intervention called the UC Diet appears to be effective for induction of remission in children with mild to moderate UC. Sequential use of diet, followed by antibiotic therapy in dietary non responders, needs further evaluation as a microbiome directed steroid sparing therapy in patient’s refractory to 5ASA and thiopurines.

Background & AimsRAC1 is a guanosine triphosphatase that has an evolutionarily conserved role in coordinating immune defenses, from plants to mammals. Chronic inflammatory bowel diseases are associated with dysregulation of immune defenses. We studied the role of RAC1 in inflammatory bowel diseases using human genetic and functional studies and animal models of colitis.MethodsWe used a candidate gene approach to HapMap-Tag single nucleotide polymorphisms in a discovery cohort; findings were confirmed in 2 additional cohorts. RAC1 messenger RNA expression was examined from peripheral blood cells of patients. Colitis was induced in mice with conditional disruption of Rac1 in phagocytes by administration of dextran sulfate sodium.ResultsWe observed a genetic association between RAC1 with ulcerative colitis in a discovery cohort, 2 independent replication cohorts, and in combined analysis for the single nucleotide polymorphisms rs10951982 (Pcombined UC = 3.3 × 10−8, odds ratio = 1.43 [95% confidence interval: 1.26–1.63]) and rs4720672 (Pcombined UC = 4.7 × 10−6, odds ratio = 1.36 [95% confidence interval: 1.19–1.58]). Patients with inflammatory bowel disease who had the rs10951982 risk allele had increased expression of RAC1 compared to those without this allele. Conditional disruption of Rac1 in macrophage and neutrophils of mice protected against dextran sulfate sodium–induced colitis.ConclusionsHuman studies and knockout mice demonstrated a role for the guanosine triphosphatase RAC1 in the development of ulcerative colitis; increased expression of RAC1 was associated with susceptibility to colitis.

Background & Aims Exclusive enteral nutrition (EEN) is recommended for children with mild to moderate Crohn’s disease (CD), but implementation is challenging. We compared EEN with the CD exclusion diet (CDED), a whole-food diet coupled with partial enteral nutrition (PEN), designed to reduce exposure to dietary components that have adverse effects on the microbiome and intestinal barrier. Methods We performed a 12-week prospective trial of children with mild to moderate CD. The children were randomly assigned to a group that received CDED plus 50% of calories from formula (Modulen, Nestle) for 6 weeks (stage 1) followed by CDED with 25% PEN from weeks 7 to 12 (stage 2) (n = 40, group 1) or a group that received EEN for 6 weeks followed by a free diet with 25% PEN from weeks 7 to 12 (n = 38, group 2). Patients were evaluated at baseline and weeks 3, 6, and 12 and laboratory tests were performed; 16S ribosomal RNA gene (V4V5) sequencing was performed on stool samples. The primary endpoint was dietary tolerance. Secondary endpoints were intention to treat (ITT) remission at week 6 (pediatric CD activity index score below 10) and corticosteroid-free ITT sustained remission at week 12. Results Four patients withdrew from the study because of intolerance by 48 hours, 74 patients (mean age 14.2 ± 2.7 years) were included for remission analysis. The combination of CDED and PEN was tolerated in 39 children (97.5%), whereas EEN was tolerated by 28 children (73.6%) (P = .002; odds ratio for tolerance of CDED and PEN, 13.92; 95% confidence interval [CI] 1.68–115.14). At week 6, 30 (75%) of 40 children given CDED plus PEN were in corticosteroid-free remission vs 20 (59%) of 34 children given EEN (P = .38). At week 12, 28 (75.6%) of 37 children given CDED plus PEN were in corticosteroid-free remission compared with 14 (45.1%) of 31 children given EEN and then PEN (P = .01; odds ratio for remission in children given CDED and PEN, 3.77; CI 1.34–10.59). In children given CDED plus PEN, corticosteroid-free remission was associated with sustained reductions in inflammation (based on serum level of C-reactive protein and fecal level of calprotectin) and fecal Proteobacteria. Conclusion CDED plus PEN was better tolerated than EEN in children with mild to moderate CD. Both diets were effective in inducing remission by week 6. The combination CDED plus PEN induced sustained remission in a significantly higher proportion of patients than EEN, and produced changes in the fecal microbiome associated with remission. These data support use of CDED plus PEN to induce remission in children with CD. Clinicaltrials.gov no: NCT01728870 .

The intestinal epithelium not only acts as a physical barrier to commensal bacteria and foreign antigens but is also actively involved in antigen processing and immune cell regulation. The inflammatory bowel diseases (IBDs) are characterized by inflammation at this mucosal surface with well-recognized defects in barrier and secretory function. In addition to this, defects in intraepithelial lymphocytes, chemokine receptors, and pattern recognition receptors promote an abnormal immune response, with increased differentiation of proinflammatory cells and a dysregulated relationship with professional antigen-presenting cells. This review focuses on recent developments in the structure of the epithelium, including a detailed account of the apical junctional complex in addition to the role of the enterocyte in antigen recognition, uptake, processing, and presentation. Recently described cytokines such as interleukin-22 and interleukin-31 are highlighted as is the dysregulation of chemokines and secretory IgA in IBD. Finally, the effect of the intestinal epithelial cell on T effector cell proliferation and differentiation are examined in the context of IBD with particular focus on T regulatory cells and the two-way interaction between the intestinal epithelial cell and certain immune cell populations.

Background: Temporal trends in the incidence of pediatric-onset inflammatory bowel disease (IBD) are controversial and a wide range of estimates have been reported worldwide. We conducted a systematic review of research describing the epidemiology of childhood-onset IBD to assess changes in incidence rates over time and to evaluate international differences. Methods: The following electronic databases were searched for articles published 1950–2009: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Cochrane IBD/Functional Bowel Disorders Group Specialised Trial Register. All included studies reported incidence or prevalence of IBD, Crohn's disease (CD) or ulcerative colitis (UC). Two authors independently completed the data extraction form for each eligible study. Choropleth maps demonstrated the international incidence of IBD, CD, and UC. Incidence of CD and UC was graphed using data from studies reporting rates in multiple time periods. Results: The search yielded 2209 references and review resulted in 139 included studies from 32 countries. A wide range of incidence was reported internationally; however, rates of IBD were not described in most countries. Twenty-eight studies (20.1%) used statistical analysis to assess trends over time, and 77.8% reported statistically significantly increased incidence of pediatric IBD. Of studies calculating statistical trends in CD incidence, 60% reported significantly increased incidence. Of similar UC studies, 20% reported significantly increased incidence. Conclusions: Globally rising rates of pediatric IBD (due primarily to the rising incidence of CD) was demonstrated in both developed and developing nations; however, most countries lack accurate estimates. Analyzing incidence trends may help identify specific environmental and genetic risk factors for pediatric IBD. (Inflamm Bowel Dis 2011;)

Inflammatory bowel disease (IBD) is an increasingly common cause of morbidity in the pediatric population. Despite the establishment of dedicated multidisciplinary IBD teams in many centers, the care offered by emergency physicians is often crucial in the period before diagnosis and at times of relapses or acute complications. Crohn's disease and ulcerative colitis can present with a myriad of acute and chronic symptoms to the emergency department. Pediatric Crohn's disease encompasses a variety of phenotypic forms and often does not present with the classic triad of diarrhea, abdominal pain, and weight loss. Pediatric ulcerative colitis tends to be more extensive than adult-onset disease, with a greater predilection to acute severe exacerbations requiring urgent recognition. Disease- and treatment-related complications of IBD, both intestinal and extraintestinal, can be life threatening and require an integration of medical and surgical care from triage until discharge from the emergency department.

Inflammatory bowel disease, including Crohn's disease (CD) and ulcerative colitis (UC), and type 1 diabetes (T1D) are autoimmune diseases that may share common susceptibility pathways. We examined known susceptibility loci for these diseases in a cohort of 1689 CD cases, 777 UC cases, 989 T1D cases and 6197 shared control subjects of European ancestry, who were genotyped by the Illumina HumanHap550 SNP arrays. We identified multiple previously unreported or unconfirmed disease associations, including known CD loci (ICOSLG and TNFSF15) and T1D loci (TNFAIP3) that confer UC risk, known UC loci (HERC2 and IL26) that confer T1D risk and known UC loci (IL10 and CCNY) that confer CD risk. Additionally, we show that T1D risk alleles residing at the PTPN22, IL27, IL18RAP and IL10 loci protect against CD. Furthermore, the strongest risk alleles for T1D within the major histocompatibility complex (MHC) confer strong protection against CD and UC; however, given the multi-allelic nature of the MHC haplotypes, sequencing of the MHC locus will be required to interpret this observation. These results extend our current knowledge on genetic variants that predispose to autoimmunity, and suggest that many loci involved in autoimmunity may be under a balancing selection due to antagonistic pleiotropic effect. Our analysis implies that variants with opposite effects on different diseases may facilitate the maintenance of common susceptibility alleles in human populations, making autoimmune diseases especially amenable to genetic dissection by genome-wide association studies.

The discovery of nucleotide-binding oligomerization domain 2/caspase recruitment domain-containing protein 15 (NOD2/CARD15) as the first susceptibility gene in Crohn's disease (CD) has shifted the focus of research into the pathogenesis of inflammatory bowel disease (IBD) firmly to the innate immune response and the integrity of the epithelial barrier. The subsequent implication in IBD of variant alleles of OCTN, DLG5, MDR1, and TLRs has provided further support for a new, more complex model of innate immunity function in the gastrointestinal tract. In this review, we examine the recent advances in our understanding of the influence of genetics of the innate immune response on IBD. We will focus on germline variation of genes encoding pathogen-recognition receptors, proteins involved in epithelial homeostasis and secreted antimicrobial proteins. Copyright © 2006 Crohn's & Colitis Foundation of America, Inc.

of patients were identified: those developing early ER (N=12) and patients without ER (N=18) (Figure 1). Before surgery, a reduction of the Lachnospiraceae family (p=0.05) and Clostridium XVIII genus (p=0.032) was seen in the predominant microbiota of patients developing early postoperative ER whereas 3 members of Clostridium XIVa genus (p=0.073), Veillonellaceae family (p=0.028) and Bifidobacterium genus (p=0.01) were higher in patients with ER compared to patients without ER. A score combining these five bacterial risk factors was calculated and showed an area under the curve of 0.87 (95% CI, 0.76–0.99). The occurrence of two or more risk factors had a sensitivity, specificity, positive predictive value, and negative predictive value of 100%, 56%, 60% and 100% respectively. At the time of postoperative endoscopy, we observed an overrepresentation of Lactobacillus genus (p=0.003) and Ruminococcus gauvreauii (p=0.01) in the patients with ER. Conclusions: An overrepresentation of Clostridium XIVa spp., Veillonellaceae, Bifidobacteria and a lower abundance of Lachnospiraceae and Clostridium XVIII spp. in the predominant profile of preoperative fecal samples is associated with a higher risk to develop postoperative ER following ileocaecal resection. At the time of postoperative endoscopy, the predominant microbiota from patients with ER also differs from patients without recurrence, with as most prominent players lactobacilli and R. gauvreauii.

To the Editor:Since the discovery of NOD2 as aCrohn’s disease (CD) susceptibilitygene, more recent genomewide associa-tion scans (GWAS), detecting loci con-ferring odds ratios (OR) of above 1.3–1.5, have uncovered a large number offurther susceptibility loci and genes,including IL23R in the TH17 pathway,and the autophagy genes ATG16L1 andIRGM.

The chronic inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC), encompass a wide spectrum of diseases, characterized by both intestinal and extra-intestinal manifestations. From the early days of IBD genetic studies, the goals have included identification of healthy relatives at high risk of disease development and recognition of patients at risk for a severe disease course. To make progress on the path to personalized medicine, genetic polymorphisms or stable biomarkers are highly sought after in the profiling of IBD patients. A genetic test with high specificity has the potential to alter the treatment course of a subset patients, as shown in the case of thiopurine S-methyl transferase genotyping.1 At present, it is impossible to confidently predict a patient’s future disease burden.2 In referral center studies, certain clinical features are indicative of a more complicated disease (younger age at diagnosis, perianal disease, steroid requirement at diagnosis [CD], endoscopic severity of ulcerations and inability to achieve mucosal healing [CD/UC]), but their therapeutic application in patient stratification for “top‐down” strategies is still debated.3 Considering that mucosal healing is overtaking symptoms as the real therapeutic goal, with a true potential for modification of the disease course, diagnostic tests, able to accurately predict the mucosal response to treatment and the longevity of this response, will be required to successfully personalize treatment. 4 Biomarkers like C-reactive protein are proving useful in monitoring disease activity (including mucosal healing) in patients treated with infliximab and early normalization of C-reactive protein correlates with long-term response. 5 The utility of biomarkers (including fecal calprotectin and serum antiglycan antibodies) was the subject of a recent GASTROENTEROLOGY review. 6 In this article, we outline how some of the recent advances in our understanding of the genetic susceptibility to IBD may start to impact on therapy of our patients.