Crohn's Disease Phenotypes and Associations With Comorbidities, Surgery Risk, Medications and Nonmedication Approaches: The MAGIC in IMAGINE Study.

BACKGROUND: We aimed to establish a cohort of persons with Crohn's disease (CD) enrolled from 14 Canadian centers to describe the contemporary presentation of CD in Canada. METHODS: All enrollees were at least 18 years old and underwent chart review for phenotype documentation by Montreal Classification at time of enrollment, comorbidities, inflammatory bowel disease (IBD) and other surgeries, and use IBD and other therapies. RESULTS: Of 2112 adults, 59% were female, and the mean age was 44.1 (+/-14.9SD) years. The phenotype distribution was B1 = 50.4%, B2 = 22.4%, B3 = 17.3%, and missing information = 9.9%. Perineal disease was present in 14.2%. Pertaining to disease location, 35.2% of patients had disease in L1, 16.8% in L2, 48% in L3, and 0.4% in L4. There was no difference in phenotype by gender, anxiety score, depression score. Disease duration was significantly different depending on disease behavior type (B1 = 12.2 ±â€…10.1; B2 = 19.4 ±â€…12.9; B3 = 18.9 ±â€…11.8, P < .0001). Isolated colonic disease was much less likely to be fibrostenotic or penetrating than inflammatory disease. Penetrating disease was more likely to be associated with ileocolonic location than other locations. Perineal disease was most commonly seen in persons with B3 disease behavior (24%) than other behaviors (11% B1; 20% B2 disease, P < .0001) and more likely to be seen in ileocolonic disease (L3;19%) vs L2 (17%) and L1 (11%; P < .0001). Surgery related to IBD occurred across each behavior types at the following rates: B1 = 23%, B2 = 64%, and B3 = 74%. Inflammatory bowel disease-related surgery rates by location of disease were L1 = 48%, L2 = 21%, and L3 = 51%. CONCLUSIONS: In exploring this large contemporary CD cohort we have determined that inflammatory disease is the main CD phenotype in Canada and that CD-related surgery remains very common.

Gut Microbiome Composition Is Associated With Future Onset of Crohn's Disease in Healthy First-Degree Relatives.

BACKGROUND & AIMS: The cause of Crohn's disease (CD) is unknown, but the current hypothesis is that microbial or environmental factors induce gut inflammation in genetically susceptible individuals, leading to chronic intestinal inflammation. Case-control studies of patients with CD have cataloged alterations in the gut microbiome composition; however, these studies fail to distinguish whether the altered gut microbiome composition is associated with initiation of CD or is the result of inflammation or drug treatment. METHODS: In this prospective cohort study, 3483 healthy first-degree relatives (FDRs) of patients with CD were recruited to identify the gut microbiome composition that precedes the onset of CD and to what extent this composition predicts the risk of developing CD. We applied a machine learning approach to the analysis of the gut microbiome composition (based on 16S ribosomal RNA sequencing) to define a microbial signature that associates with future development of CD. The performance of the model was assessed in an independent validation cohort. RESULTS: In the validation cohort, the microbiome risk score (MRS) model yielded a hazard ratio of 2.24 (95% confidence interval, 1.03-4.84; P = .04), using the median of the MRS from the discovery cohort as the threshold. The MRS demonstrated a temporal validity by capturing individuals that developed CD up to 5 years before disease onset (area under the curve > 0.65). The 5 most important taxa contributing to the MRS included Ruminococcus torques, Blautia, Colidextribacter, an uncultured genus-level group from Oscillospiraceae, and Roseburia. CONCLUSION: This study is the first to demonstrate that gut microbiome composition is associated with future onset of CD and suggests that gut microbiome is a contributor in the pathogenesis of CD.

Novel Biomarkers for Inflammatory Bowel Disease and Colorectal Cancer: An Interplay between Metabolic Dysregulation and Excessive Inflammation.

Persistent inflammation can trigger altered epigenetic, inflammatory, and bioenergetic states. Inflammatory bowel disease (IBD) is an idiopathic disease characterized by chronic inflammation of the gastrointestinal tract, with evidence of subsequent metabolic syndrome disorder. Studies have demonstrated that as many as 42% of patients with ulcerative colitis (UC) who are found to have high-grade dysplasia, either already had colorectal cancer (CRC) or develop it within a short time. The presence of low-grade dysplasia is also predictive of CRC. Many signaling pathways are shared among IBD and CRC, including cell survival, cell proliferation, angiogenesis, and inflammatory signaling pathways. Current IBD therapeutics target a small subset of molecular drivers of IBD, with many focused on the inflammatory aspect of the pathways. Thus, there is a great need to identify biomarkers of both IBD and CRC, that can be predictive of therapeutic efficacy, disease severity, and predisposition to CRC. In this study, we explored the changes in biomarkers specific for inflammatory, metabolic, and proliferative pathways, to help determine the relevance to both IBD and CRC. Our analysis demonstrated, for the first time in IBD, the loss of the tumor suppressor protein Ras associated family protein 1A (RASSF1A), via epigenetic changes, the hyperactivation of the obligate kinase of the NOD2 pathogen recognition receptor (receptor interacting protein kinase 2 [RIPK2]), the loss of activation of the metabolic kinase, AMP activated protein kinase (AMPKα1), and, lastly, the activation of the transcription factor and kinase Yes associated protein (YAP) kinase, that is involved in proliferation of cells. The expression and activation status of these four elements are mirrored in IBD, CRC, and IBD-CRC patients and, importantly, in matched blood and biopsy samples. The latter would suggest that biomarker analysis can be performed non-invasively, to understand IBD and CRC, without the need for invasive and costly endoscopic analysis. This study, for the first time, illustrates the need to understand IBD or CRC beyond an inflammatory perspective and the value of therapeutics directed to reset altered proliferative and metabolic states within the colon. The use of such therapeutics may truly drive patients into remission.

Impact of Disease Activity and Inflammatory Bowel Disease Subtype on Quality of Life in Preconception and Pregnant Patients.

BACKGROUND: Inflammatory bowel disease (IBD) and pregnancy both impact health-related quality of life (HRQoL). However, little is known about IBD-related HRQoL around pregnancy. AIMS: To assess the trajectory and predictors of HRQoL in preconception and pregnant patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: Preconception and pregnant patients with IBD were followed prospectively from preconception to twelve months postpartum at a tertiary referral centre. Participants completed the Short IBD Questionnaire (SIBDQ) and were assessed for clinical disease activity (modified Harvey Bradshaw Index or partial Mayo score) and objective disease activity (C-reactive protein [CRP], fecal calprotectin [FCP]). RESULTS: A total of 61 patients with IBD (25 CD, 36 UC) were included. During preconception, patients with UC had higher SIBDQ bowel and social sub-scores than those with CD, but this reversed during postpartum. Patients with CD but not UC developed a significant, sustained improvement in SIBDQ upon becoming pregnant, which persisted into 12 months postpartum. In a multivariable linear regression model, clinical disease activity negatively predicted SIBDQ at every pregnancy timepoint and up to 12 months postpartum. SIBDQ was significantly lower in patients with CRP ≥ 8.0 mg/L during trimester 1 (T1), but not later in pregnancy. SIBDQ bowel sub-scores were significantly lower in patients with FCP ≥ 250 mg/kg at T2, T3, and 6 months postpartum. CONCLUSIONS: Clinical disease activity is a consistent negative predictor of HRQoL from conception to 12 months postpartum. Patients with UC experience better preconception HRQoL but suffer worse postpartum HRQoL than those with CD.

Case report: Desmoid fibromatosis diagnosed in a 27-year-old male after being mistaken for a gastrointestinal stromal tumour.

Despite being distinct lesions, gastrointestinal stromal tumours (GISTs) and desmoid fibromatosis may appear similar on imaging when they involve the stomach wall or bowel. As a result, they may be confused with one another when initially diagnosed. This report aims to present a case where a desmoid tumour was mistaken for a gastric GIST in a 27-year-old gentleman despite extensive investigation prior to exploratory laparotomy, and why differentiation through pathology, with a focus on the immunohistochemistry profile, is key for proper prognostication and appropriate management, including timely investigation for associated diseases such as Familial Adenomatous Polyposis in patients with desmoid tumours.

Elevated IL-6 and IL-22 in Early Pregnancy Are Associated with Worse Disease Course in Women with Inflammatory Bowel Disease.

Inflammatory bowel diseases (IBD), including Ulcerative Colitis (UC) and Crohn's disease (CD), are inflammatory conditions of the intestinal tract that affect women in their reproductive years. Pregnancy affects Th1- and Th2-cytokines, but how these changes occur during pregnancy in IBD is unclear. We performed a longitudinal profiling of serum cytokines in a cohort of 11 healthy pregnant women and 76 pregnant women with IBD from the first trimester of pregnancy to the first 12 months post-partum. Participants were monitored for biochemical disease activity (C-reactive protein [CRP] and fecal calprotectin [FCP]) and clinical activities. Maternal cytokines were measured using ELISA. We identified changes in Th1 and Th17 cytokines throughout pregnancy in healthy pregnant women. During pregnancy, maternal serum cytokine expressions were influenced by IBD, disease activity, and medications. Active UC was associated with an elevation in IL-21, whereas active CD was associated with elevated IFN-γ, IL-6, and IL-21. Interestingly, T1 serum cytokine levels of IL-22 (>0.624 pg/mL) and IL-6 (>0.648 pg/mL) were associated with worse IBD disease activity throughout pregnancy in women with UC and CD, respectively. This shows serum cytokines in pregnancy differ by IBD, disease activity, and medications. We show for the first time that T1 IL-22 and IL-6 correlate with IBD disease course throughout pregnancy.

Mediterranean-Like Dietary Pattern Associations With Gut Microbiome Composition and Subclinical Gastrointestinal Inflammation.

BACKGROUND & AIMS: Case-control studies have shown that patients with Crohn's disease (CD) have a microbial composition different from healthy individuals. Although the causes of CD are unknown, epidemiologic studies suggest that diet is an important contributor to CD risk, potentially via modulation of bacterial composition and gut inflammation. We hypothesized that long-term dietary clusters (DCs) are associated with gut microbiome compositions and gut inflammation. Our objectives were to identify dietary patterns and assess whether they are associated with alterations in specific gut microbial compositions and subclinical levels of gut inflammation in a cohort of healthy first-degree relatives (FDRs) of patients with CD. METHODS: As part of the Genetic, Environmental, Microbial (GEM) Project, we recruited a cohort of 2289 healthy FDRs of patients with CD. Individuals provided stool samples and answered a validated food frequency questionnaire reflecting their habitual diet during the year before sample collection. Unsupervised analysis identified 3 dietary and 3 microbial composition clusters. RESULTS: DC3, resembling the Mediterranean diet, was strongly associated with a defined microbial composition, with an increased abundance of fiber-degrading bacteria, such as Ruminococcus, as well as taxa such as Faecalibacterium. The DC3 diet was also significantly associated with lower levels of subclinical gut inflammation, defined by fecal calprotectin, compared with other dietary patterns. No significant associations were found between individual food items and fecal calprotectin, suggesting that long-term dietary patterns rather than individual food items contribute to subclinical gut inflammation. Additionally, mediation analysis demonstrated that DC3 had a direct effect on subclinical inflammation that was partially mediated by the microbiota. CONCLUSIONS: Overall, these results indicated that Mediterranean-like dietary patterns are associated with microbiome and lower intestinal inflammation. This study will help guide future dietary strategies that affect microbial composition and host gut inflammation to prevent diseases.

Crohn's disease therapeutic dietary intervention (CD-TDI): study protocol for a randomised controlled trial.

INTRODUCTION: Dietary patterns that might induce remission in patients with active Crohn's disease (CD) are of interest to patients, but studies are limited in the published literature. We aim to explore the efficacy of the CD therapeutic dietary intervention (CD-TDI), a novel dietary approach developed from best practices and current evidence, to induce clinical and biomarker remission in adult patients with active CD. METHODS AND ANALYSIS: This study is a 13-week, multicentre, randomised controlled trial in patients with mild-to-moderate active CD at baseline. One hundred and two patients will be block randomised, by sex, 2:1 to the intervention (CD-TDI) or conventional management. Coprimary outcomes are clinical and biomarker remission, defined as a Harvey Bradshaw Index of <5 and a faecal calprotectin of <250 µg/g, respectively.Secondary outcomes include gut microbiota diversity and composition, faecal short-chain fatty acids, regulatory macrophage function, serum and faecal metabolomics, C reactive protein, peripheral blood mononuclear cell gene expression profiles, quality of life, sedentary time and physical activity at 7 and/or 13 weeks. Predictive models of clinical response to a CD-TDI will be investigated. ETHICS AND DISSEMINATION: The research protocol was approved by the Conjoint Health Research Ethics Board at the University of Calgary (REB19-0402) and the Health Research Ethics Board-Biomedical Panel at the University of Alberta (Pro00090772). Study findings will be presented at national and international conferences, submitted for publication in abstracts and manuscripts, shared on social media and disseminated through patient-education materials. TRIAL REGISTRATION NUMBER: NCT04596566.

Breastfeeding Patterns in Mothers with Inflammatory Bowel Disease: A Pilot Prospective Longitudinal Study.

BACKGROUND: Breastfeeding practices in patients with inflammatory bowel disease (IBD) remain unknown. We aimed to characterize these practices and describe factors that may lead to early discontinuation. METHODS: This was a pilot, prospective, longitudinal study enrolling mothers with IBD from 2014 to 2017. Patients completed surveys on breastfeeding at time of delivery and up to 12 months postpartum. Breastfeeding discontinuation rates were reported for all patients with IBD and compared between patients with ulcerative colitis and Crohn's disease. Reproductive knowledge was defined using the Crohn's and Colitis Pregnancy Knowledge score. The Mann-Whitney U test assessed for differences between continuous variables, whereas categorical variables were compared using the chi-square test. RESULTS: A total of 74 mothers with IBD were included, 47 with ulcerative colitis and 27 with Crohn's disease. Breastfeeding rates in mothers with IBD was 94.6% at delivery, 73.9% at 3 months postpartum, 55.2% at 6 months postpartum, and 30.1% at 12 months postpartum. The most common reasons for discontinuing breastfeeding before 6 months postpartum included perceived insufficient milk production and concerns of infant medication exposure through breast milk. Compared with those who continued breastfeeding beyond 6 months postpartum, those who discontinued had lower median Crohn's and Colitis Pregnancy Knowledge scores (14.0 vs 9.0; P = .04). CONCLUSIONS: Though most mothers with IBD initiate breastfeeding at time of delivery, about half continue beyond 6 months postpartum. Common reasons for this include perceived insufficient milk production and medication concerns. Larger studies are required to validate our findings in more generalizable settings such as primary and secondary care.

A Dedicated Pregnancy Clinic Improves Reproductive Knowledge in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Factors affecting pregnancy-related knowledge in women with inflammatory bowel disease (IBD) remain unknown. We aimed to determine these factors and to assess the impact of a dedicated pregnancy clinic on improving knowledge in women with IBD. METHODS: Adult women with IBD attending the pregnancy IBD clinic at the University of Alberta from 2014 to 2018 were enrolled. Each patient completed the Crohn's and Colitis Pregnancy Knowledge (CCPKnow) questionnaire at baseline and after individualized education delivered at each clinic visit. Knowledge levels were defined as very good if CCPKnow scores ≥ 14. Mean CCPKnow scores were reported with standard deviations (SD) and compared using the paired T test. RESULTS: The mean CCPKnow score in 117 patients at baseline was 9.65 (SD 4.18). Compared to those with disease duration < 5 years, those with disease duration > 5 years had higher rates of very good baseline knowledge (3.0% vs. 26.4%, p = 0.036). Similarly, those on preconception IBD-related therapy were more likely to have very good knowledge compared to those on no therapy (22.5% vs. 0%, p = 0.024). Fifty-one patients completed a post-clinic CCPKnow survey with a mean CCPKnow of 10.72 (SD 4.32). Participation in a pregnancy clinic improved reproductive knowledge in those with ulcerative colitis (p = 0.001), disease duration > 5 years (p = 0.017), those with at least a university education (p = 0.014) and those on IBD-related therapies (p = 0.026). CONCLUSIONS: Increased disease duration and preconception IBD-related therapy may be associated with increased pregnancy-related knowledge. A dedicated pregnancy clinic can improve reproductive knowledge in women with IBD.

Shared decision making in pregnancy in inflammatory bowel disease: design of a patient orientated decision aid.

BACKGROUND: Research has indicated a lack of disease-specific reproductive knowledge among patients with Inflammatory Bowel Disease (IBD) and this has been associated with increased "voluntary childlessness". Furthermore, a lack of knowledge may contribute to inappropriate medication changes during or after pregnancy. Decision aids have been shown to support decision making in pregnancy as well as in multiple other chronic diseases. A published decision aid for pregnancy in IBD has not been identified, despite the benefit of pre-conception counselling and patient desire for a decision support tool. This study aimed to develop and test the feasibility of a decision aid encompassing reproductive decisions in the setting of IBD. METHODS: The International Patient Decision Aid Standards were implemented in the development of the Pregnancy in IBD Decision Aid (PIDA). A multi-disciplinary steering committee was formed. Patient and clinician focus groups were conducted to explore themes of importance in the reproductive decision-making processes in IBD. A PIDA prototype was designed; patient interviews were conducted to obtain further insight into patient perspectives and to test the prototype for feasibility. RESULTS: Issues considered of importance to patients and clinicians encountering decisions regarding pregnancy in the setting of IBD included fertility, conception timing, inheritance, medications, infant health, impact of surgery, contraception, nutrition and breastfeeding. Emphasis was placed on the provision of preconception counselling early in the disease course. Decisions relating to conception and medications were chosen as the current focus of PIDA, however content inclusion was broad to support use across preconception, pregnancy and post-partum phases. Favourable and constructive user feedback was received. CONCLUSIONS: The novel development of a decision aid for use in pregnancy and IBD was supported by initial user testing.

Pregnancy-Related Beliefs and Concerns of Inflammatory Bowel Disease Patients Modified After Accessing e-Health Portal.

OBJECTIVE: Poor inflammatory bowel disease (IBD)-specific reproductive knowledge is associated with concerns and medication noncompliance. Having shown an educational portal can improve knowledge, we evaluated its effectiveness for addressing IBD patients' reproductive and medication concerns. METHODS: Adult IBD participants (aged 18 to 45 years) were invited to access an e-health portal providing information on heritability, fertility, surgery, pregnancy outcomes, delivery, postpartum, and breastfeeding in the context of IBD and IBD medications. At pre-, post-, and 6+-month postintervention, participants completed a questionnaire on IBD-specific pregnancy concerns, medication concerns from the Beliefs About Medicines Questionnaire (BMQ), and medication adherence via the Medication Adherence Rating Scale (MARS). The Wilcoxon signed-rank test was used to compare median differences between scores (95% confidence). RESULTS: Demographics for 78 (70.3%) participants completing postintervention questionnaires: median age 29.3 (interquartile range: 25.6 to 32.9) years; 54 (69.2%) Crohn's disease; 21 (26.9%) ulcerative colitis; 63 (80.3%) females, 5 (7.9%) pregnant; and 19 (30.2%) previously pregnant. Postintervention, the median number of reproductive concerns decreased from 3 to 1, and remained stable 6+ months later (P < 0.001*). The median BMQ score decreased from 28 to 25, and remained stable 6+ months later (P = 0.032*). Participants adherent to medications increased from 82.4% to 87.8% postintervention (P = 0.099). CONCLUSION: Using an e-health portal may potentially reduce IBD-specific reproductive and medications concerns. An e-health portal is feasible as one component of managing IBD patient's reproductive and medication concerns during preconception and pregnancy.

Associations of NOD2 polymorphisms with Erysipelotrichaceae in stool of in healthy first degree relatives of Crohn's disease subjects.

BACKGROUND: Genetic analyses have identified many variants associated with the risk of inflammatory bowel disease (IBD) development. Among these variants, the ones located within the NOD2 gene have the highest odds ratio of all IBD genetic risk variants. Also, patients with Crohn's disease (CD) have been shown to have an altered gut microbiome, which might be a reflection of inflammation itself or an effect of other parameters that contribute to the risk of the disease. Since NOD2 is an intracellular pattern recognition receptor that senses bacterial peptidoglycan in the cytosol and stimulates the host immune response (Al Nabhani et al., PLoS Pathog 13:e1006177, 2017), it is hypothesized that NOD2 variants represent perfect candidates for influencing host-microbiome interactions. We hypothesized that NOD2 risk variants affect the microbiome composition of healthy first degree relative (FDR) of CD patients and thus potentially contribute to an altered microbiome state before disease onset. METHODS: Based on this, we studied a large cohort of 1546 healthy FDR of CD patients and performed a focused analysis of the association of three major CD SNPs in the coding region of the NOD2 gene, which are known to confer a 15-40-fold increased risk of developing CD in homozygous or compound heterozygous individuals. RESULTS: Our results show that carriers of the C allele at rs2066845 was significantly associated with an increase in relative abundance in the fecal bacterial family Erysipelotrichaceae. CONCLUSIONS: This result suggests that NOD2 polymorphisms contribute to fecal microbiome composition in asymptomatic individuals. Whether this modulation of the microbiome influences the future development of CD remains to be assessed.

Host immunoglobulin G selectively identifies pathobionts in pediatric inflammatory bowel diseases.

BACKGROUND: Inflammatory bowel diseases (IBD) are a group of complex and multifactorial disorders with unknown etiology. Chronic intestinal inflammation develops against resident intestinal bacteria in genetically susceptible hosts. We hypothesized that host intestinal immunoglobulin (Ig) G can be used to identify bacteria involved in IBD pathogenesis. RESULTS: IgG-bound and -unbound microorganisms were collected from 32 pediatric terminal ileum aspirate washes during colonoscopy [non-IBD (n = 10), Crohn disease (n = 15), and ulcerative colitis (n = 7)], and composition was assessed using the Illumina MiSeq platform. In vitro analysis of invasive capacity was evaluated by fluorescence in situ hybridization and gentamicin invasion assay; immune activation was measured by qPCR. Despite considerable inter-individual variations, IgG binding favored specific and unique mucosa-associated species in pediatric IBD patients. Burkholderia cepacia, Flavonifractor plautii, and Rumminococcus sp. demonstrated increased IgG binding, while Pseudomonas ST29 demonstrated reduced IgG binding, in IBD. In vitro validation confirmed that B. cepacia, F. plautii, and Rumminococcus display invasive potential while Pseudomonas protogens did not. CONCLUSION: Using IgG as a marker of pathobionts in larger patient cohorts to identify microbes and elucidate their role in IBD pathogenesis will potentially underpin new strategies to facilitate development of novel, targeted diagnostic, and therapeutic approaches. Interestingly, this method can be used beyond the scope of this manuscript to evaluate altered gut pathobionts in a number of diseases associated with altered microbiota including arthritis, obesity, diabetes mellitus, alcoholic liver disease, cirrhosis, metabolic syndrome, and carcinomas.

The Profile of Human Milk Metabolome, Cytokines, and Antibodies in Inflammatory Bowel Diseases Versus Healthy Mothers, and Potential Impact on the Newborn.

BACKGROUND AND AIMS: For women with inflammatory bowel disease [IBD], it is not very well known how IBD or IBD treatment affects their breast milk components. We aimed to investigate whether breast milk composition differs in healthy control [HC] versus IBD mothers in terms of antibodies, cytokines, and metabolite,s to identify potential impact of IBD breast milk on neonatal immune system. METHODS: Breast milk specimens from HC [n = 17] and IBD [n = 31 for Crohn's disease [CD]; and n = 41 for ulcerative colitis [UC]; were collected at 3 and 6 months postpartum [PP3] and [PP6], respectively. Faecal samples were also collected. Cytokines and immunoglobulins [IgA/IgG/IgE] were analysed by multiplex Meso Scale Discovery [MSD] and commercial kits. Moreover, breast milk metabolites were analysed by 1H nuclear magnetic resonance [NMR]. RESULTS: We found that breast milk from IBD mothers showed significantly lower levels of IgA, sugar metabolite [lactose], and 2-aminobutyrate. In contrast, we observed that breast milk from mothers with IBD had increased levels of pro-inflammatory cytokines and higher energy metabolites [lactate and succinate] than milk from healthy mothers. In addition, we noticed that the type of treatment [5-aminosalicylic acid versus biologics] influenced the milk cytokines and metabolites profile. CONCLUSIONS: The reduction in immunoprotective components of IBD breast milk such as sIgA and lactose theoretically may modulate the potential protective effects of breastfeeding. On the other hand, presence of higher levels of pro-inflammatory cytokines, lactate, and succinate may predispose the offspring to an inflammatory condition or impact on the gut microbiome. Better understanding of the role of succinate in infants and its potential effects on microbiome or mucosal immunity merits further investigations.

Inulin-type fructans improve active ulcerative colitis associated with microbiota changes and increased short-chain fatty acids levels.

The intestinal microbiota is involved in ulcerative colitis (UC) pathogenesis. Prebiotics are hypothesized to improve health through alterations to gut microbiota composition and/or activity. Our aim was therefore to determine if inulin-type fructans induce clinical benefits in UC, and identify if benefits are linked to compositional and/or functional shifts of the luminal (fecal) and mucosal (biopsy) bacterial communities. Patients (n = 25) with mild/moderately active UC received 7.5 g (n = 12) or 15 g (n = 13) daily oral oligofructose-enriched inulin (Orafti®Synergy1) for 9 weeks. Total Mayo score, endoscopic activity and fecal calprotectin were assessed. Fecal and mucosal bacterial communities were characterized by 16S rRNA tag sequencing, and short chain fatty acids (SCFA) production were measured in fecal samples. Fructans significantly reduced colitis in the high-dose group, with 77% of patients showing a clinical response versus 33% in the low-dose group (P = 0.04). Fructans increased colonic butyrate production in the 15 g/d dose, and fecal butyrate levels were negatively correlated with Mayo score (r = -0.50; P = 0.036). The high fructan dose led to an increased Bifidobacteriaceae and Lachnospiraceae abundance but these shifts were not correlated with improved disease scores. In summary, this pilot study revealed that 15 g/d dose inulin type fructans in UC produced functional but not compositional shifts of the gut microbiota, suggesting that prebiotic-induced alterations of gut microbiota metabolism are more important than compositional changes for the benefits in UC. The findings warrant future well-powered controlled studies for the use of ß-fructans as adjunct therapy in patients with active UC.

Lower Abundance and Impaired Function of CD71+ Erythroid Cells in Inflammatory Bowel Disease Patients During Pregnancy.

BACKGROUND AND AIMS: CD71+ erythroid cells are enriched during pregnancy with immuno suppressive properties. We investigated the frequency and functionality of CD71+ erythroid cells in peripheral blood, cord blood, and placenta of inflammatory bowel disease [IBD] patients versus healthy controls [HCs]. We aimed to determine their role in IBD pathogenesis during pregnancy. METHODS: Peripheral blood was collected at preconception, the first, second and third trimesters, and postpartum. Cord blood and placental tissues were collected at the time of birth. Cells from different specimens were subjected to immune-phenotyping and functional assays. CD71+ erythroid cells were purified for quantitative polymerase chain reaction [qPCR] analysis. Using an allogeneic mouse model of pregnancy, the effects of CD71+ erythroid cells depletion on intestinal homeostasis and dysbiosis was studied. RESULTS: IBD patients had lower CD71+ erythroid cells during pregnancy compared with HCs. Placenta and cord blood CD71+ erythroid cells from IBD patients exhibited impaired functionality and expressed lower inhibitory molecules including VISTA, TGF-ß, and reactive oxygen species [ROS]. Lower CD71+ erythroid cells were correlated with reduced regulatory T cells and increased immune-activation in IBD patients. Depletion of CD71+ erythroid cells in an allogeneic pregnancy model resulted in upregulation of TLRs, IL-6, and CXCL-1, and enhanced production of TNF-α, in intestinal tissues. In contrast, TGF-ß gene expression was reduced. Excessive inflammatory response in the gut [e.g. TNF-α] affects intestinal integrity and CD71+ erythroid cells impact on the gut's bacterial composition. CONCLUSIONS: Reduced frequency and/or impaired functionality of CD71+ erythroid cells during pregnancy may predispose IBD patients to a more pro-inflammatory milieu in their gastrointestinal tract, characterised by lower Tregs, higher IL-6, and TNF-α, and dysbiosis.

Endospore forming bacteria may be associated with maintenance of surgically-induced remission in Crohn's disease.

Crohn's disease (CD) patients who undergo ileocolonic resection (ICR) typically have disease recurrence at the anastomosis which has been linked with a gut dysbiosis. The aims of this study were to define the mucosa-associated microbiota at the time of ICR and to determine if microbial community structure at the time of surgery was predictive of future disease relapse. Ileal biopsies were obtained at surgery and after 6 months from CD subjects undergoing ICR. Composition and function of mucosal-associated microbiota was assessed by 16S rRNA sequencing and PICRUSt analysis. Endoscopic recurrence was assessed using the Rutgeerts score. Analysis of mucosal biopsies taken at the time of surgery showed that decreased Clostridiales together with increased Enterobacteriales predicted disease recurrence. An increase in the endospore-forming Lachnospiraceae from surgery to 6 months post-ICR was associated with remission. A ratio of 3:1 between anaerobic endospore-forming bacterial families and aerobic families within the Firmicutes phylum was predictive of maintenance of remission. Gut recolonization following ICR is facilitated by microbes which are capable of either aerobic respiration or endospore formation. The relative proportions of these species at the time of surgery may be predictive of subsequent microbial community restoration and disease recurrence.

A Distinctive Urinary Metabolomic Fingerprint Is Linked With Endoscopic Postoperative Disease Recurrence in Crohn's Disease Patients.

Background: Crohn's disease (CD) patients who undergo ileocolonic resection frequently have disease recurrence. The aim of this preliminary study was to identify urinary metabolomic profiles associated with disease recurrence in order to identify underlying mechanisms of recurrence and possible disease biomarkers. Methods: Biopsies from the neoterminal ileum were collected from CD patients (n = 38) after ileocolonic resection in order to assess mucosa-associated microbiota using 16S rRNA multitag pyrosequencing. Urine samples were collected, and metabolomic profiling was done using high-resolution nuclear magnetic resolution spectroscopy and a combined direct infusion liquid chromatography tandem mass spectrometry. The Rutgeerts scoring system was used to assess endoscopic postoperative recurrence of CD. Results: There were 28 (73.7%) patients with endoscopic CD recurrence. CD patients who were in endoscopic remission had a higher abundance of Bacteroidetes and lower abundance of Fusobacteria and Proteobacteria in comparison with CD patients who had endoscopic recurrence. In addition, metabolomic profiling could also discriminate between these 2 groups of patients. Endoscopic recurrence was associated with increased concentration of urinary levoglucosan. Rutgeerts score was positively correlated with levoglucosan and propylene glycol levels. Conclusions: CD patients who present with endoscopic disease recurrence after surgery have a unique urinary metabolomic fingerprint that can differentiate them from CD patients who are in endoscopic remission after ileocolonic resection. In addition, mucosal-associated microbiota in CD patients with or without disease recurrence after surgery differs and correlates with some urinary metabolites.