Longitudinal Changes in Fecal Calprotectin Levels Among Pregnant Women With and Without Inflammatory Bowel Disease and Their Babies.

BACKGROUND & AIMS: The effect of pregnancy on inflammatory bowel disease (IBD) remains poorly understood. We aimed to monitor intestinal inflammation using fecal calprotectin (FC) in pregnant women and their babies during early life. METHODS: Pregnant women with or without IBD and their infants were prospectively enrolled. FC levels were measured at each trimester of pregnancy and in babies throughout the first 3 years of life. Repeated-measures analysis was applied to investigate changes in FC levels while adjusting for confounders. The FC levels were correlated with the bacterial abundance in both mothers and babies. RESULTS: Six hundred and fourteen fecal samples from 358 mothers (98 with IBD) and 1005 fecal samples from 289 infants (76 born to IBD mothers) were analyzed. Pregnant Patients with IBD maintained higher FC levels through pregnancy compared with controls (P = 7.5 × 10-54). FC gradually increased in controls and declined in Patients with IBD throughout pregnancy (P for interaction = 5.8 × 10-7). Babies born to mothers with IBD presented with significantly higher FC levels than those born to controls up to 3 years of age, after adjusting for sex, delivery mode, feeding behavior, and antibiotics exposure (2 weeks to 3 months of age, P = .015; 12-36 months of age, P = .00003). Subdoligranulum, Roseburia, Fusicatenibacter, and Alistipes negatively correlated, and Streptococcus, Prevotella, Escherichia-Shigella, and Bifidobacterium positively correlated with maternal FC levels at T3. Faecalibacterium, Bifidobacterium, and Alistipes showed negative correlations, and Streptococcus were positively correlated with FC levels within 3 months of birth. CONCLUSIONS: Pregnancy is associated with decreased inflammatory activity in mothers with IBD. Higher FC levels in babies born to mothers with IBD suggest subclinical inflammation in early life, the long-term consequences of which are uncertain.

Infants born to mothers with IBD present with altered gut microbiome that transfers abnormalities of the adaptive immune system to germ-free mice.

BACKGROUND AND AIMS: Prenatal and early life bacterial colonisation is thought to play a major role in shaping the immune system. Furthermore, accumulating evidence links early life exposures to the risk of developing IBD later in life. We aimed to assess the effect of maternal IBD on the composition of the microbiome during pregnancy and on the offspring's microbiome. METHODS: We prospectively examined the diversity and taxonomy of the microbiome of pregnant women with and without IBD and their babies at multiple time points. We evaluated the role of maternal IBD diagnosis, the mode of delivery, antibiotic use and feeding behaviour on the microbiome composition during early life. To assess the effects of IBD-associated maternal and infant microbiota on the enteric immune system, we inoculated germ-free mice (GFM) with the respective stool and profiled adaptive and innate immune cell populations in the murine intestines. RESULTS: Pregnant women with IBD and their offspring presented with lower bacterial diversity and altered bacterial composition compared with control women and their babies. Maternal IBD was the main predictor of the microbiota diversity in the infant gut at 7, 14, 30, 60 and 90 days of life. Babies born to mothers with IBD demonstrated enrichment in Gammaproteobacteria and depletion in Bifidobacteria. Finally, GFM inoculated with third trimester IBD mother and 90-day infant stools showed significantly reduced microbial diversity and fewer class-switched memory B cells and regulatory T cells in the colon. CONCLUSION: Aberrant gut microbiota composition persists during pregnancy with IBD and alters the bacterial diversity and abundance in the infant stool. The dysbiotic microbiota triggered abnormal imprinting of the intestinal immune system in GFM.

A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF.

BACKGROUND & AIMS: Crohn's disease (CD) has the highest prevalence in Ashkenazi Jewish populations. We sought to identify rare, CD-associated frameshift variants of high functional and statistical effects. METHODS: We performed exome sequencing and array-based genotype analyses of 1477 Ashkenazi Jewish individuals with CD and 2614 Ashkenazi Jewish individuals without CD (controls). To validate our findings, we performed genotype analyses of an additional 1515 CD cases and 7052 controls for frameshift mutations in the colony-stimulating factor 2-receptor ß common subunit gene (CSF2RB). Intestinal tissues and blood samples were collected from patients with CD; lamina propria leukocytes were isolated and expression of CSF2RB and granulocyte-macrophage colony-stimulating factor-responsive cells were defined by adenomatous polyposis coli (APC) time-of-flight mass cytometry (CyTOF analysis). Variants of CSF2RB were transfected into HEK293 cells and the expression and functions of gene products were compared. RESULTS: In the discovery cohort, we associated CD with a frameshift mutation in CSF2RB (P = 8.52 × 10(-4)); the finding was validated in the replication cohort (combined P = 3.42 × 10(-6)). Incubation of intestinal lamina propria leukocytes with granulocyte-macrophage colony-stimulating factor resulted in high levels of phosphorylation of signal transducer and activator of transcription (STAT5) and lesser increases in phosphorylation of extracellular signal-regulated kinase and AK straining transforming (AKT). Cells co-transfected with full-length and mutant forms of CSF2RB had reduced pSTAT5 after stimulation with granulocyte-macrophage colony-stimulating factor, compared with cells transfected with control CSF2RB, indicating a dominant-negative effect of the mutant gene. Monocytes from patients with CD who were heterozygous for the frameshift mutation (6% of CD cases analyzed) had reduced responses to granulocyte-macrophage colony-stimulating factor and markedly decreased activity of aldehyde dehydrogenase; activity of this enzyme has been associated with immune tolerance. CONCLUSIONS: In a genetic analysis of Ashkenazi Jewish individuals, we associated CD with a frameshift mutation in CSF2RB. Intestinal monocytes from carriers of this mutation had reduced responses to granulocyte-macrophage colony-stimulating factor, providing an additional mechanism for alterations to the innate immune response in individuals with CD.

Capsule endoscopy is superior to small-bowel follow-through and equivalent to ileocolonoscopy in suspected Crohn's disease.

BACKGROUND & AIMS: Evaluation of the small intestine for inflammation has traditionally relied on small-bowel follow-through (SBFT), but multiple studies have demonstrated its low diagnostic accuracy. Capsule endoscopy (CE) transmits high-quality images of the small intestinal mucosa; it can be used to visualize the entire length of the small bowel and much of the mucosa. We compared the diagnostic yields of CE vs SBFT in a prospective study of patients with suspected small-bowel Crohn's disease. METHODS: Eighty patients with signs and/or symptoms of small-bowel Crohn's disease (age, 10-65 years) underwent CE, followed by SBFT and ileocolonoscopy. Readers were blinded to other test results. The primary outcome was the diagnostic yield for inflammatory lesions found with CE before ileocolonoscopy compared with SBFT and ileocolonoscopy. A secondary outcome was the incremental diagnostic yield of CE compared with ileocolonoscopy and CE compared with SBFT. RESULTS: The combination of CE and ileocolonoscopy detected 107 of 110 inflammatory lesions (97.3%), whereas the combination of SBFT and ileocolonoscopy detected only 63 lesions (57.3%) (P < .001). The diagnostic yield of CE compared with ileocolonoscopy was not different (P = .09). The diagnostic yield was higher for CE than for SBFT (P < .001). Of the 80 patients with suspected Crohn's disease, 25 (31.3%) had the diagnosis confirmed. Eleven were diagnosed by CE findings alone and 5 by ileocolonoscopy findings alone. In the remaining 9 patients, diagnostic findings were identified by at least 2 of the 3 modalities. No diagnoses were made on the basis of SBFT findings alone. CONCLUSIONS: CE was better than SBFT and equivalent to ileocolonoscopy in detecting small-bowel inflammation. Although ileocolonoscopy remains the initial diagnostic test of choice, CE is safe and can establish the diagnosis of Crohn's disease in patients when ileocolonoscopy results are negative or the terminal ileum cannot be evaluated. ClinicalTrials.gov Number: NCT00487396.

Influence of Early Life Factors, including breast milk Composition, on the Microbiome of Infants Born to Mothers with and without Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Herein we analysed the influence of early life factors, including breast milk composition, on the development of the intestinal microbiota of infants born to mothers with and without IBD. METHODS: The MECONIUM [Exploring MEChanisms Of disease traNsmission In Utero through the Microbiome] study is a prospective cohort study consisting of pregnant women with or without IBD and their infants. Longitudinal stool samples were collected from babies and analysed using 16s rRNA sequencing and faecal calprotectin. Breast milk proteomics was profiled using Olink inflammation panel. RESULTS: We analysed gut microbiota of 1034 faecal samples from 294 infants [80 born to mothers with and 214 to mothers without IBD]. Alpha diversity was driven by maternal IBD status and time point. The major influencers of the overall composition of the microbiota were mode of delivery, feeding, and maternal IBD status. Specific taxa were associated with these exposures, and maternal IBD was associated with a reduction in Bifidobacterium. In 312 breast milk samples [91 from mothers with IBD], mothers with IBD displayed lower abundance of proteins involved in immune regulation, such as thymic stromal lymphopoietin, interleukin-12 subunit beta, tumour necrosis factor-beta, and C-C motif chemokine 20, as compared with control mothers [adjusted p = 0.0016, 0.049, 0.049, and 0.049, respectively], with negative correlations with baby´s calprotectin, and microbiome at different time points. CONCLUSION: Maternal IBD diagnosis influences microbiota in their offspring during early life. The proteomic profile of breast milk of women with IBD differs from that of women without IBD, with distinct time-dependent associations with baby's gut microbiome and feacal calprotectin.

Ulcerative colitis is characterized by a plasmablast-skewed humoral response associated with disease activity.

B cells, which are critical for intestinal homeostasis, remain understudied in ulcerative colitis (UC). In this study, we recruited three cohorts of patients with UC (primary cohort, n = 145; validation cohort 1, n = 664; and validation cohort 2, n = 143) to comprehensively define the landscape of B cells during UC-associated intestinal inflammation. Using single-cell RNA sequencing, single-cell IgH gene sequencing and protein-level validation, we mapped the compositional, transcriptional and clonotypic landscape of mucosal and circulating B cells. We found major perturbations within the mucosal B cell compartment, including an expansion of naive B cells and IgG+ plasma cells with curtailed diversity and maturation. Furthermore, we isolated an auto-reactive plasma cell clone targeting integrin αvß6 from inflamed UC intestines. We also identified a subset of intestinal CXCL13-expressing TFH-like T peripheral helper cells that were associated with the pathogenic B cell response. Finally, across all three cohorts, we confirmed that changes in intestinal humoral immunity are reflected in circulation by the expansion of gut-homing plasmablasts that correlates with disease activity and predicts disease complications. Our data demonstrate a highly dysregulated B cell response in UC and highlight a potential role of B cells in disease pathogenesis.

The utility of capsule endoscopy in patients with suspected Crohn's disease.

OBJECTIVES: In patients with suspected Crohn's disease (CD), little is known about the test characteristics of capsule endoscopy (CE) in the diagnosis of this condition. We sought to determine the utility of CE for the subsequent diagnosis of CD in patients suspected to have this condition. METHODS: All patients who underwent CE at a single tertiary-care center for investigation of suspected small bowel CD, and who had a 12-month follow-up, were included in the study. All patients had undergone other investigations that were normal or equivocal. The test characteristics of CE were determined on the basis of capsule findings of small bowel ulcers and a subsequent new diagnosis of CD within 12 months of CE. RESULTS: The study included 102 patients with 12-month follow-up data. The majority (75%) met the established criteria to define "suspected Crohn's disease" as an indication for CE. Most had undergone computed tomography scan or small bowel follow-through (92%) and colonoscopy (99%) before CE. There were abnormal CE findings suggestive of CD in 39 patients. The prevalence rate of a new diagnosis of CD by 12 months in the study population was 13%. Using the presence of more than 3 ulcers as the criterion for an abnormal CE study, the sensitivity of CE for the diagnosis of CD was 77%, the specificity was 89%, the positive predictive value (PPV) was 50%, and the negative predictive value (NPV) was 96%. CONCLUSIONS: In patients with suspected CD, CE has a high sensitivity and a NPV for this condition. The PPV varies depending on the patient population and the criteria for a CE diagnosis of CD.

Role of capsule endoscopy in inflammatory bowel disease: where we are and where we are going.

Capsule endoscopy (CE) is an innovative technological breakthrough that for the first time provides a noninvasive method to obtain high-resolution imaging of the entire small bowel. Since its recent inception, the diagnostic utility of CE has become well established for the evaluation of diverse ulcerative and inflammatory disorders of the jejunum and ileum. The incredible resolution of its lens (0.1 mm) detects focal villous edema or atrophy, denuded, as well as ulcerated mucosal lesions missed by other imaging techniques. CE has been shown by meta-analysis to be a more sensitive method to investigate patients for small bowel Crohn's disease, with an incremental yield above 30% versus other imaging modalities. In patients with indeterminate colitis, CE is useful in distinguishing between ulcerative and Crohn's colitis. Among patients with established Crohn's disease, CE may be employed to determine: (1) the extent and severity of small bowel involvement, (2) postoperative recurrence, (3) post-therapy mucosal healing, and (4) whether active small bowel inflammatory lesions exist in the clinical setting of functional bowel disorder. Complications are rare and include capsule retention at stricture sites. The new patency capsule can diminish the risk of the latter problem in at-risk patients. CE can also serve as a guide to sites that require biopsies or dilatation by push or double-balloon enteroscopy. However, other causes of small bowel lesions may mimic Crohn's disease. A standard terminology system has thus been developed, and a CE Crohn's disease severity scoring index is currently undergoing validation studies.

Use of capsule endoscopy for established Crohn's disease.

There remains significant uncertainty regarding the role of capsule endoscopy in the setting of known inflammatory bowel disease (IBD). Capsule endoscopy should be considered for patients who have indeterminate colitis, who are failing medical therapy or who may require colectomy, who have truly unexplained symptoms based on standard endoscopy and radiography, and who have IBD and obscure bleeding. Although capsule endoscopy clearly detects small bowel pathology with greater sensitivity than other methods, the implications of these lesions are not fully understood. At this time, use of capsule endoscopy as a tool for the evaluation of mucosal healing or for prognostication of post-operative recurrence remains investigational.

Innate immune receptor genetic polymorphisms in pouchitis: is CARD15 a susceptibility factor?

BACKGROUND: Pouchitis is a frequent complication after ileal pouch-anal anastamosis (IPAA) for ulcerative colitis (UC). The aim of this study was to determine whether genetic polymorphisms in the innate immune receptors toll-like receptor (TLR)4 and caspase activation and recruitment domain family member 15 (CARD15) genes are associated with pouchitis. METHODS: From a retrospectively ascertained cohort of patients with UC 5 to 12 years after IPAA (n = 101), subjects were classified into 3 groups: no pouchitis (n = 52); 1 to 2 episodes per year (n = 11), and more than 2 episodes per year (n = 38). Single nucleotide polymorphisms in the tlr4 gene (D299G, T399I) were determined by a real-time polymerase chain reaction-based fluorogenic probe technique; and card15 polymorphisms (L1007fsinsC, R702W, G908R) were determined by pyrosequencing. RESULTS: Pouchitis affected 49% (49/101) of the study population. No correlation between pouchitis and the presence of TLR4 polymorphisms was found. The percentage of patients who harbored CARD15 mutations was significantly higher in patients with pouchitis than in patients without pouchitis (18% versus 8%; P < 0.05); 24% of pouchitis patients with more than 2 episodes per year harbored CARD15 mutations (P < 0.01 compared with the no pouchitis group). The CARD15 insertion mutation L1007fsinsC was present in 14% of patients with pouchitis and in 0% without pouchitis (P < 0.05). All patients who carried L1007fsinsC developed more than 2 episodes per year. CONCLUSIONS: CARD15 polymorphisms are seen in greater frequency in patients with pouchitis after IPAA for UC. These findings, if borne out in prospective analyses, suggest that CARD15 mutations, particularly L1007fsinsC, may predispose to the development of pouchitis after IPAA for UC.

Video capsule endoscopy in inflammatory bowel disease: past, present, and future.

In this paper, we critically review the rationale, technical issues, and diagnostic findings, difficulties in interpretation, complications, potential clinical uses, and practical obstacles for capsule endoscopy in patients with inflammatory bowel disease (IBD). We will review the currently limited data on its use in IBD and discuss future areas of investigation required to evaluate critically its potential utility in these patients.

Therapeutic options in the management of strictures in Crohn's disease.

Intestinal strictures are a commonly encountered problem in patients with Crohn's disease. Endoscopic management with hydrostatic balloon dilation is an effective alternative to surgery in patients with endoscopically accessible lesions that are shorter than 7-8 cm. Endoscopic balloon dilation is the preferred initial modality in anastomotic strictures. The presence of inflammation near the stricture should not be considered a contraindication to dilation, and intralesional steroid injection should be considered in these patients with inflammation present in the area of the stricture. Further technological developments in endoscopes and balloon dilators may allow for broader application of these techniques.

Mercaptopurine-induced hepatoportal sclerosis in a patient with Crohn's disease.

Thiopurines play a pivotal role in the management of inflammatory bowel disease. Azathioprine and mercaptopurine have been associated with a number of liver abnormalities, including hepatitis, veno-occlusive disease, nodular regenerative hyperplasia, and peliosis hepatitis. Patients treated with azathioprine and mercaptopurine have their liver chemistry tests routinely checked due to this potential for hepatotoxicity. Hepatoportal sclerosis is a cause of non-cirrhotic portal hypertension that is increasingly being recognized; its etiopathogenesis is not well defined. We present the first case report of mercaptopurine-induced hepatoportal sclerosis leading to non-cirrhotic portal hypertension in a patient with Crohn's disease. He had been treated with mercaptopurine for five years, and his liver chemistry tests were always within normal limits. This case underscores the potential serious liver adverse events that may arise silently and go undetected during treatment with mercaptopurine, and should alert clinicians as to the potential need to discontinue mercaptopurine in this setting.

Video capsule endoscopy in inflammatory bowel disease: past, present, and future redux.

Over the last 8 years, capsule endoscopy (CE) has revolutionized the visualization of the small bowel. In 2004 this journal published "Capsule endoscopy in IBD: past, present and future" Kornbluth et al [2004] Inflamm Bowel Dis 10:278-285). In this article we review advances since that time and discuss whether CE has achieved its potential and what remaining goals it can and should hope to achieve. In the 2004 article we listed a series of clinical questions to be answered with regard to the use of capsule endoscopy We review those questions that have been addressed in the intervening 5 years, and also update those topics for which information was available at the time of the initial article.

Predictors and outcome of gastrointestinal complications in patients undergoing cardiac surgery.

OBJECTIVE: To determine the incidence and independent predictors of gastrointestinal complications (GICs) following cardiac surgery. SUMMARY BACKGROUND DATA: Gastrointestinal ischemia and hemorrhage represent a rare but devastating complication following heart surgery. The profile of patients referred for cardiac surgery has changed during the last decade, questioning the validity of previously reported incidence and risk factors. METHODS: We retrospectively analyzed prospectively collected data from 4819 patients undergoing cardiac surgery between 1998 and 2004. Patients with GICs were compared with the entire patient population. Study endpoints were mortality, postoperative morbidities, and long-term survival. RESULTS: GICs occurred in 51 (1.1%) patients. Etiologies were intestinal ischemia (n = 30; 59%) and hemorrhage (n = 21; 41%). The incidence decreased during the study period (1998-2001: 1.3%, 2002-2004: 0.7%; P = 0.04). The incidence per type of procedure was as follows: coronary artery bypass grafting (CABG)/valve (2.4%), aortic surgery (1.7%), valve surgery (1.0%), and CABG (0.5%; P = 0.001). Multivariate analysis revealed age (odds ratio [OR] = 2.1), myocardial infarction (OR = 2.5), CHF (OR = 2.4), hemodynamic instability (OR = 2.8), cardiopulmonary bypass time >120 minutes (OR = 6.2), peripheral vascular disease (OR = 2.2), renal (OR = 3.2), and hepatic failure (OR = 10.8) as independent predictors of GICs. The overall hospital mortality among patients with GICs was 33%. Long-term survival was significantly decreased in patients with GICs compared with the control group. CONCLUSIONS: Gastrointestinal complications following cardiac surgery remain rare with an incidence <1% in a contemporary series. The key to a lower incidence of GICs lies in systematic application of preventive measures and new advances in intraoperative management. Identification of independent risk factors would facilitate the determination of patients who would benefit from additional perioperative monitoring. Future resources should therefore be redirected to mitigate GICs in high-risk patients.

Achalasia in a patient with gastroesophageal varices: problematic treatment decisions.

The coexistence of achalasia and gastroesophageal varices has been reported sporadically in the English medical literature. We report the case of a 60-year-old Hispanic woman with cryptogenic cirrhosis who was referred for a liver transplant evaluation and subsequently developed progressive dysphagia to both solids and liquids as well as substernal chest pain and weight loss. Endoscopy revealed the presence of grade I esophageal varices and large fundic varices, as well as retained liquid and solid food in the distal esophagus. Radiographic and manometric studies were consistent with achalasia. After botulinum toxin (Botox) injections were no longer effective a transjugular intrahepatic portosystemic shunt was performed for portal decompression before proceeding with pneumatic dilation. Optimal treatment of these 2 conditions, when they occur simultaneously, is problematic. We discuss this patient's management and our approach to this infrequent combination of diseases.

The risk of retention of the capsule endoscope in patients with known or suspected Crohn's disease.

OBJECTIVES: Capsule endoscopy (CE) allows visualization of the mucosa of the entire small bowel and is therefore a potentially important tool in the evaluation of patients with known or suspected Crohn's disease (CD). However, small bowel strictures, which are not uncommon in Crohn's, are considered to be a contraindication to CE for fear of capsule retention. Our goal was to determine the risk of capsule retention in patients with suspected or known CD. METHODS: We retrospectively reviewed the records of 983 CE cases performed at three private gastroenterology practices between December 2000 and December 2003, and selected those with suspected or proven Crohn's. RESULTS: A total of 102 cases were identified in which CE was used in patients with suspected (N = 64) or known (N = 38) CD. Only one of 64 patients (1.6%) with suspected CD had a retained capsule. However, in five of 38 (13%) patients with known Crohn's, the capsule was retained proximal to a stricture. Of the five cases of retained capsules, three strictures were previously unknown. In four cases, the obstructing lesions were resected without complications, leading to complete resolution of the patient's underlying symptoms. One patient chose not to undergo surgery and has remained without an episode of small bowel obstruction for over 38 months. CONCLUSIONS: Capsule retention occurred in 13% (95% CI 5.6%-28%) of patients with known CD, but only in 1.6% (95% CI 0.2%-10%) with suspected Crohn's. A retained capsule may indicate unsuspected strictures in Crohn's that may require an unexpected, but therapeutic, surgical intervention. Patients and physicians should be aware of these potential risks when using CE in CD.

Do guidelines matter? Implementation of the ACG and AGA osteoporosis screening guidelines in inflammatory bowel disease (IBD) patients who meet the guidelines' criteria.

OBJECTIVE: The American College of Gastroenterology (ACG) and American Gastroenterology Association (AGA) have both recently issued guidelines (the "Guidelines") regarding the diagnosis and management of osteoporosis in patients with inflammatory bowel disease (IBD). The objective of this study was to determine the yield of implementing the Guidelines' recommendations in a prospective cohort of IBD patients and identify the prevalence of bone loss, risk factors, and potential influence on management. METHODS: One hundred consecutive IBD patients who fulfilled the Guidelines' criteria underwent dual energy X-ray absorptiometry scanning (DEXA) scanning of the lumbar vertebrae and bilateral hips. Demographic data, risk factor information, and changes in therapy based on screening were collected and analyzed. RESULTS: Indications for screening were history of prolonged past or concurrent steroid use (92%), postmenopausal status (7%), and history of low trauma fracture (7%). Forty-four percent of patients had osteopenia of either the lumbar spine or the hips, 12% had osteoporosis of either the spine or hips, and 44% had normal bone density. In a univariate analysis, factors predicting a greater likelihood of osteoporosis (but not osteopenia) were a diagnosis of Crohn's disease (vs. ulcerative colitis), low body mass index in women, and postmenopausal status. Specific therapies based on DEXA findings were initiated in 69% of patients: oral calcium and vitamin D supplementation in 69% and an oral bisphoshphonate in 20%. CONCLUSIONS: Implementation of the Guidelines led to the detection of osteopenia or osteoporosis and initiation of specific therapies in a majority of patients who met the Guidelines' criteria for DEXA screening.