Enterobacteriaceae Growth Promotion by Intestinal Acylcarnitines, a Biomarker of Dysbiosis in Inflammatory Bowel Disease.

BACKGROUND & AIMS: Altered plasma acylcarnitine levels are well-known biomarkers for a variety of mitochondrial fatty acid oxidation disorders and can be used as an alternative energy source for the intestinal epithelium when short-chain fatty acids are low. These membrane-permeable fatty acid intermediates are excreted into the gut lumen via bile and are increased in the feces of patients with inflammatory bowel disease (IBD). METHODS: Herein, based on studies in human subjects, animal models, and bacterial cultures, we show a strong positive correlation between fecal carnitine and acylcarnitines and the abundance of Enterobacteriaceae in IBD where they can be consumed by bacteria both in vitro and in vivo. RESULTS: Carnitine metabolism promotes the growth of Escherichia coli via anaerobic respiration dependent on the cai operon, and acetylcarnitine dietary supplementation increases fecal carnitine levels with enhanced intestinal colonization of the enteric pathogen Citrobacter rodentium. CONCLUSIONS: In total, these results indicate that the increased luminal concentrations of carnitine and acylcarnitines in patients with IBD may promote the expansion of pathobionts belonging to the Enterobacteriaceae family, thereby contributing to disease pathogenesis.

Intravenous Iron Sucrose for Treatment of Iron Deficiency Anemia in Pediatric Inflammatory Bowel Disease.

OBJECTIVES: Iron deficiency anemia (IDA) is a common complication of pediatric inflammatory bowel disease (IBD), yet the effectiveness of oral iron supplementation is limited. Intravenous iron sucrose is an effective and safe alternative treatment for IDA in adults with IBD, but its role in the treatment of IDA in pediatric IBD is unclear. The primary aim of this study was to evaluate the use of iron sucrose in pediatric IBD subjects with IDA and determine the clinical response as measured by improvement in hemoglobin concentration. The secondary aim was to describe adverse events associated with iron sucrose use in this cohort. METHODS: A retrospective chart review was performed of all pediatric patients with IBD receiving iron sucrose infusions for IDA at a single tertiary care center between 2011 and 2015. RESULTS: Seventy-two subjects (53 with Crohn disease, 11 with ulcerative colitis, and 8 with IBD-unclassified) received a total of 273 iron sucrose infusions. Forty-three subjects qualified for the efficacy analysis. There was a significant increase in hemoglobin over the treatment course, with mean (±SD) hemoglobin increasing from 9.6 ±â€Š1.2 g/dL at baseline to 12.1 ±â€Š1.3 g/dL after iron sucrose treatment (P < 0.001). Eighteen adverse events were reported in 13 subjects (18.1% of subjects and 6.6% of infusions). No anaphylaxis reactions occurred and none of the adverse events were, however, life-threatening or required hospitalization. CONCLUSIONS: Intravenous iron sucrose is a safe and potentially efficacious treatment choice for IDA in pediatric IBD.

Comparative Effectiveness of Nutritional and Biological Therapy in North American Children with Active Crohn's Disease.

BACKGROUND: Therapeutic targets in pediatric Crohn's disease include symptoms, quality of life (QOL), and mucosal healing. Although partial enteral nutrition (PEN), exclusive enteral nutritional (EEN), and anti-tumor necrosis factor alpha (anti-TNF) therapy all improve symptoms, the comparative effectiveness of these approaches to improve QOL and achieve mucosal healing has not been assessed prospectively. METHODS: In a prospective study of children initiating PEN, EEN, or anti-TNF therapy for Crohn's disease, we compared clinical outcomes using the Pediatric Crohn's Disease Activity Index (PCDAI), QOL (IMPACT score), and mucosal healing as estimated by fecal calprotectin (FCP). PCDAI, IMPACT, FCP, and diet (prompted 24-h recall) were measured at baseline and after 8 weeks of therapy. RESULTS: We enrolled 90 children with active Crohn's disease (PCDAI, 33.7 ± 13.7; and FCP, 976 ± 754), of whom 52 were treated with anti-TNF, 22 with EEN, and 16 with PEN plus ad lib diet. Clinical response (PCDAI reduction ≥15 or final PCDAI ≤10) was achieved by 64% on PEN, 88% EEN, and 84% anti-TNF (test for trend P = 0.08). FCP ≤250 µg/g was achieved with PEN in 14%, EEN 45%, and anti-TNF 62% (test for trend P = 0.001). Improvement in overall QOL was not statistically significantly different between the 3 groups (P = 0.86). However, QOL improvement was the greatest with EEN in the body image (P = 0.03) domain and with anti-TNF in the emotional domain (P = 0.04). CONCLUSIONS: Although PEN improved clinical symptoms, EEN and anti-TNF were more effective for decreasing mucosal inflammation and improving specific aspects of QOL.

Correlation between intraluminal oxygen gradient and radial partitioning of intestinal microbiota.

BACKGROUND & AIMS: The gut microbiota is a complex and densely populated community in a dynamic environment determined by host physiology. We investigated how intestinal oxygen levels affect the composition of the fecal and mucosally adherent microbiota. METHODS: We used the phosphorescence quenching method and a specially designed intraluminal oxygen probe to dynamically quantify gut luminal oxygen levels in mice. 16S ribosomal RNA gene sequencing was used to characterize the microbiota in intestines of mice exposed to hyperbaric oxygen, human rectal biopsy and mucosal swab samples, and paired human stool samples. RESULTS: Average Po2 values in the lumen of the cecum were extremely low (<1 mm Hg). In altering oxygenation of mouse intestines, we observed that oxygen diffused from intestinal tissue and established a radial gradient that extended from the tissue interface into the lumen. Increasing tissue oxygenation with hyperbaric oxygen altered the composition of the gut microbiota in mice. In human beings, 16S ribosomal RNA gene analyses showed an increased proportion of oxygen-tolerant organisms of the Proteobacteria and Actinobacteria phyla associated with rectal mucosa, compared with feces. A consortium of asaccharolytic bacteria of the Firmicute and Bacteroidetes phyla, which primarily metabolize peptones and amino acids, was associated primarily with mucus. This could be owing to the presence of proteinaceous substrates provided by mucus and the shedding of the intestinal epithelium. CONCLUSIONS: In an analysis of intestinal microbiota of mice and human beings, we observed a radial gradient of microbes linked to the distribution of oxygen and nutrients provided by host tissue.

A novel enteral nutrition protocol for the treatment of pediatric Crohn's disease.

BACKGROUND: Enteral nutritional therapy (EN) is an effective modality for inducing and maintaining remission in pediatric patients with Crohn's disease (CD). The standard protocol for EN provides patients with 100% of their caloric needs for induction of remission. The aim of this study was to determine the efficacy of delivering 80% to 90% of patient's caloric needs through EN, to induce remission in pediatric patients with CD. This approach allows patients to consume remaining calories from a normal diet. METHODS: A retrospective review of charts from 1998 to 2010 was conducted at The Children's Hospital of Philadelphia. Remission (Pediatric Crohn's Disease Activity Index <10) and response (decrease in Pediatric Crohn's Disease Activity Index score of ≥12.5 points) were calculated before and after treatment with EN. Weight z scores and laboratory parameters were evaluated in all participants. RESULTS: Forty-three charts were evaluated. Mean age of participants was 12.8 years (5.1-17.4), 67% were male and 33% female patients. Remission and response were evaluated in a group of 23 participants, with no missing data. There were reductions in erythrocyte sedimentation rate (P < 0.0001) and C-reactive protein (P < 0.02), and increases in albumin (P < 0.03). Mean Pediatric Crohn's Disease Activity Index score at baseline was 26.9 and was reduced to a score of 10.2 at follow-up (P < 0.0001). Induction of remission was achieved in 65% and response in 87% at a mean follow-up of 2 months (1-4 months). CONCLUSIONS: This novel EN protocol seems to be effective for the induction of remission in pediatric patients with CD and contributes to increasing weight and improving laboratory markers. This protocol may result in improved EN acceptance and compliance and will be evaluated prospectively.

Folate concentrations in pediatric patients with newly diagnosed inflammatory bowel disease.

BACKGROUND: Folate is postulated to protect against cell injury and long-term risk of cancer. Folate deficiency has been shown to be associated with inflammatory bowel disease (IBD). However, folate concentrations are poorly delineated in children with IBD. OBJECTIVE: The objective was to compare folate concentrations between children with newly diagnosed IBD and healthy controls. DESIGN: Red blood cell folate (RBCF) and whole-blood folate (WBF) concentrations were measured in 78 children (mean age: 12.8 +/- 2.7 y): 22 patients with newly diagnosed untreated Crohn disease, 11 patients with ulcerative colitis, 4 patients with indeterminate colitis, and 41 controls. Vitamin supplementation and dietary intakes determined by food-frequency questionnaire were recorded for 20 IBD patients and 28 controls. RESULTS: RBCF concentrations were 19.4% lower in controls (587.0 +/- 148.6 ng/mL) than in patients (728.7 +/- 185.8 ng/mL; P = 0.0004), and WBF concentrations were 11.1% lower in controls (218.2 +/- 49.7 ng/mL) than in patients (245.3 +/- 59.1 ng/mL; P = 0.031). Total folate intake was 18.8% higher in controls (444.7 +/- 266.7 microg/d) than in IBD patients (361.1 +/- 230.6 microg/d), but this difference was not statistically significant (P = 0.264). Folate intakes were below the Recommended Dietary Allowance (200-400 microg/d), adjusted for age and sex, in 35.4% of study subjects. CONCLUSIONS: In contrast with previous evidence of folate deficiency in adult IBD patients, our data indicate higher folate concentrations in children with newly diagnosed untreated IBD than in controls. This finding was unexpected, especially in light of the higher dietary folate intakes and hematocrit values in children without IBD. The influence of IBD therapy on folate metabolism and the long-term clinical implications of high RBCF and WBF concentrations at the time of IBD diagnosis should be explored further.

Patterns of complementary and alternative medicine use in a population of pediatric patients with inflammatory bowel disease.

Complementary and alternative medicine use is prominent in the United States. The use of complementary and alternative therapies appears to be common in patients with inflammatory bowel disease, but few studies have been completed in children. We sought to examine the extent that children with inflammatory bowel disease in the Greater Philadelphia area (Philadelphia County and the surrounding counties in Delaware, New Jersey, and Pennsylvania) use alternative therapies. We paid particular attention to the specific types of therapies used and whether certain demographic and disease associated factors influence the degree of usage. In this study, we questioned the families of all children diagnosed with inflammatory bowel disease, aged 6 to 16 years and living within Philadelphia and its surrounding counties, who were followed at 1 of the 2 academic pediatric gastroenterology programs that served the area. More than 80% of surveys were returned. Fifty-one percent (95% C.I. 45% to 56%) of patients surveyed reported some form of alternative medicine use within the previous year. Univariate analysis revealed increased use among patients who had Crohn disease, who used the Internet for research on their disease, who reported poor quality of life and had increased school absences in the past year. Therapies associated with alternative medicine use included biological and immunomodulatory therapy. Regression analysis revealed positive associations between use of alternative therapies and expenditure on nonprescription treatments, poor quality of life, Internet research, and the need for calorie supplementation, whereas there was a negative association with history of prior surgery for inflammatory bowel disease.

Biological and novel therapies for inflammatory bowel disease in children.

During the past decade, a tremendous wealth of information regarding the pathogenesis, genetics, and therapy of IBD has been discovered. Judging by the number of new publications published every month in scientific journals and the great enthusiasm at scientific meetings, this outstanding pace surely will continue. In the near future, clinicians may be able to classify IBD into several subtypes depending on patients' cytokine and gene profiles. For example, two groups of researchers recently have identified mutation in the NOD2 gene, which is associated with susceptibility to CD. This identification may allow the clinician to better predict outcome and response to medical therapy. At the same time, several promising new therapies are being investigated. Technologic advances will continue to result in the development of potent and specific agents that will control and possibly correct the abnormal inflammatory processes responsible for pediatric IBD.