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.

Characterization of genetic loci that affect susceptibility to inflammatory bowel diseases in African Americans.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) has familial aggregation in African Americans (AAs), but little is known about the molecular genetic susceptibility. Mapping studies using the Immunochip genotyping array expand the number of susceptibility loci for IBD in Caucasians to 163, but the contribution of the 163 loci and European admixture to IBD risk in AAs is unclear. We performed a genetic mapping study using the Immunochip to determine whether IBD susceptibility loci in Caucasians also affect risk in AAs and identify new associated loci. METHODS: We recruited AAs with IBD and without IBD (controls) from 34 IBD centers in the United States; additional controls were collected from 4 other Immunochip studies. Association and admixture loci were mapped for 1088 patients with Crohn's disease, 361 with ulcerative colitis, 62 with IBD type unknown, and 1797 controls; 130,241 autosomal single-nucleotide polymorphisms (SNPs) were analyzed. RESULTS: The strongest associations were observed between ulcerative colitis and HLA rs9271366 (P = 7.5 × 10(-6)), Crohn's disease and 5p13.1 rs4286721 (P = 3.5 × 10(-6)), and IBD and KAT2A rs730086 (P = 2.3 × 10(-6)). Additional suggestive associations (P < 4.2 × 10(-5)) were observed between Crohn's disease and IBD and African-specific SNPs in STAT5A and STAT3; between IBD and SNPs in IL23R, IL12B, and C2orf43; and between ulcerative colitis and SNPs near HDAC11 and near LINC00994. The latter 3 loci have not been previously associated with IBD, but require replication. Established Caucasian associations were replicated in AAs (P < 3.1 × 10(-4)) at NOD2, IL23R, 5p15.3, and IKZF3. Significant admixture (P < 3.9 × 10(-4)) was observed for 17q12-17q21.31 (IZKF3 through STAT3), 10q11.23-10q21.2, 15q22.2-15q23, and 16p12.2-16p12.1. Network analyses showed significant enrichment (false discovery rate <1 × 10(-5)) in genes that encode members of the JAK-STAT, cytokine, and chemokine signaling pathways, as well those involved in pathogenesis of measles. CONCLUSIONS: In a genetic analysis of 3308 AA IBD cases and controls, we found that many variants associated with IBD in Caucasians also showed association evidence with these diseases in AAs; we also found evidence for variants and loci not previously associated with IBD. The complex genetic factors that determine risk for or protection against IBD in different populations require further study.

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.