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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.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.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.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.

Background & Aims Increased intestinal permeability has been associated with Crohn’s disease (CD), but it is not clear whether it is a cause or result of the disease. We performed a prospective study to determine whether increased intestinal permeability is associated with future development of CD. Methods We assessed the intestinal permeability, measured by the urinary fractional excretion of lactulose-to-mannitol ratio (LMR) at recruitment in 1420 asymptomatic first-degree relatives (6–35 years old) of patients with CD (collected from 2008 through 2015). Participants were then followed up for a diagnosis of CD from 2008 to 2017, with a median follow-up time of 7.8 years. We analyzed data from 50 participants who developed CD after a median of 2.7 years during the study period, along with 1370 individuals who remained asymptomatic until October 2017. We used the Cox proportional hazards model to evaluate time-related risk of CD based on the baseline LMR. Results An abnormal LMR (>0.03) was associated with a diagnosis of CD during the follow-up period (hazard ratio, 3.03; 95% CI, 1.64–5.63; P = 3.97 × 10–4). This association remained significant even when the test was performed more than 3 years before the diagnosis of CD (hazard ratio, 1.62; 95% CI, 1.051–2.50; P = .029). Conclusions Increased intestinal permeability is associated with later development of CD; these findings support a model in which altered intestinal barrier function contributes to pathogenesis. Abnormal gut barrier function might serve as a biomarker for risk of CD onset.

Crohn’s disease (CD) and ulcerative colitis (UC) are recurrent, chronic forms of inflammatory bowel diseases (IBD), the diagnosis of which can entail long delays. The delays can lead to disease presentation with complications and high morbidity. Therefore, better diagnostic markers for IBD are required. We investigated whether methylation marks in the TGFB1 and IL-6 gene promoters could be of diagnostic utility in IBD. To this end, we conducted a case-control study using peripheral blood DNA samples from 67 CD and 37 UC pediatric patients, and from 43 age-matched healthy controls. The patients were recruited from three pediatric gastroenterology clinics across Canada. The DNA samples were processed to identify methylation sites (CpG) across the promoter regions of the TGFB1 and IL-6 genes using the Sequenom technology. After implementing quality control measures, and initial non-parametric univariate (Man-Whitney U test) analyses, multivariate logistic regression analyses was carried out to identify models with the best fit (Akaike Information Criteria) and the greatest discriminatory capabilities (Area Under the Receiver Operating Curve). Logistic regression analysis showed that a model comprising 14 TGFB1 CpG sites had high discriminatory ability to separate CD from controls (AUC=0.94). Similarly, a logistic model comprising 9 CpG sites in the TGFB1 gene had near perfect ability to discriminate between UC and controls (AUC=0.99). A logistic model comprising three CpG sites in the TGFB1 gene had moderate ability (AUC=0.81) to discriminate between CD and UC. In conclusion, CpG methylation in the TGFB1 gene promoter has high discriminative power for identifying CD and UC, and could serve as an important diagnostic markers.

This chapter reviews the experience utilizing elemental diet therapy in pediatric patients with Crohn's disease. It presents the results on the use of elemental diet to reverse malnutrition and growth failure. The chapter discusses the data on the use of elemental diet therapy to control disease activity in active Crohn's disease. The role of diet in the management of inflammatory bowel disease (IBD) has always been controversial. IBD patients, or their families, often request specific information concerning dietary counseling for gastrointestinal symptoms. The mechanisms contributing to the malnutrition and various micronutrient deficiencies in pediatric IBD patients are numerous. Overall, inadequate caloric intake is the primary cause of growth retardation in IBD. Nutritional therapy has generally been considered an adjunctive treatment in the management of malnourished patients with IBD. Growth failure represents a common, serious complication of IBD unique to the pediatric age group.

Sar1B GTPase is a key component of Coat protein complex II (COPII)-coated vesicles that bud from the endoplasmic reticulum to export newly synthesized proteins. The aims of this study were to determine whether Sar1B responds to lipid regulation and to evaluate its role in cholesterol (CHOL) homeostasis. The influence of lipids on Sar1B protein expression was analyzed in Caco-2/15 cells by Western blot. Our results showed that the presence of CHOL (200 μM) and oleic acid (0.5 mM), bound to albumin, increases Sar1B protein expression. Similarly, supplementation of the medium with micelles composed of taurocholate with monooleylglycerol or oleic acid also stimulated Sar1B expression, but the addition of CHOL (200 μM) to micelle content did not modify its regulation. On the other hand, overexpression of Sar1B impacted on CHOL transport and metabolism in view of the reduced cellular CHOL content along with elevated secretion when incubated with oleic acid-containing micelles for 24 h, thereby disclosing induced CHOL transport. This was accompanied with higher secretion of free- and esterified-CHOL within chylomicrons, which was not the case when oleic acid was replaced with monooleylglycerol or when albumin-bound CHOL was given alone. The aforementioned cellular CHOL depletion was accompanied with a low phosphorylated/non phosphorylated HMG-CoA reductase ratio, indicating elevated enzymatic activity. Combination of Sar1B overexpression with micelle incubation led to reduction in intestinal CHOL transporters (NPC1L1, SR-BI) and metabolic regulators (PCSK9 and LDLR). The present work showed that Sar1B is regulated in a time- and concentration-dependent manner by dietary lipids, suggesting an adaptation to alimentary lipid flux. Our data also suggest that Sar1B overexpression contributes to regulation of CHOL transport and metabolism by facilitating rapid uptake and transport of CHOL.

Tumor necrosis factor (TNF)-α inhibitors and thiopurines are among the most important classes of medications utilized in the clinical management of Crohn’s disease and ulcerative colitis. A significant proportion of patients loses response to these agents or develops adverse effects during the course of the treatment. Monitoring of drug levels and anti-drug antibodies (for TNF-α inhibitors) and metabolite levels (for thiopurines) can provide valuable insight into the possible etiology of unfavorable outcomes and allow for an appropriate management strategy for these patients. This review summarizes the current knowledge on the clinical implications of therapeutic drug monitoring in inflammatory bowel disease patients treated with TNF-α inhibitors and thiopurines.

Thirty-seven patients were listed for small bowel transplantation; 16 were transplanted and 15 died while waiting for a donor. Cyclosporine (N = 6) or tacrolimus (N = 10) were used for immune suppression. Graft rejection rates were lower in the combined liver/small bowel grafts than the isolated intestinal transplants (1/7 vs 5/7; P < 0.01) All of the cyclosporine group have died; the median survival was 25.7 months with two patients living more than five years. The tacrolimus group had fewer infections and a shorter hospital stay. All but two are alive with a median survival of 13 months. Seven of eight long-term survivors are off intravenous feedings. We conclude that small bowel transplantation is a life-saving option for patients with intestinal failure who cannot be maintained on total parenteral nutrition.

Rare instances of symptomatic fat malabsorption have been reported in patients with heterozygous hypobetalipoproteinemia, but with an unclear pathogenesis. An 8-month-old boy with chronic diarrhea and failure to thrive was found to have abnormally low plasma total cholesterol (85 mg/dl), LDL-cholesterol (48 mg/dl), apoB (52 mg/dl), apoA-I (53 mg/dl), and vitamin E (0.22 mg/dl). Decreased plasma LDL-C and apoB were noted in the father (34 and 40 mg/dl, respectively), as well as several other family members. Fasting triglycerides were normal but did not increase normally in response to a fat meal test. Lipoprotein composition showed an abnormal profile of very low density (VLDL, d 1.006 g/ml), low density (LDL, d 1.063 g/ml), and high density (HDL, d 1.21 g/ml) lipoproteins. A fasting jejunal biopsy revealed lipid-laden enterocytes. Electron microscopy of the jejunal biopsy revealed the absence of lipid particles in the intercellular spaces after a fat meal. Jejunal explants cultured with [14C]palmitate and [3H]leucine showed limited synthesis of triglycerides and apolipoproteins (36 and 42% of controls, respectively), whereas the father's results were close to normal. At 1 year of age, improvement in intestinal fat absorption was accompanied by the presence of chylomicrons in the intercellular space, concomitant with the enhanced synthesis of lipids and apoB by jejunal explants. These data provide evidence that heterozygous hypobetalipoproteinemia may present early in life as transient, symptomatic lipid malabsorption. The mechanisms responsible for improved lipid transport despite persistent hypobetalipoproteinemia remain to be established.

The role of intestinal fatty acid binding protein (I-FABP) in lipid metabolism remains elusive. To address this issue, normal human intestinal epithelial cells (HIEC-6) were transfected with cDNA to overexpress I-FABP and compared with cells treated with empty pQCXIP vector. I-FABP overexpression stimulated mitochondrial [U-14C]oleate oxidation to CO2 and acid-soluble metabolites via mechanisms including the upregulation of protein expression and the activity of carnitine palmitoyltransferase 1, a critical enzyme controlling the entry of fatty acid (FA) into mitochondria, and increased activity of 3-hydroxyacyl-CoA dehydrogenase, a mitochondrial beta-oxidation enzyme. On the other hand, the gene and protein expression of the key enzymes FA synthase and acetyl-coenzyme A carboxylase 2 was decreased, suggesting diminished lipogenesis. Furthermore, I-FABP overexpression caused a decline in [14C]free cholesterol (CHOL) incorporation. Accordingly, a significant lessening was observed in the gene expression of Niemann Pick C1-Like 1, a mediator of CHOL uptake, along with an increase in the transcripts and protein content of ABCA1 and ABCG5/ABCG8, acting as CHOL efflux pumps. Furthermore, I-FABP overexpression resulted in increased levels of mRNA, protein mass, and activity of HMG-CoA reductase, the rate-limiting step in CHOL synthesis. Scrutiny of the nuclear receptors revealed augmented peroxisome proliferator-activated receptor alpha,gamma and reduced liver X receptor-alpha in HIEC-6 overexpressing I-FABP. Finally, I-FABP overexpression did not influence acyl-coenzyme A oxidase 1, which catalyzes the first rate-limiting step in peroxisomal FA beta-oxidation. Overall, our data suggest that I-FABP may influence mitochondrial FA oxidation and CHOL transport by regulating gene expression and interaction with nuclear receptors.

The small bowel has traditionally been considered a simple organ for the transport of food-stuffs. Although the function of nutrient delivery is vital, the digestive and absorptive phases of fat were poorly understood until the past two decades. Moreover, the small bowel was not thought to have any modulating transport properties nor a role in the genesis of chronic diseases such as atherosclerosis. Given its enormous capacity to transform nutrients and to synthesize atherogenic proteins and gastro-intestinal peptides, the intestinal epithelium plays a key role in a number of metabolic pathways. The aim of the brief review is to provide an update on recent advances in our understanding of the absorption of dietary lipids with emphasis on the role and contribution of key proteins to malabsorptive syndromes as well as hyperlipidemic syndromes and eventually to atherosclerosis.

Although postprandial hypertriglyceridemia is a major contributing factor in the development of atherosclerosis, little information is available on the effect of insulin resistance and diabetes on intestinal fat transport. The aim of the present study was to examine intracellular events that govern lipid transport and apolipoprotein (apo) B-48-containing lipoprotein assembly in the small intestine of Psammomys obesus, a model of nutritionally induced insulin resistance and type 2 diabetes. Animals with normoglycemia/hyperinsulinemia and hyperglycemia/hyperinsulinemia exhibited high levels of triglycerides (TGs) in the plasma and intestine and postprandial plasma chylomicrons and apo B-48 compared with normoglycemic/normoinsulinemic animals. In vitro studies, using cultured jejunal explants incubated with either [14C]oleic acid or [35S]methionine, revealed their higher efficiency in de novo TG synthesis, apo B-48 biogenesis, and TG-rich lipoprotein assembly. Accordingly, enhanced monoacylglycerol and diacylglycerol acyltransferase activity was also discernible and concomitant with an increased content of L-fatty acid binding protein and in vivo chylomicron production rates. However, both the I-fatty acid binding protein amount and the apo B-48 proteasomal degradative pathway were decreased. Overall, our findings show that the development of an insulin-resistant/diabetic state in Psammomys obesus triggers the whole intra-enterocyte machinery, leading to lipoprotein assembly and favoring the intestinal oversecretion of apo B-48-lipoproteins, which may contribute to characteristic hypertriglyceridemia.

Background: Membrane lipid peroxidation may play a role in immune-mediated bowel diseases. Objective: We examined the effects of lipopolysaccharide (LPS), a ubiquitous endotoxin mediator of gram-negative bacteria, alone and in combination with iron-ascorbate, on enterocyte function. Furthermore, we assessed the antioxidant capacity of butylated hydroxytoluene (BHT) and butyric acid, which are known to play a significant role in the welfare of intestinal mucosa. Design: Differentiated intestinal Caco-2 cells were used to study the induction of membrane peroxidation by LPS (100 � g/mL) and iron-ascorbate (0.2 and 2 mmol/L, respectively) and to examine the beneficial effects of BHT and butyric acid. Results: A significant dose-dependent increase in malondialdehyde, accompanied by lower apical membrane fluidity and significantly decreased sucrase activity, was observed when Caco-2 cells were incubated with LPS. LPS also augmented paracellular permeability ([ 14 C]polyethylene glycol flux), prostaglandin E2 production, and cyclooxygenase-2 (EC 1.14.99.1) expression. These abnormalities were exacerbated by the coadministration of iron-ascorbate, but most of them were suppressed by butyric acid and BHT. Conclusion: Bacterial endotoxin and prooxidants may overwhelm antioxidant defenses and become deleterious to enterocyte function, whereas butyric acid and BHT may provide antioxidant protection. Am J Clin Nutr 2003;77:744‐50.

AIM: To evaluate the impact of antiviral treatment on cytomegalovirus (CMV)-positive ulcerative colitis patients. METHODS: We performed a systematic review and meta-analysis (MA) of comparative cohort and case-control studies published between January 1966 and March 2013. Studies focusing on colectomy series and studies including only less than 3 patients in the treated or non-treated arm were excluded. The primary outcome was colectomy within 30 d of diagnosis. Secondary outcomes included colectomy during the follow-up period Subgroup analyses by method of detection of CMV, study design, risk of bias and country of origin were performed. Quality of studies was evaluated according to modified New-Castle Ottawa Scale. RESULTS: After full-text review, nine studies with a total of 176 patients were included in our MA. All the included studies were of low to moderate quality. Patients who have received antiviral treatment had a higher risk of 30-d colectomy (OR = 2.40; 95%CI: 1.05-5.50; I2 = 37.2%). A subgroup analysis including only patients in whom CMV diagnosis was based did not demonstrate a significant difference between the groups (OR = 3.41; 95%CI: 0.39-29.83; I2 = 56.9%). Analysis of long-term colectomy rates was possible for 6 studies including 110 patients. No statistically significant difference was found between the treated and untreated groups (OR = 1.71; 95%CI: 0.71-4.13; 6 studies, I2 = 0%). Analysis of mortality rate was not possible due to a very limited number of cases. Stratification of the outcomes by disease severity was not possible. CONCLUSION: No positive association between antiviral treatment and a favorable outcome was demonstrated. These findings should be interpreted cautiously due to primary studies’ quality and potential biases.

A child with cryptogenic cirrhosis underwent a third session of elective sclerotherapy. Endoscopic therapy consisted of intravascular injection of ethanolamine oleate in varices newly developed at the midesophagus level. Irreversible paraplegia was documented within 8 hr postoperatively. Two years later she eventually died from gastrointestinal bleeding. Autopsy findings were compatible with an infarct of the spinal cord secondary to an occlusion of the anterior spinal artery. Various hypotheses which might explain the passage of the sclerosing material from the esophagus to the anterior spinal artery include: arterial occlusion secondary to venous thrombosis and spinal cord necrosis, accidental injection in an intercostal artery or azygous vein through the esophageal wall, the presence of a congenital arteriovenous fistula or the opening of arteriovenous shunt. Paravasal injection of dilute sclerosing agent might protect against this unusual but dramatic complication.

• Three widely used screening tests for enteropathy in childhood are the lactose breath hydrogen test, the one-hour serumd-xylose absorption test, and the 72-hour fecal fat determination. To our knowledge, no study has compared these three tests and jejunal biopsy results. A retrospective survey of all jejunal biopsy results at Children's Hospital, Boston, from July 1983 to July 1984 was undertaken to evaluate which test best predicted a normal biopsy result. None of the screening tests was ideal. The lactose breath test had low sensitivity and specificity and did not correlate significantly with biopsy results. Thed-xylose and fecal fat tests were each significantly correlated with biopsy results; a normal result of either test was highly predictive of a normal biopsy result. Combining the results of two or more screening tests did not improve predictive value. The xylose test is preferable on the basis of greater sensitivity and ease of patient compliance. ( AJDC 1987;141:435-438)

No study has compared the 3 most commonly used screening tests for enteropathy and jejunal biopsy results. A retrospective survey of all jejunal biopsies at CHMC (7/83-7/84) was undertaken to evaluate which test best predicted a normal biopsy. Screening tests: Lactose breath hydrogen test (LBHT, 2gm/kg, max 50gm; abnormal>10ppm rise after 60min); serum D-xylose (Xyl, 0.5 gm/kg, max 25gm; abnormal 10% of intake over 72 hours). Histology was reviewed and scored blindly as N (normal-minimal villous blunting) or Abn. (moderate-severe villous atrophy, crypt hyperplasia). Results: Jejunal biopsies were obtained from 117 children. 49 patients had no prior screening test and were excluded. Conclusions: None of the screening tests analyzed were ideal. Xyl and FF were significantly correlated with biopsy results. A normal result in either was highly predictive of a normal biopsy. The xylose test is preferable on the basis of greater sensitivity and ease of patient compliance.