Ad Masclee

Role of Tumor Necrosis Factor-α and Interleukin-10 Gene Polymorphisms in Irritable Bowel Syndrome

OBJECTIVES:Imbalances in the genetically controlled pro- and anti-inflammatory cytokine production may promote ongoing low-grade inflammation after an acute gastroenteritis, and subsequently, irritable bowel syndrome (IBS) (post-infectious IBS, PI-IBS). We studied gene promoter single nucleotide polymorphisms (SNPs) of tumor necrosis factor-α (TNF-α, pro-inflammatory) and interleukin-10 (IL-10, anti-inflammatory) in IBS patients and controls.METHODS:DNA was extracted from peripheral blood leucocytes of 111 IBS patients and 162 healthy controls. Genotype and allele frequencies were assessed by analyzing SNPs at position −308 (TNF-α) and −1082 and −819 (IL-10).RESULTS:Homozygous high producers for TNF-α (A/A) were rare (overall prevalence 2.6%). The heterozygous TNF-α genotype (G/A, high producer) was significantly more prevalent in IBS compared to controls (41%vs 26%, p = 0.02). More patients (41%) than controls (30%) were positive for the A allele (p = 0.044; odds ratio (OR) 1.68, 95% confidence interval (CI) 1.01–2.79), with a similar trend for diarrhea (54%) versus constipation and alternating subtypes (<33%, p = 0.079), but not for subgroups according to a history of acute gastroenteritis. IL-10 genotypes were similarly distributed in patients and controls for both SNPs. Possession of a high producer TNF-α and a low producer IL-10 genotype were significantly more prevalent in IBS (9%) versus controls (3%, p = 0.035; OR 3.11, 95% CI 1.03–9.36) and in diarrhea (20%) compared to other IBS subtypes (<4%, p = 0.026).CONCLUSIONS:Our results support the emerging hypothesis that genetically determined immune activity plays a role in the pathophysiology of IBS. Future studies in larger, clinically relevant, IBS subgroups are warranted to establish definite associations with cytokine gene polymorphisms.

Probiotics in the Management of Inflammatory Bowel Disease A Systematic Review of Intervention Studies in Adult Patients

AbstractIntroduction: Mounting evidence suggests an important role for the intestinal microbiota in the chronic mucosal inflammation that occurs in inflammatory bowel disease (IBD), and novel molecular approaches have further identified a dysbiosis in these patients. Several mechanisms of action of probiotic products that may interfere with possible aetiological factors in IBD have been postulated. Objective: Our objective was to discuss the rationale for probiotics in IBD and to systematically review clinical intervention studies with probiotics in the management of IBD in adults. Methods: A systematic search was performed in PubMed up to 1 October 2011, using defined keywords. Only full-text papers in the English language addressing clinical outcomes in adult patients were included. The 41 eligible studies were categorized on disease type (ulcerative colitis [UC] with/without an ileo-anal pouch and Crohn’s disease [CD]) and disease activity. Pooled odds ratios were only calculated per probiotic for a specific patient group when more than one randomized controlled trial was available. Results: Well designed randomized controlled trials supporting the application of probiotics in the management of IBD are still limited. Meta-analyses could only be performed for a limited number of studies revealing overall risk ratios of 2.70 (95% CI 0.47, 15.33) for inducing remission in active UC with Bifido-fermented milk versus placebo or no additive treatment (n = 2); 1.88 (95% CI 0.96, 3.67) for inducing remission in active UC with VSL#3 versus placebo (n = 2); 1.08 (95% CI 0.86, 1.37) for preventing relapses in inactive UC with Escherichia coli Nissle 1917 versus standard treatment (n= 3); 0.17 (95% CI 0.09,0.33) for preventing relapses in inactive UC/ileo-anal pouch anastomosis(IPAA) patients with VSL#3 versus placebo; 1.21 (95% CI 0.57, 2.57) for preventing endoscopic recurrences in inactive CD with Lactobacillus rhamnosus GG versus placebo (n=2); and 0.93 (95% CI 0.63, 1.38) for preventing endoscopic recurrences in inactive CD with Lactobacillus johnsonii versus placebo (n = 2). Conclusion: Further well designed studies based on intention-to-treat analyses by several independent research groups are still warranted to support the promising results for E. coli Nissle in inactive UC and the multispecies product VSL#3 in active UC and inactive pouch patients. So far, no evidence is available to support the use of probiotics in CD. Future studies should focus on specific disease subtypes and disease location. Further insight into the aetiology of IBD and the mechanisms of probiotic strains will aid in selecting probiotic strains for specific disease entities and disease locations.

The effect of host genetics on the gut microbiome

The gut microbiome is affected by multiple factors, including genetics. In this study, we assessed the influence of host genetics on microbial species, pathways and gene ontology categories, on the basis of metagenomic sequencing in 1,514 subjects. In a genome-wide analysis, we identified associations of 9 loci with microbial taxonomies and 33 loci with microbial pathways and gene ontology terms at P < 5 × 10−8. Additionally, in a targeted analysis of regions involved in complex diseases, innate and adaptive immunity, or food preferences, 32 loci were identified at the suggestive level of P < 5 × 10−6. Most of our reported associations are new, including genome-wide significance for the C-type lectin molecules CLEC4F–CD207 at 2p13.3 and CLEC4A–FAM90A1 at 12p13. We also identified association of a functional LCT SNP with the Bifidobacterium genus (P = 3.45 × 10−8) and provide evidence of a gene–diet interaction in the regulation of Bifidobacterium abundance. Our results demonstrate the importance of understanding host–microbe interactions to gain better insight into human health.

Leaky gut and diabetes mellitus: what is the link?

Diabetes mellitus is a chronic disease requiring lifelong medical attention. With hundreds of millions suffering worldwide, and a rapidly rising incidence, diabetes mellitus poses a great burden on healthcare systems. Recent studies investigating the underlying mechanisms involved in disease development in diabetes point to the role of the dys‐regulation of the intestinal barrier. Via alterations in the intestinal permeability, intestinal barrier function becomes compromised whereby access of infectious agents and dietary antigens to mucosal immune elements is facilitated, which may eventually lead to immune reactions with damage to pancreatic beta cells and can lead to increased cytokine production with consequent insulin resistance. Understanding the factors regulating the intestinal barrier function will provide important insight into the interactions between luminal antigens and immune response elements. This review analyses recent advances in the mechanistic understanding of the role of the intestinal epithelial barrier function in the development of type 1 and type 2 diabetes. Given our current knowledge, we may assume that reinforcing the intestinal barrier can offer and open new therapeutic horizons in the treatment of type 1 and type 2 diabetes.

Effect of a low dose of intraduodenal fat on satiety in humans: studies using the type A cholecystokinin receptor antagonist loxiglumide.

Satiation, the process that brings eating to an end, and satiety, the state of inhibition over further eating, may be influenced by cholecystokinin (CCK). In animal and human studies, it has been shown that infusion of exogenous CCK decreases food intake, but the doses given may well have led to supraphysiological plasma concentrations. This study was done to discover if a low dose of intraduodenal fat releasing physiological amounts of endogenous cholecystokinin exerts satiation or satiety effects, or both and if these effects could be inhibited by the CCK receptor antagonist loxiglumide. In 10 healthy lean volunteers (5 F, 5 M, mean age 26) three tests were performed in a randomised blind fashion. Intralipid 20% (6 g/h) (experiments A and C) or saline (experiment B) were given intraduodenally from 1030 until 1300. The subjects received saline (experiments A and B) or loxiglumide (experiment C) a specific CCK-receptor antagonist (10 mg/kg/h) intravenously from 0930 until 1300. At 1200 a meal was served. At regular time intervals hunger feelings were measured using visual analogue scales and food selection lists and plasma CCK was measured by radioimmunoassay. Food intake (mean (SEM)) during intraduodenal fat (206(35)g) was lower than in the control study (269(37)g, p = 0.09). Loxiglumide largely prevented the inhibitory effect of intraduodenal fat on food intake (245(30)g). From 1030 until the meal at 1200 there was a significant satiating effect of intraduodenal fat compared with the control and loxiglumide experiments according to the food selection lists, which was because of the satiating effect for the fat rich items (p<0.05). Also feelings of fullness were significantly higher during intraduodenal fat than in the control or loxiglumide experiments (p<0.05). During intraduodenal fat there was a significant increase of plasma CCK from 2.4(0.3) to 4.8(0.4) pM (p<0.001). Loxiglumide led to an exaggerated CCK release to a peak concentration of 16(2.4) pM before the meal. This study shows that in humans low dose intraduodenal fat increases satiety and satiation, mainly through the effect of CCK.

Effect of fat saturation on satiety, hormone release, and food intake

BACKGROUND Ileal delivery of fat reduces hunger and food intake through activation of the ileal brake. Physicochemical properties of fat have been shown to affect satiety and food intake. OBJECTIVE The objective of this study was to assess the effect of ileal fat emulsions with differing degrees of fatty acid saturation on satiety, food intake, and gut peptides (cholecystokinin and peptide YY). We hypothesized that long-chain triacylglycerols with diunsaturated fatty acids would increase satiety and reduce energy intake compared with long-chain triacylglycerols with monounsaturated or saturated fatty acids. DESIGN We performed a double-blind, randomized, crossover study in which 15 healthy subjects [mean age: 24 y; mean body mass index (in kg/m(2)): 22] were intubated with a naso-ileal catheter and participated in 4 experiments performed in random order on 4 consecutive days. After consumption of a liquid meal, subjects received a fat or control infusion in the ileum. Fat emulsions consisted of 6 g of 18:0 (shea oil; mainly 18:0), 18:1 (canola oil; mainly 18:1), or 18:2 (safflower oil; mainly 18:2) oils. Food intake was measured during an ad libitum lunch. Satiety questionnaires (visual analog scale) and blood samples were collected at regular intervals. RESULTS Compared with the control, only 18:2 and 18:1 significantly increased fullness and reduced hunger. No effect on food intake was observed. 18:1 and 18:2 increased cholecystokinin secretion significantly compared with the control. Fatty acid saturation did not affect peptide YY secretion. CONCLUSIONS When infused into the ileum, triacylglycerols with unsaturated fatty acids increase satiety, whereas triacylglycerols with saturated fatty acids does not. This trial was registered with the Dutch Trial Register as: ISRCTN51742545.

In Vivo Diagnosis and Classification of Colorectal Neoplasia by Chromoendoscopy-Guided Confocal Laser Endomicroscopy

BACKGROUND & AIMS Colorectal cancer surveillance guidelines rely on clinicohistologic features of adenomas. Unfortunately, in common practice, recording of these features lacks precision and uniformity, which might hamper appropriate follow-up decisions. Confocal laser endomicroscopy (CLE) is a novel technology that allows real-time in vivo microscopy of the mucosa and provides accurate histopathology. The aims of this study were (1) to define and validate differential features of adenomatous and nonadenomatous colorectal polyps by chromoendoscopy-guided CLE (C-CLE) and (2) to assess predictive value of this technique for diagnosis of colorectal neoplasia. METHODS Patients at risk for colorectal cancer were prospectively investigated by using CLE. During extubation, fluorescein 10% was used in conjunction with acriflavine hydrochloride 0.05% to characterize global tissue architecture as well as cytonuclear features of colorectal epithelium. Ex vivo histology was used as gold standard. Reproducibility tests were performed. RESULTS In total, 116 colorectal polyps from 72 patients were examined. Ex vivo histology showed 68 adenomas, 6 invasive carcinomas, 30 hyperplastic polyps, and 12 inflammatory polyps. C-CLE of adenomas revealed lack of epithelial surface maturation, crypt budding, altered vascular pattern, and loss of cell polarity. In contrast, C-CLE of nonadenomatous polyps revealed epithelial surface maturation, and minor abnormalities of crypt architecture and of vascular pattern, and maintained cell polarity. Adenoma dysplasia score reliably discriminated high-grade dysplasia from low-grade dysplasia (accuracy, 96.7%). Interobserver agreement was high (K coefficients: pathologist, 0.92; endomicroscopist, 0.88). In vivo histology predicted ex vivo data with sensitivity of 97.3%, specificity of 92.8%, and accuracy of 95.7%. CONCLUSIONS C-CLE accurately discriminates adenomatous from nonadenomatous colorectal polyps and enables evaluation of degree of dysplasia during ongoing endoscopy. This technology might offer considerable potential to ultimately fine-tune surveillance programs, particularly in high-risk groups.

Satiety effects of cholecystokinin in humans

BACKGROUND/AIMS Cholecystokinin (CCK) inhibits gastric emptying and may exert satiety effects in several species, including humans. Because the effects of physiological doses of CCK on satiety in humans is unclear, the satiety effects of CCK-33 in physiological levels in lean and obese subjects were studied. METHODS CCK-33 was infused intravenously to 32 healthy men or women (14 obese, all women; 18 lean, 4 men and 14 women) in doses that elicited plasma CCK concentrations in the physiological range. The effects of these infusions on feelings of hunger, wish to eat, fullness, and prospective feeding intentions were measured on visual analogue scales and compared with saline during a 1-hour infusion period. RESULTS The CCK infusions induced significant decreases in hunger feelings, wish to eat, and prospective feeding intentions (P < 0.05), whereas fullness tended to be increased (P = 0.054). No clear differences between lean and obese subjects were observed apart from a more marked decrease in fullness and increase in prospective feeding intentions during the 1-hour saline infusion in the lean group (P < 0.05). CONCLUSIONS CCK infusion leading to physiological plasma levels significantly increases satiety in humans.

Proton pump inhibitor use is associated with an increased risk for microscopic colitis: a case–control study

Aliment Pharmacol Ther 2010; 32: 1124–1128

Prospective, randomized trial on the effect of cyclic versus continuous enteral nutrition on postoperative gastric function after pylorus-preserving pancreatoduodenectomy.

OBJECTIVE The effect of a cyclic versus a continuous enteral feeding protocol on postoperative delayed gastric emptying, start of normal diet, and hospital stay was assessed in patients undergoing pylorus-preserving pancreatoduodenectomy (PPPD). SUMMARY BACKGROUND DATA Delayed gastric emptying occurs in approximately 30% of patients after PPPD and causes prolonged hospital stay. Enteral nutrition through a catheter jejunostomy is used to provide postoperative nutritional support. Enteral infusion of fats and proteins activates neurohumoral feedback mechanisms and therefore can potentially impair gastric emptying and prolong postoperative gastroparesis. METHODS From September 1995 to December 1996, 72 consecutive patients underwent PPPD at the Academic Medical Center, Amsterdam. Fifty-seven patients were included and randomized for either continuous (CON) jejunal nutrition (0-24 hr; 1500 kCal/24 hr) or cyclic (CYC) enteral nutrition (6-24 hr; 1125 kCal/18 hr). Both groups had an equal caloric load of 1 kCal/min. The following parameters were assessed: days of nasogastric intubation, days of enteral nutrition, days until normal diet was tolerated orally, and hospital stay. On postoperative day 10, plasma cholecystokinin (CCK) levels were measured during both feeding protocols. RESULTS Nasogastric intubation was 9.1 days in the CON group (n = 30) and 6.7 days in the CYC group (n = 27) (not statistically significant). First day of normal diet was earlier for the CYC group (15.7 vs. 12.2 days, p < 0.05). Hospital stay was shorter in the CYC group (21.4 vs. 17.5 days, p < 0.05). CCK levels were lower in CYC patients, before and after feeding, compared with CON patients (p < 0.05). CONCLUSIONS Cyclic enteral feeding after PPPD is associated with a shorter period of enteral nutrition, a faster return to a normal diet, and a shorter hospital stay. Continuously high CCK levels could be a cause of prolonged time until normal diet is tolerated in patients on continuous enteral nutrition. Cyclic enteral nutrition is therefore the feeding regimen of choice in patients after PPPD.