Bacterial infections in cirrhosis: role of proton pump inhibitors and intestinal permeability.

BACKGROUND: Cirrhotic patients are at considerable risk for bacterial infections, possibly through increased intestinal permeability and bacterial overgrowth. Proton pump inhibitors (PPIs) may increase infection risk. We aimed to explore the potential association between PPI use and bacterial infection risk in cirrhotic patients and potential underlying mechanisms in complementary patient and animal models. MATERIALS AND METHODS: Bacterial overgrowth was determined in jejunum of 30 rats randomly allocated to 6-week PPI treatment, gastrectomy or no treatment. In 84 consecutive cirrhotic patients, bacterial infection risk was prospectively assessed and related to PPI use. Intestinal permeability was determined by polyethylene glycol (PEG) test in nine healthy individuals and 12 cirrhotic patients. RESULTS: Bacterial overgrowth was much more common in jejunum of rats treated with PPI or gastrectomy compared with nontreated rats. Twenty-four patients (29%) developed a bacterial infection during a median follow-up of 28 months. Although PPI users tended to experience infection more often than patients without PPI therapy, PPI use was not an independent predictor of bacterial infection (HR 1·2, 95% CI 0·5-3·0, P = 0·72), after correction for Child-Pugh class (HR 3·6, 95% CI 1·5-8·7, P = 0·004) and age (HR 1·05, 95%CI 1·01-1·09, P = 0·02). In cirrhotic patients, 24-h urinary recovery of PEGs 1500 and 3350 was significantly higher compared with healthy controls. CONCLUSIONS: Although in our animal model PPIs induced intestinal overgrowth, stage of liver disease rather than PPI use was the predominant factor determining infection risk in cirrhotic patients. Increased intestinal permeability may be a factor contributing to infection risk.

Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is characterised by chronic intestinal inflammation, resulting from dysregulation of the mucosal immune system and compromised intestinal epithelial barrier function. The bile salt, nuclear farnesoid X receptor (FXR), was recently implicated in intestinal antibacterial defence and barrier function. The aim of this study was to investigate the therapeutic potential of FXR agonists in the treatment of intestinal inflammation in complementary in vivo and in vitro models. METHODS: Colitis was induced in wild-type (WT) and Fxr-null mice using dextran sodium sulfate, and in WT mice using trinitrobenzenesulfonic acid. Mice were treated with vehicle or the FXR agonist INT-747, and colitis symptoms were assessed daily. Epithelial permeability assays and cytokine expression analysis were conducted in mouse colon and enterocyte-like cells (Caco-2/HT29) treated with medium or INT-747. Inflammatory cytokine secretion was determined by ELISA in various human immune cell types. RESULTS: INT-747-treated WT mice are protected from DSS- and TNBS-induced colitis, as shown by significant reduction of body weight loss, epithelial permeability, rectal bleeding, colonic shortening, ulceration, inflammatory cell infiltration and goblet cell loss. Furthermore, Fxr activation in intestines of WT mice and differentiated enterocyte-like cells downregulates expression of key proinflammatory cytokines and preserves epithelial barrier function. INT-747 significantly decreases tumour necrosis factor α secretion in activated human peripheral blood mononuclear cells, purified CD14 monocytes and dendritic cells, as well as in lamina propria mononuclear cells from patients with IBD. CONCLUSIONS: FXR activation prevents chemically induced intestinal inflammation, with improvement of colitis symptoms, inhibition of epithelial permeability, and reduced goblet cell loss. Furthermore, FXR activation inhibits proinflammatory cytokine production in vivo in the mouse colonic mucosa, and ex vivo in different immune cell populations. The findings provide a rationale to explore FXR agonists as a novel therapeutic strategy for IBD.

Influence of prophylactic probiotics and selective decontamination on bacterial translocation in patients undergoing pancreatic surgery: a randomized controlled trial.

Bacterial translocation (BT) is suspected to play a major role in the development of infections in surgical patients. However, the clinical association between intestinal barrier dysfunction, BT, and septic morbidity has remained unconfirmed. The objective of this study was to study BT in patients undergoing major abdominal surgery and the effects of probiotics, selective decontamination of the digestive tract (SDD), and standard treatment on intestinal barrier function. In a randomized controlled setting, 30 consecutive patients planned for elective pylorus-preserving pancreaticoduodenectomy (PPPD) were allocated to receive perioperatively probiotics, SDD, or standard treatment. To assess intestinal barrier function, intestinal fatty acid-binding protein (mucosal damage) and polyethylene glycol recovery (intestinal permeability) in urine were measured perioperatively. BT was assessed by real-time polymerase chain reaction and multiplex ligation-dependent probe amplification (MLPA) in mesenteric lymph nodes (MLNs) harvested early (baseline control) and at the end of surgery ("end-of-surgery" MLNs, after 3h in PPPD patients). Polymerase chain reaction detected bacterial DNA in 18 of 27 end-of-surgery MLNs and in 13 of 23 control MLNs (P = 0.378). Probiotics and SDD had no significant effect on the number of positive MLNs or the change in bacterial DNA during operation. Multiplex ligation-dependent probe amplification analysis showed significantly increased expression of only 4 of 30 inflammatory mediator-related genes in end-of-surgery compared with early sampled MLN (P < 0.05). Polyethylene glycol recovery was unaffected by operation, probiotics and SDD as compared with standard treatment. Intestinal fatty acid-binding protein levels were increased shortly postoperatively only in patients treated with SDD (P = 0.02). Probiotics and SDD did not influence BT, intestinal permeability, or inflammatory mediator expression. Bacterial translocation after abdominal surgery may be part of normal antigen-sampling processes of the gut.

Intestinal permeability in irritable bowel syndrome patients: effects of NSAIDs.

Intestinal permeability and the effect of NSAIDs on permeability were investigated in 14 irritable bowel syndrome (IBS) patients and 15 healthy subjects. In the study, 24-h urinary recoveries of orally administered polyethylene glycols (PEGs 400, 1500, and 4000) were not significantly different in healthy subjects and IBS patients before or after NSAID ingestion. Lactulose mannitol ratios in healthy subjects and IBS patients were not significantly different. Only time-dependent monitoring of PEG excretion showed that NSAIDs enhanced intestinal permeability for PEG 4000 in healthy subjects (P = 0.050) and for PEGs 400, 1500, and 4000 in IBS patients (P = 0.012, P = 0.041, and P = 0.012, respectively). These results show that intestinal permeability in IBS patients is not different from that in healthy subjects; NSAIDs compromise intestinal permeability in IBS patients to a greater extent than in healthy subjects, which suggests that IBS is associated with an altered response of the intestinal barrier to noxious agents.

Clinical and basal aspects of anemia during antiviral therapy for hepatitis C.

BACKGROUND AND RATIONALE: Anemia is a major side effect of combination therapy for chronic hepatitis C. In this study, severity, potential risk factors for and potential underlying mechanisms of anemia were evaluated. PATIENTS AND METHODS: 44 chronic hepatitis C patients on interferon-ribavirin treatment were included. Anemia-related parameters were measured before and during treatment. Potential changes in membrane phospholipids composition of erythrocytes of patients on anti-viral treatment and potentially increased erythrocyte susceptibility to osmotic or bile salt induced stress were explored. RESULTS: Anemia was almost universal during treatment, with evidence of hemolysis. Decrease of Hb after six months of therapy was 2.1 +/- 0.1 mmol/L (range -0.6-4.1). Higher pre-treatment Hb, highest ribavirin dose (15-17.5 mg/kg) and lower pre-treatment platelet level were independent risk factors for decrease of Hb. Serum erythropoietin levels increased during treatment with negative correlation to Hb levels at week 12 (r = -0.70, p = 0.002) and 24 (r = -0.72, p = 0.002). Erythrocyte membrane phospholipid composition did not differ between anemic patients and healthy controls. Also, resistance to osmotic or bile salt induced stress was normal in anemic patients. Phosphatidylserine exposure at the outer membrane leaflet did not change upon 24 hrs ex vivo incubation with pharmacological ribavirin concentration. CONCLUSIONS: Anemia is almost universal during anti-HCV treatment. The extent of anemia correlates with pre-treatment levels of thrombocytes and Hb and with high ribavirin dosing. Although we found hemolysis as contributing factor, our data do not indicate that altered membrane phospholipids composition is an important factor in pathogenesis of anemia.

Intestinal barrier dysfunction in a randomized trial of a specific probiotic composition in acute pancreatitis.

OBJECTIVES: To determine the relation between intestinal barrier dysfunction, bacterial translocation, and clinical outcome in patients with predicted severe acute pancreatitis and the influence of probiotics on these processes. SUMMARY OF BACKGROUND DATA: Randomized, placebo-controlled, multicenter trial on probiotic prophylaxis (Ecologic 641) in patients with predicted severe acute pancreatitis (PROPATRIA). METHODS: Excretion of intestinal fatty acid binding protein (IFABP, a parameter for enterocyte damage), recovery of polyethylene glycols (PEGs, a parameter for intestinal permeability), and excretion of nitric oxide (NOx, a parameter for bacterial translocation) were assessed in urine of 141 patients collected 24 to 48 h after start of probiotic or placebo treatment and 7 days thereafter. RESULTS: IFABP concentrations in the first 72 hours were higher in patients who developed bacteremia (P = 0.03), infected necrosis (P = 0.01), and organ failure (P = 0.008). PEG recovery was higher in patients who developed bacteremia (PEG 4000, P = 0.001), organ failure (PEG 4000, P < 0.0001), or died (PEG 4000, P = 0.009). Probiotic prophylaxis was associated with an increase in IFABP (median 362 vs. 199 pg/mL; P = 0.02), most evidently in patients with organ failure (P = 0.001), and did not influence intestinal permeability. Overall, probiotics decreased NOx (P = 0.05) but, in patients with organ failure, increased NOx (P = 0.001). CONCLUSIONS: Bacteremia, infected necrosis, organ failure, and mortality were all associated with intestinal barrier dysfunction early in the course of acute pancreatitis. Overall, prophylaxis with this specific combination of probiotic strains reduced bacterial translocation, but was associated with increased bacterial translocation and enterocyte damage in patients with organ failure.

Systemic inflammation increases intestinal permeability during experimental human endotoxemia.

Although the gut is often considered the motor of sepsis, the relation between systemic inflammation and intestinal permeability in humans is not clear. We analyzed intestinal permeability during experimental endotoxemia in humans. Before and during experimental endotoxemia (Escherichia coli LPS, 2 ng/kg), using polyethylene glycol (PEG) as a permeability marker, intestinal permeability was analyzed in 14 healthy subjects. Enterocyte damage was determined by intestinal fatty acid binding protein. Endotoxemia induced an inflammatory response. Urinary PEGs 1,500 and 4,000 recovery increased from 38.8 +/- 6.3 to 63.1 +/- 12.5 and from 0.58 +/- 0.31 to 3.11 +/- 0.93 mg, respectively (P < 0.05). Intestinal fatty acid binding protein excretion was not affected by endotoxemia. The peak serum IL-10 concentrations correlated with the increase in PEG 1,500 recovery (r = 0.48, P = 0.027). Systemic inflammation results in an increased intestinal permeability. The increase in intestinal permeability is most likely caused by inflammation-induced paracellular permeability, rather than ischemia-mediated enterocyte damage.

Concurrent duodenal manometric and impedance recording to evaluate the effects of hyoscine on motility and flow events, glucose absorption, and incretin release.

Upper gastrointestinal motor function and incretin hormone secretion are major determinants of postprandial glycemia and insulinemia. However, the impact of small intestinal flow events on glucose absorption and incretin release is poorly defined. Intraluminal impedance monitoring is a novel technique that allows flow events to be quantified. Eight healthy volunteers were studied twice, in random order. A catheter incorporating six pairs of electrodes at 3-cm intervals, and six corresponding manometry sideholes, was positioned in the duodenum. Hyoscine butylbromide (20 mg) or saline was given as an intravenous bolus, followed by a continuous intravenous infusion of either hyoscine (20 mg/h) or saline over 60 min. Concurrently, glucose and 3-O-methylglucose (3-OMG) were infused into the proximal duodenum (3 kcal/min), with frequent blood sampling to measure glucose, 3-OMG, insulin, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The frequency of duodenal pressure waves and propagated pressure wave sequences was reduced by hyoscine in the first 10 min (P<0.01 for both), but not after that time. In contrast, there were markedly fewer duodenal flow events throughout 60 min with hyoscine (P<0.005). Overall, blood glucose (P<0.01) and plasma 3-OMG concentrations (P<0.05) were lower during hyoscine than saline, whereas plasma insulin, GLP-1, and GIP concentrations were initially (t=20 min) lower during hyoscine (P<0.05). In conclusion, intraluminal impedance measurement may be more sensitive than manometry in demonstrating alterations in duodenal motor function. A reduction in the frequency of duodenal flow events is associated with a decreased rate of glucose absorption and incretin release in healthy subjects.

Small gallstones, preserved gallbladder motility, and fast crystallization are associated with pancreatitis.

Acute pancreatitis is a severe complication of gallstones with considerable mortality. We sought to explore the potential risk factors for biliary pancreatitis. We compared postprandial gallbladder motility (via ultrasonography) and, after subsequent cholecystectomy, numbers, sizes, and types of gallstones; gallbladder bile composition; and cholesterol crystallization in 21 gallstone patients with previous pancreatitis and 30 patients with uncomplicated symptomatic gallstones. Gallbladder motility was stronger in pancreatitis patients than in patients with uncomplicated symptomatic gallstones (minimum postprandial gallbladder volumes: 5.8 +/- 1.0 vs. 8.1 +/- 0.7 mL; P = .005). Pancreatitis patients had more often sludge (41% vs. 13%; P = .03) and smaller and more gallstones than patients with symptomatic gallstones (smallest stone diameters: 2 +/- 1 vs. 8 +/- 2 mm; P = .001). Also, crystallization occurred much faster in the bile of pancreatitis patients (1.0 +/- 0.0 vs. 2.5 +/- 0.4 days; P < .001), possibly because of higher mucin concentrations (3.3 +/- 1.9 vs. 0.8 +/- 0.2 mg/mL; P = .04). No significant differences were found in types of gallstones, relative biliary lipid contents, cholesterol saturation indexes, bile salt species composition, phospholipid classes, total protein or immunoglobulin (G, M, and A), haptoglobin, and alpha-1 acid glycoprotein concentrations. In conclusion, patients with small gallbladder stones and/or preserved gallbladder motility are at increased risk of pancreatitis. The potential benefit of prophylactic cholecystectomy in this patient category has yet to be explored.

Effects of hydrophobic and hydrophilic bile salts on gallstone growth and dissolution in model biles.

UNLABELLED: Cholesterol crystallization is a prerequisite for gallstone formation and growth, whereas dissolution of crystallized cholesterol forms the basis of nonsurgical therapy. Crystallization has been studied in detail, but dissolution mechanisms and effects of gallstones are largely unknown. METHODS: We evaluated gallstone growth or dissolution, cholesterol crystallization and lipid distribution into various phases, in model biles with low or intermediate phospholipid contents (crystal-containing left two-phase or central three-phase zones), and with high phospholipid or low cholesterol contents (crystal-free right two-phase or bottom one-phase zones). RESULTS: In model biles with added gallstones plotting in left two-phase and central three-phase zones, gallstone masses increased, whereas crystallization in the aqueous phase was less than without gallstones (P<0.001). In biles plotting in the right two-phase zone, gallstone masses decreased, depending on bile salt hydrophobicity (TUDC>TC>TCDC: P<0.001). In biles plotting in the bottom one-phase zone containing TC or TCDC, gallstone masses increased. In contrast, gallstone masses decreased in case of TUDC with preferential distribution of cholesterol into emerging vesicles. CONCLUSIONS: Our findings suggest competition between gallstone surface and surrounding aqueous phase for precipitation of cholesterol in crystal-containing zones. Different gallstone dissolution mechanisms may exist for TUDC and TCDC.

Upper gastrointestinal responses to intraduodenal nutrient in type 1 diabetes mellitus.

BACKGROUND: Abnormal nutrient-related small-intestinal feedback may contribute to disordered gastric motility and upper gastrointestinal symptoms in patients with diabetes. AIM: To evaluate the motor, sensory and incretin responses to intraduodenal nutrients in patients with type 1 diabetes and in controls. METHODS: Eight type 1 diabetes patients (two with autonomic neuropathy) and nine controls were studied during euglycaemia. A manometric catheter was positioned across the pylorus, and nutrient was infused intraduodenally (90 kcal over 30 min). Blood glucose and plasma glucagon-like peptide 1 and gastric inhibitory polypeptide were measured, and sensations were assessed with visual analogue questionnaires. RESULTS: During nutrient infusion, neither the number of antral waves nor the stimulation of phasic or basal pyloric pressures differed between patients and controls. Upper gut sensations and areas under the plasma incretin peptide curves did not differ between the groups. CONCLUSIONS: During euglycaemia, the upper gastrointestinal motor, sensory and incretin peptide responses to small-intestinal nutrient are comparable in patients with relatively uncomplicated type 1 diabetes and in healthy subjects.

Small bowel motility affects glucose absorption in a healthy man.

OBJECTIVE: To investigate the relationship between duodenojejunal motor activity and glucose absorption and to evaluate the effect of modification of duodenojejunal motility on glucose absorption by using the prokinetic drug cisapride. RESEARCH DESIGN AND METHODS: We examined seven healthy males, mean age 22 years, who were treated with cisapride 10 mg t.i.d. and placebo during 3 days in a randomized order, with a 2-week time interval. Duodenojejunal manometry was performed after each treatment on the morning of day 3, using an 18-lumen catheter. A liquid nutrient (3 kcal/min) was administered intraduodenally for 30 min, followed by a bolus of the glucose analog 3-O-methylglucose (3-OMG). Plasma 3-OMG concentrations were measured to assess absorption kinetics. RESULTS: The area under the 3-OMG concentration curve in the first 30 min after infusion was related to the number of antegrade propagated pressure waves (r = 0.49, P < 0.05), but not to the peak concentration, time to peak, and absorption fraction. The mean amplitude of pressure waves was higher during cisapride than placebo (P < 0.05), but the reoccurrence of interdigestive motility, numbers of pressure waves, and propagated pressure waves, as well as 3-OMG absorption characteristics, were not significantly different between the two treatments. During both treatments >60% of antegrade propagated pressure waves were propagated over a very short distance (1.5 cm). CONCLUSIONS: Glucose absorption in the human small intestine is related to short-traveling propagated intestinal contractile activity. Cisapride increases the amplitude of pressure waves, but does not affect the organization of pressure waves or the absorption of 3-OMG.