Dyer, Roy

INTRODUCTION: Altered intestinal permeability (IP) is implicated in multiple gastrointestinal and systemic disease conditions; an experimental model of perturbed IP in healthy subjects is needed. Traditional approaches to perturbing IP include use of nonsteroidal anti-inflammatory drugs. METHODS: We conducted a single-center, randomized, placebo-controlled pilot study of dose-related effects of castor oil (CO) (and its ingredient ricinoleic acid) at 750, 1,500, or 3,000 mg daily doses on IP. Permeability was assessed using validated 13 C-mannitol and lactulose urine excretion at 0–2, 8–24, and 0–24 hours after oral administration. RESULTS: Permeability analysis across all groups demonstrated significant difference among the groups for 0–2 hours 13 C-mannitol, 0–24 hours 13 C-mannitol, and borderline significant difference for 2–8 hours 13 C-mannitol ( P = 0.060) and 0–24 hours lactulose ( P = 0.056). Direct comparison of 3,000 mg CO vs placebo ( t test) demonstrated higher excretion of 13 C-mannitol and lactulose at 0–2, and 0–24 hours, and lactulose at 2–8 hours. DISCUSSION: CO may perturb small intestinal and colonic permeability in healthy adults.

Increased gut permeability has been suggested in patients with celiac disease (CD). We aimed to compare gut permeability in children using the lactulose/rhamnose permeability test. We prospectively recruited 55 children into 3 groups; 27 in group 1 (children with newly diagnosed celiac disease, 12 in group 2 (siblings of children with celiac disease) and 16 in group 3 (control group). The median age of participants was 11 years 2 months in group 1, 9 years 5 months in group 2 and 10 years 3 months in group 3. Standardized median delta rhamnose was lower in CD group as compared to control group (147.5 vs 3153.1, P = 0.040). The low median rhamnose absorption in children with celiac disease as compared to other groups suggests that this test can differentiate between damaged and healthy mucosa, hence can it potentially can be used as a noninvasive test of mucosal healing in children with celiac disease.

Prior studies in with irritable bowel syndrome with diarrhea (IBS-D) patients showed immune activation, secretion, and barrier dysfunction in jejunal or colorectal mucosa. We measured mRNA expression by RT-PCR of 91 genes reflecting tight junction proteins, chemokines, innate immunity, ion channels, transmitters, housekeeping genes, and controls for DNA contamination and PCR efficiency in small intestinal mucosa from 15 IBS-D and 7 controls (biopsies negative for celiac disease). Fold change was calculated using 2(−ΔΔCT) formula. Nominal P values ( P < 0.05) were interpreted with false detection rate (FDR) correction ( q value). Cluster analysis with Lens for Enrichment and Network Studies (LENS) explored connectivity of mechanisms. Upregulated genes (uncorrected P < 0.05) were related to ion transport (INADL, MAGI1, and SONS1), barrier (TJP1, 2, and 3 and CLDN) or immune functions (TLR3, IL15, and MAPKAPK5), or histamine metabolism (HNMT); downregulated genes were related to immune function (IL-1β, TGF-β1, and CCL20) or antigen detection (TLR1 and 8). The following genes were significantly upregulated ( q < 0.05) in IBS-D: INADL, MAGI1, PPP2R5C, MAPKAPK5, TLR3, and IL-15. Among the 14 nominally upregulated genes, there was clustering of barrier and PDZ domains (TJP1, TJP2, TJP3, CLDN4, INADL, and MAGI1) and clustering of downregulated genes (CCL20, TLR1, IL1B, and TLR8). Protein expression of PPP2R5C in nuclear lysates was greater in patients with IBS-D and controls. There was increase in INADL protein (median 9.4 ng/ml) in patients with IBS-D relative to controls (median 5.8 ng/ml, P > 0.05). In conclusion, altered transcriptome (and to lesser extent protein) expression of ion transport, barrier, immune, and mast cell mechanisms in small bowel may reflect different alterations in function and deserves further study in IBS-D.

Background: Recent advances in accuracy and reliability of continuous glucose monitoring (CGM) devices have focused renewed interest on the use of such technology for therapeutic dosing of insulin without the need for independent confirmatory blood glucose meter measurements. An important issue that remains is the susceptibility of CGM devices to erroneous readings in the presence of common pharmacologic interferences. We report on a new method of assessing CGM sensor error to pharmacologic interferences using the example of oral administration of acetaminophen. Materials and Methods: We examined the responses of several different Food and Drug Administration–approved and commercially available CGM systems (Dexcom [San Diego, CA] Seven ® Plus™, Medtronic Diabetes [Northridge, CA] Guardian ® , and Dexcom G4 ® Platinum) to oral acetaminophen in 10 healthy volunteers without diabetes. Microdialysis catheters were placed in the abdominal subcutaneous tissue. Blood and microdialysate samples were collected periodically and analyzed for glucose and acetaminophen concentrations before and after oral ingestion of 1 g of acetaminophen. We compared the response of CGM sensors with the measured acetaminophen concentrations in the blood and interstitial fluid. Results: Although plasma glucose concentrations remained constant at approximately 90 mg/dL (approximately 5 m M ) throughout the study, CGM glucose measurements varied between approximately 85 to 400 mg/dL (from approximately 5 to 22 m M ) due to interference from the acetaminophen. The temporal profile of CGM interference followed acetaminophen concentrations measured in interstitial fluid (ISF). Conclusions: This is the first direct measurement of ISF concentrations of putative CGM interferences with simultaneous measurements of CGM performance in the presence of the interferences. The observed interference with glucose measurements in the tested CGM devices coincided temporally with appearance of acetaminophen in the ISF. The method applied here can be used to determine the susceptibility of current and future CGM systems to interference from acetaminophen or other exogenous pharmacologic agents.