NIHR Nottingham Digestive Diseases Biomedical Research Unit

Applications of nanotechnology for treatment, diagnosis, monitoring, and control of biological systems has recently been referred to as "nanomedicine" by the National Institutes of Health. Research into the rational delivery and targeting of pharmaceutical, therapeutic, and diagnostic agents is at the forefront of projects in nanomedicine. These involve the identification of precise targets (cells and receptors) related to specific clinical conditions and choice of the appropriate nanocarriers to achieve the required responses while minimizing the side effects. Mononuclear phagocytes, dendritic cells, endothelial cells, and cancers (tumor cells, as well as tumor neovasculature) are key targets. Today, nanotechnology and nanoscience approaches to particle design and formulation are beginning to expand the market for many drugs and are forming the basis for a highly profitable niche within the industry, but some predicted benefits are hyped. This article will highlight rational approaches in design and surface engineering of nanoscale vehicles and entities for site-specific drug delivery and medical imaging after parenteral administration. Potential pitfalls or side effects associated with nanoparticles are also discussed.

Abstract Background This review aims to present a consensus for optimal perioperative care in colonic surgery and to provide graded recommendations for items for an evidenced‐based enhanced perioperative protocol. Methods Studies were selected with particular attention paid to meta‐analyses, randomised controlled trials and large prospective cohorts. For each item of the perioperative treatment pathway, available English‐language literature was examined, reviewed and graded. A consensus recommendation was reached after critical appraisal of the literature by the group. Results For most of the protocol items, recommendations are based on good‐quality trials or meta‐analyses of good‐quality trials (quality of evidence and recommendations according to the GRADE system). Conclusions Based on the evidence available for each item of the multimodal perioperative care pathway, the Enhanced Recovery After Surgery (ERAS) Society, International Association for Surgical Metabolism and Nutrition (IASMEN) and European Society for Clinical Nutrition and Metabolism (ESPEN) present a comprehensive evidence‐based consensus review of perioperative care for colonic surgery.

BACKGROUND: Iron deficiency anaemia (IDA) occurs in 2-5% of adult men and postmenopausal women in the developed world and is a common cause of referral to gastroenterologists. Gastrointestinal (GI) blood loss from colonic cancer or gastric cancer, and malabsorption in coeliac disease are the most important causes that need to be sought. DEFINING IRON DEFICIENCY ANAEMIA: The lower limit of the normal range for the laboratory performing the test should be used to define anaemia (B). Any level of anaemia should be investigated in the presence of iron deficiency (B). The lower the haemoglobin the more likely there is to be serious underlying pathology and the more urgent is the need for investigation (B). Red cell indices provide a sensitive indication of iron deficiency in the absence of chronic disease or haemoglobinopathy (A). Haemoglobin electrophoresis is recommended when microcytosis and hypochromia are present in patients of appropriate ethnic background to prevent unnecessary GI investigation (C). Serum ferritin is the most powerful test for iron deficiency (A). INVESTIGATIONS: Upper and lower GI investigations should be considered in all postmenopausal female and all male patients where IDA has been confirmed unless there is a history of significant overt non-GI blood loss (A). All patients should be screened for coeliac disease (B). If oesophagogastroduodenoscopy (OGD) is performed as the initial GI investigation, only the presence of advanced gastric cancer or coeliac disease should deter lower GI investigation (B). In patients aged >50 or with marked anaemia or a significant family history of colorectal carcinoma, lower GI investigation should still be considered even if coeliac disease is found (B). Colonoscopy has advantages over CT colography for investigation of the lower GI tract in IDA, but either is acceptable (B). Either is preferable to barium enema, which is useful if they are not available. Further direct visualisation of the small bowel is not necessary unless there are symptoms suggestive of small bowel disease, or if the haemoglobin cannot be restored or maintained with iron therapy (B). In patients with recurrent IDA and normal OGD and colonoscopy results, Helicobacter pylori should be eradicated if present. (C). Faecal occult blood testing is of no benefit in the investigation of IDA (B). All premenopausal women with IDA should be screened for coeliac disease, but other upper and lower GI investigation should be reserved for those aged 50 years or older, those with symptoms suggesting gastrointestinal disease, and those with a strong family history of colorectal cancer (B). Upper and lower GI investigation of IDA in post-gastrectomy patients is recommended in those over 50 years of age (B). In patients with iron deficiency without anaemia, endoscopic investigation rarely detects malignancy. Such investigation should be considered in patients aged >50 after discussing the risk and potential benefit with them (C). Only postmenopausal women and men aged >50 years should have GI investigation of iron deficiency without anaemia (C). Rectal examination is seldom contributory, and, in the absence of symptoms such as rectal bleeding and tenesmus, may be postponed until colonoscopy. Urine testing for blood is important in the examination of patients with IDA (B). MANAGEMENT: All patients should have iron supplementation both to correct anaemia and replenish body stores (B). Parenteral iron can be used when oral preparations are not tolerated (C). Blood transfusions should be reserved for patients with or at risk of cardiovascular instability due to the degree of their anaemia (C).

It is increasingly perceived that gut host-microbial interactions are important elements in the pathogenesis of functional gastrointestinal disorders (FGID). The most convincing evidence to date is the finding that functional dyspepsia and irritable bowel syndrome (IBS) may develop in predisposed individuals following a bout of infectious gastroenteritis. There has been a great deal of interest in the potential clinical and therapeutic implications of small intestinal bacterial overgrowth in IBS. However, this theory has generated much debate because the evidence is largely based on breath tests which have not been validated. The introduction of culture-independent molecular techniques provides a major advancement in our understanding of the microbial community in FGID. Results from 16S rRNA-based microbiota profiling approaches demonstrate both quantitative and qualitative changes of mucosal and faecal gut microbiota, particularly in IBS. Investigators are also starting to measure host-microbial interactions in IBS. The current working hypothesis is that abnormal microbiota activate mucosal innate immune responses which increase epithelial permeability, activate nociceptive sensory pathways and dysregulate the enteric nervous system. While we await important insights in this field, the microbiota is already a therapeutic target. Existing controlled trials of dietary manipulation, prebiotics, probiotics, synbiotics and non-absorbable antibiotics are promising, although most are limited by suboptimal design and small sample size. In this article, the authors provide a critical review of current hypotheses regarding the pathogenetic involvement of microbiota in FGID and evaluate the results of microbiota-directed interventions. The authors also provide clinical guidance on modulation of gut microbiota in IBS.

Defects in intestinal barrier function are associated with diseases of the gastrointestinal (GI) tract. There is growing evidence that increases in intestinal permeability plays a pathogenic role in diseases, such as inflammatory bowel disease (IBD) and celiac disease, and functional bowel disorders, such as irritable bowel syndrome (IBS). This review takes a unique translational approach to discuss the physiological and pathophysiological mechanisms involved in the regulation of intestinal barrier function in IBS. The review summarizes the components of the intestinal barrier including the tight junction complex within the epithelium, and the methods used to assess gut permeability both in vitro and in vivo. Throughout the review, the authors have attempted to critically review the latest research from both experimental animal models and human studies to appraise whether intestinal barrier dysfunction is a primary cause of functional GI disorders, such as IBS.…

Despite current recommendations on the management of pre-operative anaemia, there is no pragmatic guidance for the diagnosis and management of anaemia and iron deficiency in surgical patients. A number of experienced researchers and clinicians took part in an expert workshop and developed the following consensus statement. After presentation of our own research data and local policies and procedures, appropriate relevant literature was reviewed and discussed. We developed a series of best-practice and evidence-based statements to advise on patient care with respect to anaemia and iron deficiency in the peri-operative period. These statements include: a diagnostic approach for anaemia and iron deficiency in surgical patients; identification of patients appropriate for treatment; and advice on practical management and follow-up. We urge anaesthetists and peri-operative physicians to embrace these recommendations, and hospital administrators to enable implementation of these concepts by allocating adequate resources.

BACKGROUND: IBS affects 5-11% of the population of most countries. Prevalence peaks in the third and fourth decades, with a female predominance. AIM: To provide a guide for the assessment and management of adult patients with irritable bowel syndrome. METHODS: Members of the Clinical Services Committee of The British Society of Gastroenterology were allocated particular areas to produce review documents. Literature searching included systematic searches using electronic databases such as Pubmed, EMBASE, MEDLINE, Web of Science, and Cochrane databases and extensive personal reference databases. RESULTS: Patients can usefully be classified by predominant bowel habit. Few investigations are needed except when diarrhoea is a prominent feature. Alarm features may warrant further investigation. Adverse psychological features and somatisation are often present. Ascertaining the patients' concerns and explaining symptoms in simple terms improves outcome. IBS is a heterogeneous condition with a range of treatments, each of which benefits a small proportion of patients. Treatment of associated anxiety and depression often improves bowel and other symptoms. Randomised placebo controlled trials show benefit as follows: cognitive behavioural therapy and psychodynamic interpersonal therapy improve coping; hypnotherapy benefits global symptoms in otherwise refractory patients; antispasmodics and tricyclic antidepressants improve pain; ispaghula improves pain and bowel habit; 5-HT(3) antagonists improve global symptoms, diarrhoea, and pain but may rarely cause unexplained colitis; 5-HT(4) agonists improve global symptoms, constipation, and bloating; selective serotonin reuptake inhibitors improve global symptoms. CONCLUSIONS: Better ways of identifying which patients will respond to specific treatments are urgently needed.

BACKGROUND: The Chicago Classification of esophageal motility was developed to facilitate the interpretation of clinical high resolution esophageal pressure topography (EPT) studies, concurrent with the widespread adoption of this technology into clinical practice. The Chicago Classification has been an evolutionary process, molded first by published evidence pertinent to the clinical interpretation of high resolution manometry (HRM) studies and secondarily by group experience when suitable evidence is lacking. PURPOSE: This publication summarizes the state of our knowledge as of the most recent meeting of the International High Resolution Manometry Working Group in Ascona, Switzerland in April 2011. The prior iteration of the Chicago Classification was updated through a process of literature analysis and discussion. The major changes in this document from the prior iteration are largely attributable to research studies published since the prior iteration, in many cases research conducted in response to prior deliberations of the International High Resolution Manometry Working Group. The classification now includes criteria for subtyping achalasia, EGJ outflow obstruction, motility disorders not observed in normal subjects (Distal esophageal spasm, Hypercontractile esophagus, and Absent peristalsis), and statistically defined peristaltic abnormalities (Weak peristalsis, Frequent failed peristalsis, Rapid contractions with normal latency, and Hypertensive peristalsis). The Chicago Classification is an algorithmic scheme for diagnosis of esophageal motility disorders from clinical EPT studies. Moving forward, we anticipate continuing this process with increased emphasis placed on natural history studies and outcome data based on the classification.

OBJECTIVE: We compared the effects of intravenous infusions of 0.9% saline ([Cl] 154 mmol/L) and Plasma-Lyte 148 ([Cl] 98 mmol/L, Baxter Healthcare) on renal blood flow velocity and perfusion in humans using magnetic resonance imaging (MRI). BACKGROUND: Animal experiments suggest that hyperchloremia resulting from 0.9% saline infusion may affect renal hemodynamics adversely, a phenomenon not studied in humans. METHODS: Twelve healthy adult male subjects received 2-L intravenous infusions over 1 hour of 0.9% saline or Plasma-Lyte 148 in a randomized, double-blind manner. Crossover studies were performed 7 to 10 days apart. MRI scanning proceeded for 90 minutes after commencement of infusion to measure renal artery blood flow velocity and renal cortical perfusion. Blood was sampled and weight recorded hourly for 4 hours. RESULTS: Sustained hyperchloremia was seen with saline but not with Plasma-Lyte 148 (P < 0.0001), and fall in strong ion difference was greater with the former (P = 0.025). Blood volume changes were identical (P = 0.867), but there was greater expansion of the extravascular fluid volume after saline (P = 0.029). There was a significant reduction in mean renal artery flow velocity (P = 0.045) and renal cortical tissue perfusion (P = 0.008) from baseline after saline, but not after Plasma-Lyte 148. There was no difference in concentrations of urinary neutrophil gelatinase-associated lipocalin after the 2 infusions (P = 0.917). CONCLUSIONS: This is the first human study to demonstrate that intravenous infusion of 0.9% saline results in reductions in renal blood flow velocity and renal cortical tissue perfusion. This has implications for intravenous fluid therapy in perioperative and critically ill patients. NCT01087853.

The British Society of Gastroenterology in collaboration with British Association for the Study of the Liver has prepared this document. The aim of this guideline is to review and summarise the evidence that guides clinical diagnosis and management of ascites in patients with cirrhosis. Substantial advances have been made in this area since the publication of the last guideline in 2007. These guidelines are based on a comprehensive literature search and comprise systematic reviews in the key areas, including the diagnostic tests, diuretic use, therapeutic paracentesis, use of albumin, transjugular intrahepatic portosystemic stent shunt, spontaneous bacterial peritonitis and beta-blockers in patients with ascites. Where recent systematic reviews and meta-analysis are available, these have been updated with additional studies. In addition, the results of prospective and retrospective studies, evidence obtained from expert committee reports and, in some instances, reports from case series have been included. Where possible, judgement has been made on the quality of information used to generate the guidelines and the specific recommendations have been made according to the 'Grading of Recommendations Assessment, Development and Evaluation (GRADE)' system. These guidelines are intended to inform practising clinicians, and it is expected that these guidelines will be revised in 3 years' time.

infection, family history of gastric cancer-in particular, hereditary diffuse gastric cancer and pernicious anaemia. The stages in the progression to cancer include chronic gastritis, gastric atrophy (GA), gastric intestinal metaplasia (GIM) and dysplasia. The key to early detection of cancer and improved survival is to non-invasively identify those at risk before endoscopy. However, although biomarkers may help in the detection of patients with chronic atrophic gastritis, there is insufficient evidence to support their use for population screening. High-quality endoscopy with full mucosal visualisation is an important part of improving early detection. Image-enhanced endoscopy combined with biopsy sampling for histopathology is the best approach to detect and accurately risk-stratify GA and GIM. Biopsies following the Sydney protocol from the antrum, incisura, lesser and greater curvature allow both diagnostic confirmation and risk stratification for progression to cancer. Ideally biopsies should be directed to areas of GA or GIM visualised by high-quality endoscopy. There is insufficient evidence to support screening in a low-risk population (undergoing routine diagnostic oesophagogastroduodenoscopy) such as the UK, but endoscopic surveillance every 3 years should be offered to patients with extensive GA or GIM. Endoscopic mucosal resection or endoscopic submucosal dissection of visible gastric dysplasia and early cancer has been shown to be efficacious with a high success rate and low rate of recurrence, providing that specific quality criteria are met.

Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition, strongly associated with the metabolic syndrome, that can lead to progressive hepatic fibrosis, cirrhosis and hepatic failure. Subtle inter-patient genetic variation and environmental factors combine to determine variation in disease progression. A common non-synonymous polymorphism in TM6SF2 (rs58542926 c.449 C>T, p.Glu167Lys) was recently associated with increased hepatic triglyceride content, but whether this variant promotes clinically relevant hepatic fibrosis is unknown. Here we confirm that TM6SF2 minor allele carriage is associated with NAFLD and is causally related to a previously reported chromosome 19 GWAS signal that was ascribed to the gene NCAN. Furthermore, using two histologically characterized cohorts encompassing steatosis, steatohepatitis, fibrosis and cirrhosis (combined n=1,074), we demonstrate a new association, independent of potential confounding factors (age, BMI, type 2 diabetes mellitus and PNPLA3 rs738409 genotype), with advanced hepatic fibrosis/cirrhosis. These findings establish new and important clinical relevance to TM6SF2 in NAFLD.

Humans have been colonized by Helicobacter pylori for at least 50,000 years and probably throughout their evolution. H. pylori has adapted to humans, colonizing children and persisting throughout life. Most strains possess factors that subtly modulate the host environment, increasing the risk of peptic ulceration, gastric adenocarcinoma, and possibly other diseases. H. pylori genes encoding these and other factors rapidly evolve through mutation and recombination, changing the bacteria-host interaction. Although immune and physiologic responses to H. pylori also contribute to pathogenesis, humans have evolved in concert with the bacterium, and its recent absence throughout the life of many individuals has led to new human physiological changes. These may have contributed to recent increases in esophageal adenocarcinoma and, more speculatively, other modern diseases.

Helicobacter pylori is the main cause of peptic ulceration, distal gastric adenocarcinoma, and gastric lymphoma. Only 15% of those colonized develop disease, and pathogenesis depends upon strain virulence, host genetic susceptibility, and environmental cofactors. Virulence factors include the cag pathogenicity island, which induces proinflammatory, pro-proliferative epithelial cell signaling; the cytotoxin VacA, which causes epithelial damage; and an adhesin, BabA. Host genetic polymorphisms that lead to high-level pro-inflammatory cytokine release in response to infection increase cancer risk. Pathogenesis is dependent upon inflammation, a Th-1 acquired immune response and hormonal changes including hypergastrinaemia. Antral-predominant inflammation leads to increased acid production from the uninflamed corpus and predisposes to duodenal ulceration; corpus-predominant gastritis leads to hypochlorhydria and predisposes to gastric ulceration and adenocarcinoma. Falling prevalence of H. pylori in developed countries has led to a falling incidence of associated diseases. However, whether there are disadvantages of an H. pylori-free stomach, for example increased risk of esosphageal adenocarcinoma, remains unclear.

25-30% of families fulfilling the criteria for hereditary diffuse gastric cancer have germline mutations of the CDH1 (E-cadherin) gene. In light of new data and advancement of technologies, a multidisciplinary workshop was convened to discuss genetic testing, surgery, endoscopy and pathology reporting. The updated recommendations include broadening of CDH1 testing criteria such that: histological confirmation of diffuse gastric criteria is only required for one family member; inclusion of individuals with diffuse gastric cancer before the age of 40 years without a family history; and inclusion of individuals and families with diagnoses of both diffuse gastric cancer (including one before the age of 50 years) and lobular breast cancer. Testing is considered appropriate from the age of consent following counselling and discussion with a multidisciplinary team. In addition to direct sequencing, large genomic rearrangements should be sought. Annual mammography and breast MRI from the age of 35 years is recommended for women due to the increased risk for lobular breast cancer. In mutation positive individuals prophylactic total gastrectomy at a centre of excellence should be strongly considered. Protocolised endoscopic surveillance in centres with endoscopists and pathologists experienced with these patients is recommended for: those opting not to have gastrectomy, those with mutations of undetermined significance, and in those families for whom no germline mutation is yet identified. The systematic histological study of prophylactic gastrectomies almost universally shows pre-invasive lesions including in situ signet ring carcinoma with pagetoid spread of signet ring cells. Expert histopathological confirmation of these early lesions is recommended.

OBJECTIVE: Food security has been suggested to be a risk factor for depression, stress and anxiety. We therefore undertook a systematic review and meta-analysis of available publications to examine these associations further. DESIGN: Relevant studies were identified by searching Web of Science, Embase, Scopus and PubMed databases up to January 2019. SETTING: OR was pooled using a random-effects model. Standard methods were used for assessment of heterogeneity and publication bias. PARTICIPANTS: Data were available from nineteen studies with 372 143 individual participants from ten different countries that were pooled for the meta-analysis. RESULTS: The results showed there was a positive relationship between food insecurity (FI) and risk of depression (OR = 1·40; 95 % CI: 1·30, 1·58) and stress (OR = 1·34; 95 % CI: 1·24, 1·44) but not anxiety. Subgroup analysis by age showed that subjects older than ≥65 years exhibited a higher risk of depression (OR = 1·75; 95 % CI: 1·20, 2·56) than younger participants (OR = 1·34; 95 % CI: 1·20, 1·50), as well as a greater risk of depression in men (OR = 1·42; 95 % CI: 1·17, 1·72) than women (OR = 1·30; 95 % CI: 1·16, 1·46). Finally, subgroup analysis according to geographical location illustrated that food insecure households living in North America had the highest risk of stress and anxiety. CONCLUSIONS: The evidence from this meta-analysis suggests that FI has a significant effect on the likelihood of being stressed or depressed. This indicates that health care services, which alleviate FI, would also promote holistic well-being in adults.

Irritable bowel syndrome (IBS) remains one of the most common gastrointestinal disorders seen by clinicians in both primary and secondary care. Since publication of the last British Society of Gastroenterology (BSG) guideline in 2007, substantial advances have been made in understanding its complex pathophysiology, resulting in its re-classification as a disorder of gut-brain interaction, rather than a functional gastrointestinal disorder. Moreover, there has been a considerable amount of new evidence published concerning the diagnosis, investigation and management of IBS. The primary aim of this guideline, commissioned by the BSG, is to review and summarise the current evidence to inform and guide clinical practice, by providing a practical framework for evidence-based management of patients. One of the strengths of this guideline is that the recommendations for treatment are based on evidence derived from a comprehensive search of the medical literature, which was used to inform an update of a series of trial-based and network meta-analyses assessing the efficacy of dietary, pharmacological and psychological therapies in treating IBS. Specific recommendations have been made according to the Grading of Recommendations Assessment, Development and Evaluation system, summarising both the strength of the recommendations and the overall quality of evidence. Finally, this guideline identifies novel treatments that are in development, as well as highlighting areas of unmet need for future research.

BACKGROUND: Previous studies have shown that the incidence of idiopathic pulmonary fibrosis (IPF) is rising in the U.K. and U.S.A. Death registrations and primary care data were used to determine the current trends in IPF incidence in the U.K. Because routine clinical data sets were used, the term IPF clinical syndrome (IPF-CS) is used to describe individuals in this study. METHODS: Age- and stratum-specific death registration rates between 1968 and 2008 were calculated and these were applied to the 2008 population to generate annual standardised expected number of deaths. Annual mortality rate ratios were calculated using Poisson regression. Computerised primary care records were used to determine incidence rates of IPF-CS between 2000 and 2008 stratified by age, sex and geographical region, and survival rates between calendar periods were compared. RESULTS: Annual death certificate recording of IPF-CS rose sixfold across the study period from 0.92 per 100,000 in the 1968-1972 calendar periods to 5.10 per 100,000 in the 2006-2008 calendar period, and were higher in men and the older age groups. The incidence of IPF-CS in primary care increased by 35% from 2000 to 2008, with an overall incidence rate of 7.44 per 100,000 person-years (95% CI 7.12 to 7.77). Incidence was higher in men, the older population and in Northwest England. CONCLUSIONS: The incidence of IPF-CS in primary care and registered deaths from this cause in the U.K. continues to rise in the 21st century. The current findings suggest that there are >5000 new cases diagnosed each year in the U.K.

Idiosyncratic drug-induced liver injury (IDILI) is a rare but potentially severe adverse drug reaction that should be considered in patients who develop laboratory criteria for liver injury secondary to the administration of a potentially hepatotoxic drug. Although currently used liver parameters are sensitive in detecting DILI, they are neither specific nor able to predict the patient's subsequent clinical course. Genetic risk assessment is useful mainly due to its high negative predictive value, with several human leucocyte antigen alleles being associated with DILI. New emerging biomarkers which could be useful in assessing DILI include total keratin18 (K18) and caspase-cleaved keratin18 (ccK18), macrophage colony-stimulating factor receptor 1, high mobility group box 1 and microRNA-122. From the numerous in vitro test systems that are available, monocyte-derived hepatocytes generated from patients with DILI show promise in identifying the DILI-causing agent from among a panel of coprescribed drugs. Several computer-based algorithms are available that rely on cumulative scores of known risk factors such as the administered dose or potential liabilities such as mitochondrial toxicity, inhibition of the bile salt export pump or the formation of reactive metabolites. A novel DILI cluster score is being developed which predicts DILI from multiple complimentary cluster and classification models using absorption-distribution-metabolism-elimination-related as well as physicochemical properties, diverse substructural descriptors and known structural liabilities. The provision of more advanced scientific and regulatory guidance for liver safety assessment will depend on validating the new diagnostic markers in the ongoing DILI registries, biobanks and public-private partnerships.

OBJECTIVES: Irritable bowel syndrome (IBS) is a heterogeneous condition and defined according to symptoms. Low-grade inflammation has been associated with IBS, particularly that following infection, but whether altered intestinal permeability profiles relate to irritable bowel subtype or onset is uncertain. Our aim was to compare small and large intestinal permeability in various subtypes of IBS to healthy controls. METHODS: Intestinal permeability was measured using 1.8 MBq of 51Cr-EDTA and collecting urine over 24 h; Study 1: patients with diarrhea-predominant postinfectious IBS (N=15), constipation-predominant IBS (N=15), and healthy controls (N=15); Study 2: two groups of diarrhea-predominant IBS (D-IBS), one with a history of onset after acute gastroenteritis (postinfectious) (N=15) and the other without such a history (nonpostinfectious) (N=15) both compared with healthy controls (N=12). RESULTS: Permeability expressed as percentage of total dose excreted in urine (median [inter-quartile range]). Study 1: Proximal small intestinal permeability was increased in postinfectious IBS (0.19 [0.12-0.23]) in contrast to constipated IBS (0.085 [0.043-0.13]) and controls (0.07 [0.035-0.19]) (p=0.02). IBS patients with eczema, asthma, or hayfever had increased proximal small intestinal permeability compared with IBS patients without atopy (p=0.02). Study 2: Small intestinal permeability was greater in nonpostinfectious diarrhea-predominant IBS (0.84 [0.69-1.49]) compared with postinfectious IBS (0.43 [0.29-0.63], p=0.028) or controls (0.27 [0.2-0.39]), p=0.001). CONCLUSIONS: Small intestinal permeability is frequently abnormal in diarrhea-predominant IBS. Those without a history of infectious onset appear to have a more severe defect.