Proteomics Highlights Common and Distinct Pathophysiological Processes Associated with Ileal and Colonic Ulcers in Crohn's Disease.

BACKGROUND AND AIMS: Based on genetics and natural history, Crohn's disease can be separated into two entities, an ileal and a colonic disease. Protein-based approaches are needed to elucidate whether such subphenotypes are related to distinct pathophysiological processes. METHODS: The proteome of ulcer edges was compared with that of paired control tissue samples [n = 32 biopsies] by differential proteomics in the ileum and the colon of Crohn's disease patients [n = 16]. The results were analysed using a hypothesis-driven approach [based on the literature] and a hypothesis-free approach [pathway enrichment analyses] to determine common and segment-specific pathophysiological processes associated with ileal and colonic CD ulcer edges. To confirm the involvement of a key pathway highlighted by proteomics, two proteins were also studied by immunochemistry. RESULTS: In the ileum and the colon, 4428 and 5204 proteins, respectively, were identified and quantified. Ileal and colonic ulcer edges differed in having a distinct distribution of proteins associated with epithelial-mesenchymal transition, neutrophil degranulation, and ribosomes. Ileal and colonic ulcer edges were similarly characterized by an increase in the proteins implicated in the endoplasmic reticulum protein-processing pathway and a decrease in mitochondrial proteins. Immunochemistry confirmed the presence of endoplasmic reticulum stress in the mucosa of ileal and colonic ulcer edges. CONCLUSION: This study provides protein-based evidence for partially distinct pathophysiological processes being associated with ileal and colonic ulcer edges in Crohn's disease patients. This could constitute a first step toward the development of gut segment-specific diagnostic markers and therapeutics.

Diagnostic challenge of the non-specific presentation of adult intussusception.

The following report will discuss the diagnosis and management of non-specific abdominal pain in a 77-year-old woman who presented to a district general hospital in South London. CT imaging demonstrated ileo-colic intussusception with free air and fluid indicating perforation. The images of the specimen clearly show the ileal tumour within the intussusception. Thus, the patient underwent an emergency right hemicolectomy and formation of a double-barrelled ileostomy. Histology subsequently confirmed this was secondary to a colonic adenocarcinoma. This case report is unique as it highlights that intussusception in adults is very difficult to accurately diagnose based on clinical features (due to non-specific findings) and even with radiology can be challenging. This is also the first documented case of the site of perforation not being directly involved with the site of intussusception. The perforation site was in fact distal to the intussusception. At the time of surgery, it was noted that the patient had significantly faecal loading up to her rectum. The resulting closed loop was the cause of her perforation.

Outpatient management of intussusception: a systematic review and meta-analysis.

BACKGROUND: Variability in management of intussusception after enema reduction exists. Historically, inpatient observation was recommended; however, there is a lack of evidence-based guidelines for this practice. METHODS: A systematic review and meta-analysis evaluating outcomes between inpatient (IP) and outpatient (OP) management after enema reduction was performed. The following databases were searched: PubMed, EBSCOhost CINAHL, EMBASE, Web of Science, and Cochrane Database. Data from an institutional review were included in the meta-analysis. RESULTS: Ten studies of patients aged 0-18 years with intussusception who underwent successful enema reduction that reported outcomes of outpatient management were included. Overall recurrence rates were 6% for IP and 8% for OP (p = 0.20). Recurrences within 24 (IP: 1% vs OP: 0%, p = 0.90) and 48 h (IP: 1% vs OP: 2%, p = 0.11) were similar. There was no significant difference in the rate of return to the emergency department (IP: 6% vs OP: 14%, p = 0.11). Both groups had a similar rate of requiring an operation (IP: 2% vs OP: 1%, p = 0.84). CONCLUSIONS: Outpatient management of intussusception after enema reduction results in a shorter hospital stay with no difference in the rate of return to the emergency department, recurrence, need for operation, or mortality. The findings of the meta-analysis suggest that outpatient management may be safe and could reduce hospital resource utilization. TYPE OF STUDY: Treatment study. LEVEL OF EVIDENCE: III.

PATTERNS AND SEASONAL VARIATION OF INTUSSUSCEPTION IN CHILDREN: A RETROSPECTIVE ANALYSIS OF CASES OPERATED IN A TERTIARY HOSPITAL IN ETHIOPIA.

BACKGROUND: Intussusception is one of the frequent causes of bowel obstruction in infants and toddlers (1). It involves invagination of a portion of intestine into another(2-4). The peak age of occurrence is between the age of 4 and 8 months. The aim of this study is to review the pattern of clinical presentation and seasonal variation of intussusception in our hospital, and to analyze the mode and outcomes of treatment. PATIENTS AND METHODS: This is a four-year retrospective study of children aged 13 years and below who were admitted and treated for intussusception between January 2011 and December 2014 at the pediatric surgery unit of Tikur Anbesa Specialized Hospital (TAH) in Ethiopia. Information on the patients' demographic characteristics, clinical presentation, and month of occurrence as well as the operative findings and outcome were obtained from the pediatric surgery unit record book, patient charts, and the operating theatre registry. RESULTS: One hundred and thirty six cases of intussusception were admitted to TAH, Addis Ababa over a four year period, of which 130 charts were retrieved and analyzed. Males dominated in the series. Age distribution showed that 59.2% of the cases were ≤ one year old, and 77.7 % were ≤ two years old. Abdominal pain, vomiting, bloody mucoid diarrhea and a mass palpated abdominally and/or rectally were the most common modes of presentations, with the classic triad of abdominal pain, vomiting and bloody mucoid diarrhea occurring in nearly two third of cases. The highest peak of presentation was in the month of June with 18 (13.9%) cases. The mean duration of symptoms before presentation to our hospital was 5.2 days with a range of 1-21 days. Intraoperatively, it was found that ileocolic intussusception was the most common type. Simple reduction without bowel resection was possible in 70.8% of cases. There were 44 (33.9 %) complications, wound site infection being the most common occurring in 20 (15.4%) cases and there were 6 deaths. CONCLUSION: Intussusception was more common in the wet season. There was delayed presentation with a higher rate of operative management and bowel resection. The mortality rate has decreased significantly compared with a previous study from this institution.

Transient and Non-Transient Intussusceptions of the Large Bowel in Adults: Two Case Reports.

BACKGROUND: Intussusception of the large bowel in adults is a very rare pathological condition. However, it has its clinical importance because intussusception is very often associated with an intraluminal lesion. CASE REPORT: We report two cases of the large bowel intussusception, ileocolic and colorectal. Both intussusceptions were associated with a malignant tumor. However, the clinical presentation was different. One of the intussusceptions was of non-transient character, while the second one resolved spontaneously before operation. Both patients underwent surgery and malignant tumors were found and removed. RESULTS: The purpose of the article is to draw attention to intussusception and emphasize that intussusception, either transient or non-transient, should be further examined. CONCLUSIONS: The intussusception may be the first and the only signal of the existence of a malignant tumor, very often colorectal carcinoma.

In vitro smooth muscle contractility before and after relief of experimental obstruction in the rat: application to the surgical management of ileal dilatation.

PURPOSE: Bowel dilatation occurs proximal to an obstruction and predisposes to intestinal dysmotility. The present study sought to determine whether or not changes in smooth muscle contractility and the thickness of the proximal, dilated bowel wall can be reversed following relief of the obstruction. MATERIALS AND METHODS: Three groups of seven male Wistar rats were studied. In 8-week-old animals in a control group and a sham-operated group, a small segment of bowel (designated as R1 for controls and R2 for shams) was resected 5.0 cm from the cecum. In the third (operated) group, a narrow, isoperistaltic intestinal loop was created proximal to an end-to-end anastomosis of the ileum in 4-week-old animals. When these animals were 6 weeks old, the loop was re-anastomosed to the distal small bowel (after resection of the loop's distal portion, referred to as R3). Two weeks later, a small segment of bowel was resected proximal to the anastomosis (R4). We evaluated the thickness of the smooth muscle layers and the in vitro contractile responses of circular smooth muscle ileal strips (R1-R4) to electrical stimulation and pharmacological stimulation (with KCl, acetylcholine (ACh), substance P, N(G)-nitro-l-arginine methyl ester (L-NAME) and histamine). RESULTS: The amplitudes of contraction in response to electrical and Ach-mediated stimulation were higher for R3 than for R4 (P<0.001), R1 and R2 (both P<0.05). Compared with R1 and R2, the smooth muscle layer was three times as thick in R3 (P<0.001) and 2.5 times as thick in R4 (P<0.01). CONCLUSION: Our study provides evidence of the possible recovery of intestinal motility (in response to neurotransmitters involved in gut function) after the relief of an obstruction. If ileal motility can conceivably return to normal values, conservative surgical procedures in pediatric patients should be preferred (in order to leave a sufficient length of bowel and avoid short bowel syndrome).

Gastrointestinal manifestations of Behçet's disease in Japan: a study of 43 patients.

We analyzed the clinical gastrointestinal (GI) characteristics of Behçet's disease (BD) patients in Japan. We retrospectively reviewed the clinical charts of 412 patients who fulfilled the 1987 Japanese criteria for BD and were treated in two university hospitals from July 1991 to December 2007. Forty-three patients (10.4 %) had BD-related GI lesions, which were shown by imaging examinations. Median age at BD diagnosis and onset of GI episodes were 29.6 and 31.0 years, respectively. The patients suffered from abdominal pain (30/43) and GI bleeding (18/43), while they had lower frequency of eye involvement and higher incidence of arthritis and vascular involvement than BD patients without GI lesions. The lesions were prevalent in the ileum (32/43) followed by cecum (21/43) and esophagus (9/43). The patients were treated with mesalazine and sulfasalazine (41/43), corticosteroids (32/43), immunosuppressants (13/43), and infliximab for 7 patients having refractory lesions, while 10 patients had surgical operation. Two patients died due to non-GI events during the observation. The diagnosis of BD was often difficult because of lack of eye involvement. Surgery is required for some patients in spite of intensive immunosuppressive therapies. Appropriate use of anti-TNF agents may be promising for the GI involvement.

Comparison of different methods of intestinal obstruction in a rat model.

AIM: To investigate different methods of creating incomplete intestinal obstruction in a rat model and to compare their electrophysiologic, morphologic and histologic characteristics. METHODS: Rat ileum was partially obstructed by the respective application of: braided silk (penetrated the mesentery and surrounded intestine); half ligation (penetrated directly and ligated 1/2 cross-section of the intestine); wide pipe (6 mm in width, surrounded the intestine); narrow pipe (2 mm in width, surrounded the intestine). A control was also included (no obstruction). Various behavioral and electrophysiologic variables, as well as morphologic and immunohistochemical observations were recorded by blinded investigators at different time points (12, 24, 48, 72 h), including daily general condition, ileal wet weight and circumference, macromorphous and micromorphous intestine, bowel movement capability in vivo and in vitro, slow wave and neural electrical activity, and the number of c-Kit positive interstitial cells of Cajal (ICC). RESULTS: Despite being of a similar general condition, these methods resulted in different levels of obstruction in each group compared with the control at different time points (12, 24, 48, 72 h). However, these fields of the wide pipe rat showed significantly differences when compared with the other three obstructed groups at 12 to 72 h, including macroscopic and histological presentation, intestinal transit ratio and contractility, circumference and wet weight, amplitude and frequency of nerve electrical discharge and slow wave, and ICC numbers (all P < 0.01). CONCLUSION: The wide pipe rat method is significantly more reliable and stable than the other methods of obstruction, demonstrating that use of the wide pipe method can be a useful model of incomplete intestinal obstruction.

Stimulating the central nervous system to prevent intestinal dysfunction after traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) causes gastrointestinal dysfunction and increased intestinal permeability. Regulation of the gut barrier may involve the central nervous system. We hypothesize that vagal nerve stimulation prevents an increase in intestinal permeability after TBI. METHODS: Balb/c mice underwent a weight drop TBI. Selected mice had electrical stimulation of the cervical vagus nerve before TBI. Intestinal permeability to 4.4 kDa FITC-Dextran was measured 6 hours after injury. Ileum was harvested and intestinal tumor necrosis factor-alpha and glial fibrillary acidic protein (GFAP), a marker of glial activity, were measured. RESULTS: TBI increased intestinal permeability compared with sham, 6 hours after injury (98.5 microg/mL +/- 12.5 vs. 29.5 microg/mL +/- 5.9 microg/mL; p < 0.01). Vagal stimulation prevented TBI-induced intestinal permeability (55.8 +/- 4.8 microg/mL vs. 98.49 microg/mL +/- 12.5; p < 0.02). TBI animals had an increase in intestinal tumor necrosis factor-alpha 6 hours after injury compared with vagal stimulation + TBI (45.6 +/- 8.6 pg/mL vs. 24.1 +/- 1.4 pg/mL; p < 0.001). TBI increased intestinal GFAP 6.2-fold higher than sham at 2 hours and 11.5-fold higher at 4 hours after injury (p < 0.05). Intestinal GFAP in vagal stimulation + TBI animals was also 6.7-fold higher than sham at 2 hours, however, intestinal GFAP was 18.0-fold higher at 4 hours compared with sham and 1.6-fold higher than TBI alone (p < 0.05). CONCLUSION: In a mouse model of TBI, vagal stimulation prevented TBI-induced intestinal permeability. Furthermore, vagal stimulation increased enteric glial activity and may represent the pathway for central nervous system regulation of intestinal permeability.

Cine magnetic resonance imaging evaluation of peristalsis of small bowel with longitudinal ulcer in Crohn disease: preliminary results.

OBJECTIVE: To evaluate peristalsis of the small bowel with a longitudinal ulcer in Crohn disease using cine magnetic resonance imaging (MRI). METHODS: Fifteen patients with suspected or diagnosed Crohn disease were examined by cine MRI using a multislice and multiphase method. Inclusion criteria were pathological evidence of Crohn disease and confirmation of longitudinal ulceration in the small bowel by ileocolonoscopy, single- or double-contrast radiography of the small bowel, or surgery. Six of these patients were included in this study. Cine MRI findings of the small bowels were retrospectively reviewed by 2 radiologists. RESULTS: Asymmetric involvement or mesenteric rigidity with antimesenteric flexibility was seen in all patients by cine MRI. This finding was not seen in normal small bowel segments. A combination of ileocolonoscopy and contrast radiography detected longitudinal ulcers in 5 of the 6 patients, and surgery revealed ulceration in the remaining patient. CONCLUSIONS: Cine MRI was a feasible approach for detecting a longitudinal ulcer in small-bowel Crohn disease.

New hypothesis on the pathogenesis of ileocecal intussusception.

PURPOSE: Ileocecal intussusception is a relatively common surgical emergency in infants and young children. The etiology of intussusception is not clearly understood. Nitric oxide (NO) is a major inhibitory neurotransmitter in the enteric nervous system, which causes relaxation of the smooth muscles. In a lipopolysaccharide-induced experimental model of intussusception, altered intestinal motility is shown to be the result of increased NO released from various inflammatory mediators, which in turn leads to increased incidence of intussusception. The aim of this study was to examine the age-related changes in the nitrergic innervation of the ileocecal valve (ICV) to gain insights into the pathogenesis of intussusception. METHOD: Whole-mount preparations of the myenteric plexus from the ileum, ICV, and proximal colon were stained using NADPH diaphorase histochemistry in newborn piglets (n = 3), 4-week-old (n = 3), 12-week-old (n = 3), and adult pigs (n = 3). Using light microscopy, the number of ganglia per square centimeter, the number of cells per ganglion, and the number of ganglion cells per square centimeter were determined. RESULTS: There were striking regional and age-related differences in nitrergic innervation of myenteric plexus. Density of nitrergic neurons was significantly higher in the ICV than in the terminal ileum and proximal large bowel in the young animals (P < .001). CONCLUSION: These findings suggest that the inflammatory reactions that usually precede intussusception may cause overproduction of NO by the nitrergically hyperinnervated ICV causing relaxation of the ICV and thereby facilitating ileocecal intussusception.

Íleo adinâmico em eqüinos: fisiopatologia e tratamento / Adynamic ileus in horses: pathophysiology and treatment / Íleo adinámico en equinos: fisiopatología y tratamiento

A motilidade gastrointestinal é um evento complexo, envolvendo interação entre vias neurais, hormonais e neuromusculares, promovendo o movimento aboral do material alimentar. A interrupção dessas vias provoca o íleo. O íleo adinâmico é classicamente caracterizado pela ausência da coordenação gastroduodenal e atividade contrátil, levando à formação de refluxo enterogástrico, acúmulo de fluido intraluminal e distensão luminal. O íleo adinâmico pode afetar todas as partes do trato gastrointestinal. Prováveis mecanismos etiológicos incluem o choque sistêmico, distúrbios eletrolíticos, distensão luminal persistente, isquemia, inflamação, peritonite e endotoxemia. Devido à etiologia do íleo ser complexa e multifatorial, várias estratégias têm sido utilizadas para atenuar seu início ou conseqüências. Embora uma variedade de drogas procinéticas seja utilizada visando à melhoria da motilidade gastrointestinal, não existe consenso quanto à sua eficácia. Conseqüentemente, a base do tratamento permanece a terapia de suporte.

Progressive motility is a complex process that involves interaction between neural, hormonal, and neuromuscular pathways ultimately leading to the aboral movement of feed material. Disruption to these pathways leads to ileus. Adynamic ileus is classically characterized by loss of gastroduodenal coordenation and propulsive contractile activity leading to the formation of gastric reflux, intraluminal fluid pooling, and luminal distention. Adynamic ileus may affect all parts of the gastrointestinal tract. Possible contributing mechanisms include systemic shock, electrolyte disturbances, persistent luminal distention, ischemia, inflammation, peritonitis, and endotoxemia. Since the etiology ileus is multifactorial and complex, various strategies have been used to attenuate either its onset or consequences. Although a variety of prokinetic agents have been administered to horses in an attempt to improve GI motility in adynamic ileus cases, there is not an agreement regarding its efficiency. Consequently, supportive therapy remains as the basis of the treatment.

Down-regulation of hepatic transporters for BSP in rats with indomethacin-induced intestinal injury.

Previous reports have demonstrated that an intestinal injury causes hypofunctions of the liver associated with down-regulations of cytochrome P450, but an influence on hepatic transporters remains unclear. Here, we tested hepatic transporter functions in a rat model of bowel injury using indomethacin (IDM). After administration of IDM (8.5 mg/kg, i.p., 3 d), the rats suffered the intestinal impairment indicated by a reduction of alkaline phosphatase activity in mucosa. In vivo pharmacokinetic experiments of bromosulfophthalein (BSP) showed that there was a reduction in its plasma elimination rate and cumulative biliary excretion in IDM-treated rats and systemic and biliary clearances reduced to nearly 50% of the control group. Protein expressions in plasma membrane and mRNA levels of organic anion transporting polypeptide 1b2 (Oatp1b2) and multidrug resistance-associated protein 2 (Mrp2), which play hepatic BSP uptake and biliary excretion, respectively, in the liver were significantly reduced following the IDM treatment. In portal plasma, the levels of proinflammatory cytokines were unchanged, while the level of nitric oxide metabolites (NO2- + NO3-) increased to 6.5-fold that of the control. The time-course on IDM treatment indicated that, firstly, intestinal injury was induced, the NO level increased, and the hepatic Oatp1b2 and Mrp2 expression began to fall followed by an increase in plasma ALT. In conclusion, IDM-induced injury to the small intestine causes the hypofunction of hepatic Oatp1b2 and Mrp2 independently on the hepatic impairment, and NO arising from bowel injury may be one of key factors for it through the remote effect.

Microcirculatory changes in experimental mesenteric longitudinal ulcers of the small intestine in rats.

Rats receiving intracolonic administration of indomethacin develop longitudinal ulcers on the mesenteric side of the small intestine that are similar to those seen in the acute phase of Crohn's disease. To investigate the causative role of microcirculatory disturbances and to elucidate the therapeutic effect of antioxidants on this enteropathy in rats, we serially evaluated changes in regional blood flow of the small intestine using laser Doppler perfusion imaging and the colored microsphere injection method. Both methods disclosed stepwise hyperperfusion limited to the mesenteric side of the small intestine following transient ischemia during the initial 30-60 minutes. In addition, both a radical scavenger and a radical production inhibitor significantly ameliorated the mesenteric longitudinal ulcers. We concluded that ischemia-reperfusion on the mesenteric side accompanying excessive production of radicals might be strongly involved in indomethacin-induced longitudinal ulcers of the small intestine in rats.

[Crohn's disease: influence of age at diagnosis on clinical type of disease]. / Maladie de Crohn: influence de l'âge au moment du diagnostic sur le type évolutif.

UNLABELLED: The aim of the study was to examine the influence of age at diagnosis of Crohn's disease on disease site and course in Tunisian patients. METHODS: All hospital patients for Crohn's disease between 1993 and 2002 were included. They were segregated by age at diagnosis as follows: younger than 20 years, 20-39 years, and 40 years or older. And all patients were classified at the time of the latest visit into one of three subtypes of disease (non complicating, stricturing, and fistulizing) according Vienna's classification. Crohn's disease was devised also by site (ileum, ileocecal, colon and higher site). RESULTS: Sixty one patients (50.4%) were 20-39 years old and 43 patients (35.5%) were 40 years and older. Colonic involvement was significantly more common (46,5%) in the 40 years and older group compared with 20-39 years group (24.6%) (p = 0.01). The subtype without complication was significantly more common (58.1%) in the 40 years and older group compared with 20-39 years group (39.3%) (p = 0.05). The frequency of the need for surgery for any indication for Crohn's disease didn't differ significantly according to age. CONCLUSION: In this study, Crohn's disease diagnosed in tunisian patients that were 40 years and older had often a colonic site and a less severe phenotype supporting the concept of genetic heterogeneity.

Comparison between prospective and retrospective evaluation of Crohn's disease activity index.

The Crohn's disease activity index (CDAI) is the most widely used measure of clinical disease activity in patients entered into clinical trials. The prospective nature of the CDAI calculation precludes its use as a clinical assessment tool. We compared the retrospective evaluation of the CDAI with the prospective evaluation in a heterogeneous patient population of 100 patients with Crohn's disease. The correlation between the two assessment methods was good with an r-value of 0.84 (p < 0,0001). There was a tendency of patients with a high retrospective CDAI to have a lower prospective CDAI which is explained by intention to treat. This study shows that a retrospective assisted evaluation of the CDAI is as accurate as the traditional prospective evaluation.

A survey of perceptions and attitudes among European surgeons towards the clinical impact and management of postoperative ileus.

OBJECTIVE: Postoperative ileus (POI) can negatively affect patient recovery and morbidity, yet the lack of an internationally accepted definition and clinical management pathway for this condition suggest POI may be under-recognized as a clinical problem. The purpose of this survey was therefore to assess current attitudes of surgeons towards the clinical impact and management of POI. SUBJECTS AND METHODS: Telephone interviews were conducted with 230 surgeons from hospitals in the UK, France, Germany, Italy and Spain. RESULTS: Across Europe, there are differences in the terms surgeons use to refer to delayed recovery of gastrointestinal (GI) function and the symptoms, concerns and risks they associate with this condition. Furthermore, there is marked variation in the attitudes of European surgeons towards minimizing the risk of delayed recovery of GI function and in the strategies to manage POI. Additionally, some of the measures applied most commonly by European surgeons are in contrast to evidence in the literature indicating that they have no benefit for quicker resolution of GI function. CONCLUSION: The results suggest that there is a need for clearer definition of the factors that constitute POI, increased recognition of the impact of this condition and improved understanding of the most effective peri-/postoperative care for surgical patients.

Resuscitation-induced gut edema and intestinal dysfunction.

BACKGROUND: Mesenteric venous hypertension and subsequent gut edema play a pivotal role in the development of intra-abdominal hypertension. Although gut edema is one cause of intra-abdominal hypertension, its impact on gut function is unknown. The purpose of this study was to create a model of acute hydrostatic gut edema and to evaluate its effect on gut motility and barrier function. METHODS: The first study, group A, evaluated the effect of gut edema on transit over time using 20 mL/kg 0.9% saline. The second study, group B, focused on the 12-hour time period using 80 mL/kg 0.9% saline. Rats were randomized to superior mesenteric vein partial occlusion (venous hypertension) or sham surgery. At 6, 12, and 24 hours, group A underwent intestinal transit and tissue water weight measurements. At 12 hours, group B underwent tissue water, transit, ileal permeability and resistance, lactate and myeloperoxidase activity, and mucosal injury measurements. RESULTS: Venous hypertension with fluid resuscitation caused acute hydrostatic gut edema, delayed intestinal transit, increased mucosal permeability to macromolecules, and decreased tissue resistance over time. Mucosal injury was minimal in mesenteric venous hypertension. CONCLUSION: Acute mesenteric venous hypertension and resuscitation-induced gut edema, in the absence of ischemia/reperfusion injury, is associated with delayed intestinal transit and altered gut barrier function.