K. R. Gardiner

The dextran sulphate sodium (DSS) model of colitis: an overview

The dextran sulphate sodium model of colitis has demonstrated several correlations with human inflammatory bowel disease and is deemed suitable for investigating pathogenesis, therapeutic options and the dysplasia–adenocarcinoma sequence of inflammatory bowel disease. It is widely applicable to mice, rats, hamsters and guinea pigs. This review explores the features of this model and identifies areas for further research studies.

Reduced intestinal absorption of arginine during sepsis

OBJECTIVE To investigate the effect of sepsis on the intestinal absorption of arginine. DESIGN Controlled, nonintervention study. SETTING Surgical research laboratories of Sinai Hospital of Baltimore. SUBJECTS Male Sprague-Dawley rats. INTERVENTIONS Experimental sepsis induced by cecal ligation and puncture or intraperitoneal injection of lipopolysaccharide. MEASUREMENTS AND MAIN RESULTS Sepsis assessed by peritoneal and blood cultures. Intestinal absorption estimated by measuring the transfer of 3H-arginine by everted jejunal sacs prepared from septic and control animals (n = 6 per group) at multiple time points after the induction of sepsis (6, 12, 24, 48, and 72 hrs after cecal ligation and puncture; 6 and 12 hrs after intraperitoneal injection of lipopolysaccharide). Induction of peritonitis in the rat by cecal ligation and puncture significantly reduced the in vitro uptake of arginine by everted jejunal sacs at 12, 24, and 48 hrs after laparotomy. Arginine transfer by everted jejunal sacs was also significantly reduced in rats as early as 6 hrs after intraperitoneal injection of endotoxin (endotoxin 273 +/- 14; saline 377 +/- 14 nmol/sac/hr). Data are expressed as mean +/- SEM. Recovery from sepsis was associated with normalization of arginine transfer by intestinal sacs. CONCLUSIONS Experimental sepsis, induced by either cecal ligation and puncture or intraperitoneal injection of lipopolysaccharide, resulted in impaired intestinal amino acid uptake. Impaired intestinal arginine absorption may explain the lack of benefit of enteral, compared with parenteral, arginine therapy on survival from a septic insult.

Role of adenosine in immunomodulation: review of the literature.

ObjectiveAdvances in the understanding of sepsis have failed to deliver satisfactory new treatments aimed at attenuating inflammatory-mediated organ dysfunction. Phagocytic cells play a pivotal role in driving the inflammatory response and causing direct tissue injury. Adenoreceptor stimulation may attenuate such inflammatory-mediated damage by down-regulating phagocytic activity and preventing excessive respiratory burst activation. DataA Medline database was used to perform a literature search for all articles relating to the use of adenosine as an immunomodulatory agent. ConclusionThere is convincing evidence to suggest that adenoreceptor modulation can prevent tissue injury through a variety of pathways. The use of adenosine modulation in ischemia/reperfusion injury has been the subject of considerable investigation, although experience with its use in sepsis is limited.

Sepsis impairs gut amino acid absorption

Sepsis has been shown to adversely affect the barrier and metabolic functions of the small intestine as well as to reduce mesenteric blood flow and cause histologic damage. However, the effect of sepsis on gut absorptive function has been largely ignored. In this study, intestinal absorption of arginine and an amino acid analogue, aminoisobutyric acid, was studied using in vivo and in vitro techniques in an experimental model of sepsis. In vivo studies showed a significant impairment in the absorption of both amino acids from the intestinal lumen 24 and 72 hours after cecal ligation and puncture. Uptake of these amino acids by everted gut sacs prepared from septic animals was also significantly reduced. This reduction in absorptive capacity of the gut may limit the ability of enteral feeding alone to supply nutritional requirements during sepsis and may also contribute to the associated morbidity and mortality.

Review: Intestinal Amino Acid Absorption During Sepsis

Sepsis has been shown to cause a decrease in mesenteric blood flow in association with ultrastructural changes in the small intestine and impaired immune, barrier, and metabolic functions of the gut. These impairments in the structure and function of the gastrointestinal tract may have a detrimental effect on the morbidity and mortality of sepsis. Two recent studies have shown that the ability of the small intestine to absorb amino acids is also impaired during sepsis, but the systemic and cellular mechanisms of this impairment are not known. Release of cytokines induced by systemic bacteria or endotoxin may lead to a reduction in the synthesis of transporter proteins by the enterocyte at a time when there is reduced availability of both luminal (because of anorexia) and circulating (because of reduced mesenteric blood flow) substrates. Future research needs to investigate the systemic and local mediation of the sepsis-induced reduction in intestinal amino acid absorption and the possibility of correcting...

Novel Substrates to Maintain Gut Integrity

CONTENTS INTRODUCTION . . 4 4 EVIDENCE FOR G U T MUCOSAL BARRIER DYSFUNCTION . . 4 4 CLINICAL SIGNIFICANCE OF G U T MUCOSAL BARRIER DYSFUNCTION . . 46 GUT DERIVED SEPSIS: THERAPEUTIC STRATEGIES. . . 41 NOVEL SUBSTRATES A N D G U T INTEGRITY . . 48 GLUTAMINE . . 48 Metabolism of glutamine . . 48 Glutamine and the gut mucosa . . 48 Glutamine and experimental disease models . . * 49 Glutamine supplemented TPN and experimental disease models . . . 49 Glutamine supplemented enteral nutrition and experimental disease models . . 49 Rationale for clinical use of glutamine . . . 50

NUTRITIONAL MODULATION OF GUT INFLAMMATION

Nutritional therapy is an important component of the management of gastrointestinal inflammation, which disrupts the gut mucosal barrier leading to sepsis, SIRS and MODS. Future studies will be needed to define the role of specific nutrients in enhancing mucosal barrier function and supporting general immune function, and how this affects morbidity and mortality of critically-ill patients.

Promotion of a favorable gut flora in inflammatory bowel disease.

Recent evidence suggests that the composition of colonic flora plays a role in intestinal inflammation in inflammatory bowel disease (IBO). This review examines the evidence that altering the concentrations of colonic bacteria might benefit patients with this condition.

The Role of the Imino Transporter Protein in Sepsis-Impaired Intestinal Proline Absorption

Recently, sepsis has been shown to impair intestinal amino acid absorption in addition to gut metabolic and barrier functions. We investigated intestinal proline absorption in a rabbit model of sepsis. Twelve hours after intraperitoneal injection of lipopolysaccharide, proline uptake by everted jejunal sacs prepared from septic animals (480.4 +/- 67.4 nmol per sac per hour) was significantly reduced compared with controls (846.8 +/- 73.5 nmol per sac per hour) (p < .001 by t test). We next investigated whether reduced expression of transporter proteins contributed to the impaired intestinal proline uptake during sepsis. The proline (imino) carrier of rabbit jejunum is covalently bound by fluorescein isothiocyanate (FITC) and/or phenylisothiocyanate with irreversible inhibition of proline uptake. This binding and inhibition is prevented by sodium chloride and L-proline. Single-cell suspensions of rabbit enterocytes were prepared 12 hours after intraperitoneal injection of lipopolysaccharide/saline or saline alone. Enterocytes were incubated for 30 minutes in tris(hydroxymethyl)aminomethane/ethylenediaminetetraacetate (Tris/EDTA) buffer; buffer with 1 mM phenylisothiocyanate; or buffer with 10 mM proline, 100 mM sodium chloride, and 1 mM phenylisothiocyanate. After incubation with 10 microM FITC in Tris/EDTA buffer for 15 minutes, the percent positivity and fluorescent intensity of FITC binding to enterocytes were determined by using flow cytometry. Sepsis significantly reduced the percentage of enterocytes binding FITC and the fluorescent intensity of FITC binding of proline/sodium chloride-pretreated or untreated cells. This suggests that sepsis depresses the expression of imino transporters by rabbit enterocytes, which may explain the reduced intestinal proline absorption.

Immunosuppression in patients with Crohn's disease and neoplasia: an ongoing clinical dilemma.

DISEASES OF THE COLON & RECTUM VOLUME 55: 9 (2012) Thiopurines have been shown to induce remission in approximately 50% of patients and maintain remission in about 70% of patients with IBD. In a recent Cochrane Review, a response rate of 54% was reported with the use of azathioprine (AZT) or 6-mercaptopurine (6-MP) in patients with Crohn’s disease (CD). The pooled odds ratio for response to AZT or 6-MP was 2.43 (95% CI 1.62–3.64). The odds ratio for maintenance of remission with AZT was 2.32 (95% CI 1.55–3.49). However, thiopurines have been implicated in the development of malignancy while patients are on these immunosuppressants. This often leads to a dilemma as to the role of thiopurines in patients who have a past history of malignancy or who develop malignancy while on treatment. There are no specific guidelines as to whether or not immunosuppressants should be stopped in these patient groups and, if so, for how long.