LPS and Digestive Malfunction

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J Clin Invest. 1988 November; 82(5): 1714�1721.

Bacterial lipopolysaccharide-induced intestinal microvascular lesions leading to acute diarrhea.

V I Mathan, G R Penny, M M Mathan, and D Rowley

Wellcome Research Unit, Christian Medical College Hospital, Vellore, India.

Subcutaneous challenge of mice with lipopolysaccharide (LPS) from gram negative bacteria, produced an intestinal microvascular lesion causing fluid exudation into the lumen of the intestine and diarrhea. The microvascular lesion was characterized by endothelial cell damage and microthrombi in the venules and capillaries of the intestinal lamina propria. Marker organisms, given orally to challenged mice, grew in the exuded fluid and could invade the mucosa. Intravenous transfer of postchallenge plasma produced the lesion in normal mice and absorption of such plasma by Sepharose coupled to LPS-antibody abolished this effect. Instillation of large quantities of LPS into the lumen of the intestine produced scattered microvascular lesions, although none of these animals developed diarrhea. Since a similar microvascular lesion has been described in the rectal mucosal lamina propria of adults with acute diarrhea, it is suggested that LPS-induced vascular damage may be a novel mechanism in the pathogenesis of acute diarrhea.

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Gastrointestinal transit during endotoxemia: the role of nitric oxide.

Wirthlin DJ, Cullen JJ, Spates ST, Conklin JL, Murray J, Caropreso DK, Ephgrave KS.

Department of Surgery, University of Iowa College of Medicine, Iowa City, 52242, USA.

We hypothesized that the disrupted gastrointestinal transit that occurs during endotoxemia is mediated by nitric oxide (NO) and that the inhibition of NO synthesis will normalize intestinal transit and gastric emptying. To determine the effects of endotoxin and steroids on the activity of gastrointestinal smooth muscle NO synthase, rats underwent placement of an intravenous (iv) line and then were given Escherichia coli lipopolysaccharide (LPS) 10 mg/kg/iv; LPS, 10 mg/kg/iv + dexamethasone, 3 mg/kg/iv; or saline. The activity of nitric oxide synthase in the stomach, small intestine, and colon were determined by measuring the conversion of L-[3H]arginine to L-[3H]citrulline. To determine intestinal transit and gastric emptying, gavage feedings of nonabsorbable liquid markers were given and rats divided into eight groups: 0.9% NaCl, 1 ml/hr x 5 hr (control); LPS, 10 mg/kg/iv; LPS + N-omega-nitro-L-arginine methyl ester (L-NAME), 10 mg/kg/hr x 5 hr; LPS + N-omega-nitro-D-arginine methyl ester (D-NAME), 10 mg/kg/hr x 5 hr; LPS + L-arginine, 100 mg/kg/hr x 5 hr; LPS + L+NAME + L-arginine; LPS + N-omega-nitro-L-arginine (L-NNA) 10 mg/kg/hr; or LPS + L-NNA + L-arginine. LPS increased the enzymatic activity of both the constitutive and the inducible forms of NO synthase in the small intestine and fundus of the stomach. The acceleration of intestinal transit produced by endotoxemia was reversed with both L-NAME and L-NNA but not with D-NAME. Endotoxemia slowed gastric emptying but this effect was not reversed with either L-NAME or L-NNA. We conclude that NO plays a major role in mediating the rapid intestinal transit during endotoxemia.

PMID: 8598659 [PubMed - indexed for MEDLINE]

Cullen JJ, Mercer D, Hinkhouse M, Ephgrave KS, Conklin JL.

Department of Surgery, University of Iowa College of Medicine, Iowa City, USA.

BACKGROUND: The disrupted intestinal transit during endotoxemia may be mediated by nitric oxide (NO). We hypothesized that the isoforms of nitric oxide synthase (NOS) are up-regulated in intestinal smooth muscle during endotoxemia and that the scavenging of NO will normalize transit. METHODS: Rats were given Escherichia coli lipopolysaccharide (LPS) 10 mg/kg intravenously and were killed 4 hours later. To determine the activity of NOS isoforms in the jejunum and ileum, the conversion of tritiated L-arginine to tritiated L-citrulline was measured. Western immunoblots were performed by incubating the extracted protein with specific polyclonal antibodies. To determine intestinal transit, rats were divided into 4 groups: 0.9% sodium chloride 1 mL/h intravenously for 5 hours, LPS 10 mg/kg intravenous bolus plus 1 mL/h 0.9% sodium chloride intravenously, LPS plus oxyhemoglobin 0.5 g/kg/h intravenously, and oxyhemoglobin 0.5 g/kg/h intravenously. RESULTS: LPS increased the constitutive and inducible NOS enzyme activities in the jejunum and ileum. Western blots demonstrated that LPS up-regulates both the NOS1 and NOS2 isoforms in jejunal and ileal smooth muscle. Oxyhemoglobin alone increased intestinal transit compared with controls, whereas endotoxemia increased intestinal transit, which was ameliorated with infusions of oxyhemoglobin. CONCLUSIONS: NO may play a major role in mediating the rapid intestinal transit induced by endotoxemia.

PMID: 10076620 [PubMed - indexed for MEDLINE]

Constipation-predominant IBS patients showed increased lipopolysaccharide (LPS)-induced IL-1beta levels compared with Healthy Controls and diarrhea-predominant IBS patients who showed an increase in all cytokine levels.

*cytokines-a group of proteins and peptides that are used in organisms as signaling compounds View this article in PubMed

1: Gastroenterology. 2007 Mar;132(3):913-20. Epub 2007 Jan 26. Links

Immune activation in patients with irritable bowel syndrome.

Liebregts T, Adam B, Bredack C, Roth A, Heinzel S, Lester S, Downie-Doyle S, Smith E, Drew P, Talley NJ, Holtmann G.

Department of Gastroenterology and Hepatology, University of Adelaide, Royal Adelaide Hospital, South Australia; Nerve-Gut Research Laboratory, Hanson Institute, Adelaide, SA, Australia.

Background & Aims: The objective was to test the hypothesis that irritable bowel syndrome (IBS) is characterized by an augmented cellular immune response with enhanced production of pro inflammatory *cytokines. We also explored whether symptoms and psychiatric comorbidity in IBS are linked to the release of pro-inflammatory cytokines.

Methods:
We characterized basal and Escherichia coli lipopolysaccharide (LPS)-induced cytokine production in peripheral blood mononuclear cells (PBMCs) from 55 IBS patients (18 mixed-, 17 constipation-, 20 diarrhea-predominant) and 36 healthy controls (HCs). PBMCs were isolated by density gradient centrifugation and cultured for 24 hours with or without (1 ng/mL) LPS. Cytokine production (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1beta, and IL-6) was measured by enzyme-linked immunosorbent assay.

Abdominal symptoms and psychiatric comorbidities were assessed by using the validated Bowel Disease Questionnaire and the Hospital Anxiety and Depression Scale.

Results:
IBS patients showed significantly (P < .017) higher baseline TNF-alpha, IL-1beta, IL-6, and LPS-induced IL-6 levels compared with HCs. Analyzing IBS subgroups, all cytokine levels were significantly (P < .05) higher in diarrhea-predominant IBS (D-IBS) patients;constipation-predominant IBS patients showed increased LPS-induced IL-1beta levels compared with HCs. Baseline TNF-alpha and LPS-induced TNF-alpha and IL-6 levels were significantly higher in patients reporting more than three bowel movements per day, urgency, watery stools, and pain associated with diarrhea compared with patients without these symptoms (all P < .05). LPS-induced TNF-alpha production was associated significantly (r = 0.59, P < .001) with anxiety in patients with IBS.

Conclusions: Patients with D-IBS display enhanced proinflammatory cytokine release, and this may be associated with symptoms and anxiety.

PMID: 17383420 [PubMed - in process]

*cytokines-a group of proteins and peptides that are used in organisms as signaling compounds