The immune system in vertebrates senses exogenous and endogenous danger signals by way of complex cellular and humoral processes, and responds with an inflammatory reaction to combat putative attacks. A strong protective immunity is imperative to prevent invasion of pathogens; however, equivalent responses to commensal flora and dietary components in the intestine have to be avoided. The autonomic nervous system plays an important role in sensing luminal contents in the gut by way of hard-wired connections and chemical messengers, such as cholecystokinin (CCK). Here, we report that ingestion of dietary fat stimulates CCK receptors, and leads to attenuation of the inflammatory response by way of the efferent vagus nerve and nicotinic receptors. Vagotomy and administration of antagonists for CCK and nicotinic receptors significantly blunted the inhibitory effect of high-fat enteral nutrition on hemorrhagic shock-induced tumor necrosis factor-α and interleukin-6 release (P < 0.05). Furthermore, the protective effect of high-fat enteral nutrition on inflammation-induced intestinal permeability was abrogated by vagotomy and administration of antagonists for CCK and nicotinic receptors. These data reveal a novel neuroimmunologic pathway, controlled by nutrition, that may help to explain the intestinal hyporesponsiveness to dietary antigens, and shed new light on the functionality of nutrition.

Obesity is demonstrated to be associated with an enhanced inflammatory state, which is suggested to be a cause for the development of obesity-related morbidity. It was hypothesized that a decrease in body weight in morbid obese subjects would lead to a reduction of the inflammatory state in these subjects.Weight loss was achieved by gastric restrictive surgery in 27 morbidly obese patients. Preoperative as well as 3-, 6-, 12-, and 24-month postoperative plasma concentrations of inflammatory mediators macrophage inhibitory factor, plasminogen activator inhibitor-1, lipopolysaccharide binding protein, ␣-1 acid glycoprotein, C-reactive protein, soluble TNF␣ receptors 55 and 75, and leptin were measured.Macrophage inhibitory factor levels remained low normal for 6 months, during weight loss, after which they significantly increased to normal levels at 24 months postoperatively. The other inflammatory mediators remained elevated up to minimally 3 months postoperatively; thereafter they decreased significantly. Both TNF␣ receptors remained elevated up to at least 12 months postoperatively to decrease significantly at 2 yr postoperatively.This study demonstrates that during weight loss, after gastric restrictive surgery, inflammatory mediators remain elevated for at least 3 months postoperatively, suggesting initially an ongoing inflammatory state. However, 2 yr after surgery, the inflammatory mediators reach near normal values.These findings may be an explanation for the reduced comorbidity seen in morbidly obese patients after gastric restrictive surgery. (J Clin Endocrinol Metab 89: [4062][4063][4064][4065][4066][4067][4068] 2004)

Gram-negative sepsis is a potentially fatal clinical syndrome characterized by a proinflammatory response (tumor necrosis factor-alpha) to bacterial (endo)toxins and gut barrier function loss. Recently, we found that high-fat enteral nutrition protects against late bacterial translocation in a model of hemorrhagic shock in rats. However, the basis for this protection is unknown. We hypothesized that the observed protection is the result of an early inhibition of endotoxin and the subsequent inflammatory response resulting in a preserved gut barrier function. Sprague-Dawley rats were divided into a group that was starved overnight (HS-S), fed with a low-fat enteral diet (HS-LF) or fed wih a high-fat enteral diet (HS-HF), and subsequently subjected to a nonlethal hemorrhagic shock. Ninety minutes after hemorrhage, arterial endotoxin significantly decreased in HS-HF rats (4.0 +/- 0.6 pg/mL) compared with HS-LF rats (10.7 +/- 0.9 pg/mL, P = 0.002) and HS-S rats (15.2 +/- 2.2 pg/mL P = 0.001). Interestingly, arterial tumor necrosis factor-alpha was also decreased in HS-HF rats (17.9 +/- 10.4 pg/mL) compared with HS-LF (83.5 +/- 16.7 pg/mL, P < 0.01) and HS-S rats (180.9 +/- 67.9 pg/mL, P < 0.02). Loss of tight junction structure (ZO-1) observed in ileum and colon of control hemorrhagic shock rats was prevented in HS-HF rats. In parallel, intestinal barrier function was preserved in HS-HF rats, evidenced by a reduced permeability to horseradish peroxidase (P < 0.05), less bacterial invasion, and a 10-fold reduction of bacterial translocation early after hemorrhagic shock. This report describes a new strategy to nutritionally prevent endotoxemia, the subsequent inflammatory response and gut barrier failure following hemorrhagic shock. High-fat enteral nutrition requires further evaluation as an intervention to prevent a potentially fatal systemic inflammatory response in patients at risk for sepsis.

Probiotic therapy modulates the composition of the intestinal flora and inhibits the inflammatory response. These properties may be of benefit in the preservation of gut barrier integrity after injury or stress. In this study, we examined the effect of two Lactobacillus strains selected for their pathogen exclusion properties on intestinal barrier integrity following hemorrhagic shock. Additionally, the responsiveness of the macrophage cell line RAW 264.7 to combined exposure to Lactobacillus DNA or oligodeoxynucleotides containing CpG motifs (CpG-ODN) and endotoxin was assessed by measuring tumor necrosis factor alpha (TNF-␣) release. Rats were administered lactobacilli (5 ؋ 10 9 CFU) or vehicle for 7 days and were subjected subsequently to hemorrhagic shock by withdrawal of 2.1 ml blood/100 g tissue. Levels of plasma endotoxin, bacterial translocation to distant organs, and filamentous actin (F-actin) in the ileum were determined 24 h later. Rats treated with Lactobacillus rhamnosus showed reduced levels of plasma endotoxin (8 ؎ 2 pg/ml versus 24 ؎ 4 pg/ml; P ‫؍‬ 0.01), bacterial translocation (2 CFU/gram versus 369 CFU/gram; P < 0.01), and disruption of F-actin distribution following hemorrhagic shock compared with nontreated control rats. In contrast, pretreatment with Lactobacillus fermentum had no substantial effect on gut barrier integrity. Interestingly, DNA preparations from both lactobacilli reduced endotoxin-induced TNF-␣ release dose dependently, whereas CpG-ODN increased TNF-␣ release. In conclusion, the pathogen exclusion properties of both Lactobacillus strains and the reduction of endotoxin-induced inflammation by their DNA in vitro are not prerequisites for a beneficial effect of probiotic therapy on gut barrier function following hemorrhagic shock. Although pretreatment with Lactobacillus spp. may be useful to preserve gut barrier integrity following severe hypotension, a thorough assessment of specific strains seems to be essential.

An unassigned and prominent resonance in the region from delta 2.0-2.1 ppm has frequently been found in the in vivo MR spectra of cancer patients. We demonstrated the presence of this resonance with in vivo MRS in the cyst fluid of a patient with an ovarian tumor. (1)H-NMRS on the aspirated cyst fluid of this patient confirmed the observation. A complex of resonances was observed between 2.0 and 2.1 ppm. It was also present in 11 additional ovarian cyst fluid samples randomly chosen from our biobank. The resonance complex was significantly more prominent in samples from mucinous tumors than in samples from other histological subtypes. A macromolecule (>10 kDa) was found responsible for this complex of resonances. A correlation spectroscopy (COSY) experiment revealed cross peaks of two different types of bound sialic acid suggesting that N-glycans from glycoproteins and/or glycolipids cause this resonance complex. In the literature, plasma alpha-1 acid glycoprotein (AGP), known for its high content of N-linked glycans, has been suggested to contribute to the delta 2.0-2.1 spectral region. The AGP cyst fluid concentration did not correlate significantly with the peak height of the delta 2.0-2.1 resonance complex in our study. AGP may be partly responsible for the resonance complex but other N-acetylated glycoproteins and/or glycolipids also contribute. After deproteinization of the cyst fluid, N-acetyl-L-aspartic acid (NAA) was found to contribute significantly to the signal in this spectral region in three of the 12 samples. GC-MS independently confirmed the presence of NAA in high concentration in the three samples, which all derived from benign serous tumors. We conclude that both NAA and N-acetyl groups from glycoproteins and/or glycolipids may contribute to the delta 2.0-2.1 ppm resonance complex in ovarian cyst fluid. This spectral region seems to contain resonances from biomarkers that provide relevant clinical information on the type of ovarian tumor.