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Background  The small intestine plays a crucial role in the pathophysiology of sepsis and has been referred to as the “motor” of the systemic inflammatory response. One proposed mechanism is that toxic gut-derived lipid factors, transported in mesenteric lymph, induce systemic injury and distant organ failure. However, the pathways involved are yet to be defined and the role of intestinal chylomicron assembly and secretion in transporting these lipid factors is unknown. Here we studied the outcome of sepsis in mice with conditional, intestine-specific deletion of microsomal triglyceride transfer protein ( Mttp-IKO ), which exhibit a block in chylomicron assembly together with lipid malabsorption.    Methodology/Principal Findings    Mttp-IKO  mice and controls underwent intratracheal injection with either  Pseudomonas aeruginosa  or sterile saline.  Mttp-IKO  mice exhibited decreased seven-day mortality, with 0/20 (0%) dying compared to 5/17 (29%) control mice (p<0.05). This survival advantage in  Mttp-IKO  mice, however, was not associated with improvements in pulmonary bacterial clearance or neutrophil infiltration. Rather,  Mttp-IKO  mice exhibited protection against sepsis-associated decreases in villus length and intestinal proliferation and were also protected against increased intestinal apoptosis, both central features in control septic mice. Serum IL-6 levels, a major predictor of mortality in human and mouse models of sepsis, were elevated 8-fold in septic control mice but remained unaltered in septic  Mttp-IKO  mice. Serum high density lipoprotein (HDL) levels were reduced in septic control mice but were increased in septic  Mttp-IKO  mice. The decreased levels of HDL were associated with decreased hepatic expression of apolipoprotein A1 in septic control mice.    Conclusions/Significance  These studies suggest that strategies directed at blocking intestinal chylomicron secretion may attenuate the progression and improve the outcome of sepsis through effects mediated by metabolic and physiological adaptations in both intestinal and hepatic lipid flux.

plos one

Intestine-Specific Mttp Deletion Decreases Mortality and Prevents Sepsis-Induced Intestinal Injury in a Murine Model of Pseudomonas aeruginosa Pneumonia