Insulin-like Growth Factor–1 Levels Contribute to the Development of Bacterial Translocation in Sepsis

Abstract

Rationale: Many lines of evidence point toward the gastrointestinal (GI) tract in the pathophysiology of organ dysfunction in sepsis. Splanchnic hypoperfusion during sepsis leads to enterocyte apoptosis, diminished barrier function, and release of bacterial products. Sepsis lowers levels of insulin-like growth factor (IGF)-1, a known antiapoptotic factor. We recently demonstrated that treatment with IGF-1 is protective in murine sepsis. Objectives: We hypothesize that decreased IGF-1 levels in sepsis contributes to the development of bacterial translocation. Methods: Sepsis was induced in C57BL/6 mice via intratracheal instillation of Pseudomonas aeruginosa. Human subjects with sepsis were enrolled if they had a documented positive blood culture with a nonenteric organism. Bacterial translocation was measured in serum by quantitative real-time polymerase chain reaction with primers specific for enteric bacteria. Serum IGF-1 was measured by ELISA. Apoptosis of the GI epithelium was assessed via immunohistochemistry. Measurements and Main Results:We found that mice with severe sepsis had evidence of bacterial translocation by 24 hours. Enteric bacterial load correlated inversely with levels of serum IGF-1. If we treated mice with IGF-1, bacterial translocation was significantly decreased. In addition, we found increased GI epithelial cell apoptosis after sepsis, which was significantly decreased after IGF-1 treatment. Human subjects with nonenteric sepsis developed progressive enteric bacteremia over 3 days. The degree of enteric bacteremia correlated inversely with serum IGF-1 levels. Conclusions: These data support the hypothesis that sepsis-induced reductions in IGF-1 levels contribute to the development of bacterial translocation in both a murine model and human subjects.

Toll-Like Receptor Stimulation Induces Nondefensin Protein Expression and Reverses Antibiotic-Induced Gut Defense Impairment

“…The number of specific bacterial groups was determined by using a StepOnePlus real-time PCR system (Applied Biosystems 7300). The sequences of specific bacterial primers were as previously published (14).…”

Protective effects of growth hormone on bacterial translocation and intestinal damage in rats with partial intestinal obstruction

“…IGF-1 can prevent intestinal atrophy in septic rats and protect the integrity of intestinal structure (11,12,13,18,21). Gary et al reported that the development of bacterial translocation is inversely correlated with serum IGF-1 levels and treatment with IGF-1 decreased enterocyte apoptosis (19). Thus, GH improves the impairment of the intestinal mucosa and maintains the structure and function of the intestinal mucosal barrier (12)(13)(14)20).…”

The Understanding and Management of Organism Toxicity in Septic Shock

“…Reduced levels of IGF were previously demonstrated in patients with sepsis [64]. Additionally, a decline in IGF1 level was inversely correlated with the degree of bacterial translocation across the gastrointestinal epithelium in patients with gram-positive sepsis [63]. …”

“…Drugs associated with intestinal barrier protection, antiapoptotic properties, and/or protection against increases in intestinal permeability, such as IL-11 [62] and insulin-like growth factor (IGF) [63], have been analyzed in preclinical studies. Reduced levels of IGF were previously demonstrated in patients with sepsis [64].…”