OBJECTIVE: In a murine model of intestinal injury, we hypothesized that Toll-like receptor 2 (TLR2), a recognition molecule for commensal bacteria, plays an important role in the development of mucosal immunity and is protective against ischemia/reperfusion injury via the modulation of both innate and acquired immunity. DESIGN: Interventional laboratory study. SETTING: Academic medical research center. SUBJECTS: Four-week-old C57BL/6 wild-type (n = 12) and C57BL/6 TLR2-deficient mice (TLR2) (n = 12). INTERVENTIONS: Twenty-four mice underwent laparotomy only or laparotomy plus superior mesenteric artery occlusion (n = 6/group) for 60 mins, followed by 90 mins of recovery. MEASUREMENTS AND MAIN RESULTS: Mid-jejunal sections were taken for histopathology and messenger RNA expression (reverse transcriptase-polymerase chain reaction, normalized to 18s and laparotomy-only controls). Intestinal injury was scored from 0 (no injury) to 4 (transmural necrosis). Statistical analyses were performed using Mann-Whitney U test and Student's t-test (p < .05 significant). TLR2 mice had elevated intestinal injury scores (mean ± sem) after ischemia/reperfusion vs. wild-type (2.17 ± 0.40 vs. 0.67 ± 0.33, p < .05). Intestinal cytokine messenger RNA (mean fold change ± sem) of interferon-γ (0.29 ± 0.12 vs. 3313 ± 1710), interleukin-4 (0.25 ± 0.13 vs. 2.70 ± 1.08), and interleukin-6 (250.63 ± 69.60 vs. 320,300 ± 215,964) in TLR2 was significantly decreased (p < .05) after ischemia/reperfusion vs. wild-type. Tumor necrosis factor-α messenger RNA levels were unchanged. CONCLUSIONS: TLR2 mice have a dysregulated mucosal innate immune response and fail to mount a protective response after ischemia-reperfusion compared with wild-type mice. This murine model of intestinal injury may correlate with the early postnatal course of premature infants who may have decreased TLR2 expression and/or decreased luminal commensal bacteria secondary to antibiotic therapy, thus decreasing TLR2-mediated signaling. ©2008The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.