Gut injury is a pivotal initiating event in the dysfunctional inflammatory response that causes postinjury multiple organ failure. Heme oxygenase-1 (HO-1) is an important enzyme that provides cellular protection against oxidative stress in different in vitro and in vivo systems. In this study, we evaluated the protective effects of intragastrically administered live Lactococcus lactis secreting bioactive HO-1 to treat intestinal mucosal injury induced by lipopolysaccharide in rats. Intragastric administration with this recombinant L. lactis strain led to active delivery of HO-1 at the mucosa and significantly decreased morbidity and mortality of lipopolysaccharide -induced endotoxemia as confirmed by blinded macroscopic and microscopic inflammatory scores (Chiu's grade), myeloperoxidase activity, mortality, and tumor necrosis factor-alpha and IL-10 cytokine stimulation. This protective effect could be abolished by an HO-1 inhibitor, the zinc protoporphyrin-IX. Our results suggest that a food-grade bacterium genetically modified to deliver bioactive HO-1 in situ exerts a protective effect against intestinal mucosal injury in rats with endotoxemia via modulation of the immune system. This novel approach may be beneficial for the maintenance of the intestinal barrier and anti-inflammatory response of the lower intestine.