The intestine is home to one of the most diverse and populous ecosystems on earth. The intestinal epithelium the single layer sheet of columnar cells that provides key functions to maintain homeostasis including nutrient absorption and metabolism, innate immune system toning and the sampling of luminal contents. One of the most important roles of the epithelium is to provide a physical barrier between the host and gut microbes. Intestinal epithelial cells (IECs) are stitched together by tight junctions that maintain the architecture of the epithelial sheet and prevent uncontrolled access of luminal content to the underlying immune system compartments and the blood stream. Intestinal ischemia/reperfusion (I/R) compromises the integrity of this structure potentially leading to sepsis and multi-organ dysfunction. The epithelium experiences steady-state regeneration through migration and proliferation of IECs from the base of the intestinal crypts to tips of the villi. Microbial signals through pattern-recognition receptors foster this enterprise. Herein, I discuss my insights into the contributions of microbial signals to the host response to intestinal I/R-induced injury. I demonstrate the deleterious role of TLR adapter, MyD88, and protective role of the intracellular microbial receptor, NOD2. Then, I discuss plausible mechanisms by which these two signaling proteins yield such contrasting effects on injury.