Membrane TLR Signaling Mechanisms in the Gastrointestinal Tract During Sepsis

Our bacterial residents are deadly Janus-faced indwellers that can lead to a sepsis-induced systemic inflammatory response syndrome and multiple organ failure. Over half of ICU patients suffer from infections and sepsis remains one of the top 10 causes of death worldwide. Severe ileus frequently accompanies sepsis setting up an insidious cycle of gut-derived microbial translocation and the copious intestinal production of potent systemic inflammatory mediators. Few therapeutic advances have occurred to prevent/treat the sequelae of sepsis. Here, we selectively review studies on cellular membrane-bound Toll-like receptor (TLR) mechanisms of ileus. Virtually, no data exist on Gram-positive/TLR2 signaling mechanisms of ileus; however, TLR2 is highly inducible by numerous inflammatory mediators and studies using clinically relevant scenarios of Gram-positive sepsis are needed. Specific Gram-negative/TLR4 signaling pathways are being elucidated using a 'reverse engineering' approach, which has revealed that endotoxin-induced ileus is dually mediated by classical leukocyte signaling and by a MyD88-dependent non-bone marrow-derived mechanism, but the specific roles of individual cell populations are still unknown. Like TLR2, little is also know of the role of flagellin/TLR5 signaling in ileus. But, much can be learned by understanding TLR signaling in other systems. Clearly, the use of polymicrobial models provides important clinical relevancy, but the simultaneous activation of virtually all pattern recognition receptors makes it impossible to discretely study specific pathways. We believe that the dissection of individual TLR pathways within the gastrointestinal tract, which can then be intelligently reassembled in a meaningful manner, will provide insight into treatments for sepsis.