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Background and aims: We have previously reported that LPS or intestinal manipulation (IM) causes ileus by initiating a molecular and cellular inflammatory response within the intestinal muscularis. Intraperitoneally administered LPS directly activates the resident macrophages of the muscularis through Toll-Like Receptor (TLR)-4. The mechanism, by which IM leads to the activation of resident macrophages, is unkown. Beside direct mechanical stretch activation, IM could provoke a direct translocation of bacterial products from the gut lumen to the muscularis or to the mesenterial lymph nodes. C3H/HeJ mice carry a TLR-4 receptor mutation, that makes them hyporesponsive to LPS compared to C3H/HeN wild-type mice. The aim of our study was to examine the inflammatory response after intraperitoneally administered LPS or IM within the muscularis and within the mesenterial lymphnodes. Methods: Gastrointestinal motility was measured in vivo by transit and in vitro by organ bath techniques. Cytokine mRNA expression was quantified within the muscularis and within mesenterial lymphnodes by real time PCR in both mouse strains. Leukocyte recruitment into the muscularis was detected by myeloperoxidase histochemistry and activation of resident macrophages was detected by immunohistochemistry. Results: After LPS the inflammatory response within the muscularis, the decrease in smooth muscle cell contractility and the inflammatory response within the mesenterial lymphnodes was blunted in C3H/HeJ mice compared to wild-typ mice. In contrast the inflammatory response within the muscularis and the reduction of contractility was not blunted in C3H/HeJ mice after IM. The inflammtory response within the mesenterial lymphnodes was blunted after IM in C3H/HeJ mice. Discussion: IM does not lead to a direct translocation of LPS from the gut lumen into the muscularis but is followed by translocation of LPS to the lymphatic tissue. Inflammatory mediators or bacterial products can thus gain access to the systemic circulation.