The intestinal anastomotic failure is one of the most severe complications in gastrointestinal surgery. Despite the great surgical improvements during the last decade, anastomotic leak rates remain practically the same, with a dramatically high grade of morbidity for patients. Leakages are usually the final consequence of ischemia in the anastomosis, leading to tissue hypoxia. In response to hypoxia, the cell orchestrates a variety of coordinated responses in order to restore oxygen homeostasis. The molecular mechanism of hypoxia sensitivity involves oxygen sensing hydroxylases, prolyl-hydroxylases, orchestrating two main transcription factors related to induction of inflammation and angiogenesis, namely nuclear factor-κB and hypoxia-inducible factors. The immunohistochemical expression of two transcription factors hypoxia-inducible factors-1α and nuclear factor-κB p65 has already been described in several disorders, including wound healing, asthma and chronic obstructive lung disease, rheumatoid arthritis, cancer, inflammatory bowel disease, and acute colitis. In the surgical field, fibrin sealants have been widely used to prevent leaks in lung surgery and they might also be useful as a reinforcement of sutures in intestinal anastomosis. The commercial fibrin sealant patches are hemostatic and adhesive surgical agents mainly derived from human plasma. We herein report the results of a prospective randomized experimental study on pigs. We performed a high-risk leakage model of bowel anastomosis, causing a significant devascularization of 10-15 cm of the bowel wall before performing a conventional colo-ileal anastomosis. We randomized the animals to receive a covering of the anastomosis with a fibrin patch (case group) or not (control group). We report the changes in the immunohistochemical expression of the proteins involved in tissue response to hypoxia in the experimental model. Our results indicate that the fibrin patch delays the healing response, promoting a longer lasting inflammation in the surgical bed. Nevertheless, the fibrin patches effectiveness to reduce dehiscence shown in clinical practice suggests that this delay does not negatively affect patients' outcome. Impact statement The consequences of the anastomotic failure are dramatic for patients. Understanding how the ever-increasing use of fibrin sealant, that seems to have a beneficial effect on the anastomoses, interacts with the tissue and the healing process can help to justify its use and encourage research on how to improve this effect even more. We feel that the present work shows that the patch can improve healing by complex mechanisms other than the mere contention and physical support of the intestine. Furthermore, research is needed to confirm our preliminary findings.