Research Projects

Intestinal anastomotic leakage, characterized by the release of non-sterile fluids and bacterial contents into the abdominal cavity, continues to be one of the most feared postoperative complications of abdominal surgery. The reported incidence and mortality rates vary depending on the site and patient condition, with incidence ranging from 4% to 21%, and mortality rates reaching up to 27%. Existing surgical sealants generally perform poorly in addressing this issue, primarily because commonly used fibrin glues often fail due to inadequate adhesion and chemical instability. Although numerous biomaterials-based and synthetic polymer-based adhesives were developed, they could not make into the clinics due to inadequate wet-tissue adhesion. Therefore, on the contrary to all the approaches so far have taken, we are proposing an innovate solution to prevent anastomosis leaks and promote accelerated gut healing. Here, we propose to develop small molecules to stimulate intestinal (stem) cells to promote gut regeneration to prevent postoperative anastomosis leaks. Earlier, we have developed gut microbial metabolite, urolithin A-based analogues (UAS-03 or ARTX-2) to overexpress tight junction proteins (TJPs) to promote gut healing which has shown therapeutic benefit in the treatment of inflammatory bowel diseases (Nat. Commun. 2019, 10, 89). With this proof-of-concept, we hypothesize that stimulation of intestinal (stem) cells and overexpressing TJPs to promote gut regeneration will prevent anastomosis leaks and accelerate postoperative recovery. Therefore, we propose four objectives in this proposal, Objective-1) To determine the mechanisms of action for urolithin analogues (ARTX-2 and ARTX-413) mediated AhR-Cyp1-Nrf2 activation in gut barrier function, in vitro, Objective-2) To demonstrate the therapeutic efficacy of urolithin-analogues to prevent anastomosis leaks, and promote postoperative recovery, in vivo, Objective-3) To perform spatial transcriptomic profiling of urolithin-analogue-treated intestinal tissue to elucidate cellular dynamics and molecular mechanisms underpinning therapeutic efficacy, and Objective-4) To evaluate the potential of urolithin-analogues in suppressing platelet activation and thrombosis through redox modulating mechanism IMPACT: The execution and completion of this proposed project will enable to develop a potential prophylactic modality to prevent anastomosis leaks, which will have enormous impact on healthcare. Thus far, entire field was focusing on only developing better tissue adhesives to prevent anastomosis leaks, however, no attempt has been made to explore promoting the gut regeneration as therapeutic strategy to prevent anastomosis leaks. Therefore, execution of this proposal will establish a new paradigm in treating the anastomosis leaks and promoting postoperative recovery. Additionally, we have an industry partner, who can immediately initiate investigative new drug (IND) enabling studies for these analogues to take them into the clinic. Currently, this project is at TRL-1 stage, at the end of the project execution it will reach to TRL-4.