P2Y12 pharmacological blockade in platelets prevents intestinal damage and preserves the intestinal barrier in intra-abdominal sepsis

The intestine is a multifunctional organ for food digestion and maintaining body homeostasis. The intestinal barrier protects the tissue against invading pathogens and their toxins. If the intestine is infected, the body can develop a gastrointestinal disease, such as intra-abdominal sepsis. The subsequent inflammation can exacerbate and, as a result, compromise the intestinal barrier. Platelets are important mediators of inflammation, and antiplatelet therapy is a promising treatment option for septic patients. We previously observed a sex-dependent reduction in bacterial and cytokine levels with the antiplatelet therapy, Ticagrelor (P2Y12 blocker), in the peritoneal cavity (PC) of septic mice. In addition, Ticagrelor significantly reduced platelet factor 4 levels in the small intestines of male and female septic mice. Hence, antiplatelet therapy reduced inflammation and decreased platelet recruitment to the PC in sepsis, but the role of platelets in the intestinal tissue is still unclear. We now aim to understand whether activation of platelets in the intestines of male and female mice will affect gut inflammation and intestinal barrier functions in intra-abdominal sepsis. We hypothesized that blocking the P2Y12 purinergic receptor modulates platelet activation to restore and preserve intestinal barrier functions in a sex dependent manner. We induced sepsis in C57BL/6J male and female mice by cecal ligation and puncture (CLP) with sham surgery as control. Next, we administered Ticagrelor (30 mg/kg) intraperitoneally after surgery to block platelet secretion. We harvested the ileum 24 hours after surgery and evaluated cytokine release and intestinal apoptosis using the IP-10 ELISA kit and the Click-iT TUNEL assay, respectively. Additionally, we assessed intestinal barrier functions using the in vivo Fluorescein isothiocyanate (FITC) conjugated dextran intestinal permeability assay. We observed an increase in IP-10 levels in the intestine of both septic males and females. A trend towards a decrease was noted in IP10 levels in the male-treated group only. FITC dextran permeability was increased in CLP compared to the sham control as expected. A trend towards a decrease was noted upon treatment with Ticagrelor in both male and female septic mice. Interestingly, intestinal apoptosis was markedly reduced in mice exposed to Ticagrelor (30 mg/kg) in both sexes. These data suggest the potential benefit of Ticagrelor as a localized therapeutic strategy in preserving intestinal barrier functions in both sexes. Overall, antiplatelet therapy appears to prevent intestinal damage and preserve the intestinal barrier in both sexes, highlighting its promising prospects as a therapeutic option in intra-abdominal sepsis. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.