Lactobacillus Amplifies DHA-MaR1 Conversion to Attenuate Intestinal Ischemia-Reperfusion Injury via RORalpha-induced Pyroptosis

This study aims to address the unmet therapeutic challenge of intestinal ischemia/reperfusion (I/R) injury, an acute, life-threatening condition characterized by mucosal barrier disruption, inflammatory overactivation, and high mortality. Current supportive therapies and single-target pharmacological interventions offer limited efficacy due to the interconnected nature of its pathological mechanisms. Given that pyroptosis, a pro-inflammatory programmed cell death pathway, is a key driver of intestinal I/R injury, and that maresin 1 (MaR1), a pro-resolving lipid mediator synthesized from docosahexaenoic acid (DHA) via LOX12 catalysis, has demonstrated anti-inflammatory and tissue-protective effects in other contexts, this work focuses on exploring the protective role and underlying mechanisms of MaR1 and DHA in intestinal I/R injury. Specifically, we investigate how MaR1, regulated by retinoic acid receptor-related orphan receptor alpha (RORalpha), suppresses intestinal epithelial pyroptosis, and how Lactobacillus enhances the conversion of DHA to MaR1 to reinforce epithelial protection. By elucidating the novel "microbiota-MaR1-RORalpha-epithelium" regulatory axis, this study advances understanding of MaR1's endogenous protective functions in intestinal epithelial cells and highlights the translational potential of combining nutritional (DHA) and probiotic (Lactobacillus) interventions. Ultimately, these findings aim to provide a multimodal therapeutic strategy to mitigate intestinal I/R injury and improve patient outcomes, filling a critical gap in current treatment paradigms.