Granisetron Alleviates Sepsis-Induced Intestinal Injury via Microbiota-Dependent Modulation of the Tryptophan-Quinolinic Acid-AhR Axis

Zhaojin Zeng,1,* Xinlei He,1,* Xiao Cui,1 Abudureyimujiang Aili,2 Haoyue Li,1 Xueqi Li,3 Zongfeng Zhang,4 Xi Zhu,1 Zhaoxing Tian,3 Yuxin Leng1,51Department of Intensive Care Unit, Peking University Third Hospital, Beijing, People’s Republic of China; 2Department of Medical Oncology and Radiation Sickness, Peking University Third Hospital, Beijing, People’s Republic of China; 3Department of Emergency Medicine, Beijing Jishuitan Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Department of Nutrition and Food Hygiene, School of Public Health, Peking University/Beijing Key Laboratory of Food Safety Toxicology and Risk Assessment, Beijing, People’s Republic of China; 5Beijing Key Laboratory of Digital and Intelligent Emergency Treatment Core Technologies for Public Emergencies, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuxin Leng; Zhaoxing Tian, Email lengyx@bjmu.edu.cn; tjtzx@126.comBackground: Sepsis-induced intestinal injury, driven by sepsis-triggered systemic inflammation, is characterized by leaky gut, which induces/aggravates multi-organ failure. Promoting gut health is vital to improve the prognosis of sepsis. Previous studies indicated that transplantation of gut microbiota enriched with granisetron (GA) - a 5-hydroxytryptamine receptor 3 antagonist located downstream of tryptophan (Trp) metabolism - significantly alleviated hepatic injury in septic models. This study aimed to investigate whether GA ameliorates sepsis-induced intestinal injury and to elucidate the underlying microbiota-metabolite-host interactions.Methods: We established sepsis models by intraperitoneal Lipopolysaccharides (LPS) injection in conventional and antibiotic-treated (ABX) male C57BL/6 mice, with GA intervention. Hematoxylin-eosin (HE) staining and enzyme-linked immunosorbent assay (ELISA) were performed to assess intestinal injury and inflammation. We then employed multi-omics analyses to assess the effects of GA on gut microbial composition and Trp metabolic flux. Metabolite changes were mapped to host injury indices through correlation analysis, and the microbial source of a beneficial metabolite was identified via MetOrigin. The implicated aryl hydrocarbon receptor (AhR) pathway and its downstream signaling were further verified in vitro.Results: GA administration significantly alleviated intestinal injury in septic mice by remodeling the gut microbiota and modulating Trp metabolism, leading to increased levels of quinolinic acid (QA). QA was shown to activate the AhR pathway, which subsequently stimulated the Wnt/β-catenin signaling pathway, thereby reinforcing intestinal barrier integrity. Probiotic strains such as Lactobacillus johnsonii, capable of producing high levels of QA, were identified as contributors to this protective effect.Conclusion: The study identifies a novel GA‑driven axis involving gut microbiota remodeling and metabolic reprogramming that mitigates sepsis‑induced intestinal injury. Specifically, granisetron alleviates sepsis‑induced intestinal injury via microbiota‑dependent modulation of the tryptophan‑quinolinic acid‑AhR axis. These findings underscore the therapeutic potential of targeting specific microbiota‑host metabolic interactions to improve sepsis management.Keywords: sepsis, intestinal injury, gut microbiota, tryptophan metabolism, granisetron, quinolinic acid