肠道微生物群和肠肝器官之间的平衡相互作用对于胆汁酸稳态以及正常的胃肠道功能至关重要。癌症治疗破坏这些相互作用会导致胆汁酸吸收不良，导致治疗延迟、营养不良和生活质量下降。然而，化疗引起的胆汁酸吸收不良的性质仍然不清楚，治疗选择有限。因此，本研究试图表征化疗引起的毒性小鼠模型中肝脏、肠道和微生物胆汁酸代谢的变化。与临床胆汁酸吸收不良一致，化疗增加了初级胆汁酸和水的粪便排泄，同时减少了微生物组多样性、次级胆汁酸形成和小肠胆汁酸信号传导。我们发现了胆汁酸吸收不良病理学的新贡献者，其形式为脂多糖诱导的胆汁淤积和次级胆汁酸信号传导减少导致的结肠隐窝增生。化疗减少了肝胆汁流量和胆汁酸合成的标志物，升高了纤维化和内毒素血症的标志物，并改变了胆汁酸代谢各个阶段的基因转录。暴露于脂多糖（但不是化疗）的原代肝细胞复制了化疗引起的转录差异，而肠道微生物移植到无菌小鼠体内则复制了很少的差异。在结肠中，化疗改变的胆汁酸谱（特别是较高的牛磺胆酸和较低的猪去氧胆酸）与隐窝增生一致。将原代类集落暴露于猪去氧胆酸会减少增殖，而肠道微生物群移植则会增强增殖。总之，这些研究揭示了整个微生物群-肠肝轴在化疗引起的胆汁酸吸收不良中的复杂参与。减少肝脏脂多糖暴露和增强微生物胆汁酸代谢的干预措施代表了有希望的癌症治疗联合疗法。

Balanced interactions between the enteric microbiota and enterohepatic organs are essential to bile acid homeostasis, and thus normal gastrointestinal function. Disruption of these interactions by cancer treatment instigates bile acid malabsorption, leading to treatment delays, malnutrition, and decreased quality of life. However, the nature of chemotherapy-induced bile acid malabsorption remains poorly characterized with limited treatment options. Therefore, this study sought to characterize changes in hepatic, enteric, and microbial bile acid metabolism in a mouse model of chemotherapy-induced toxicity. Consistent with clinical bile acid malabsorption, chemotherapy increased fecal excretion of primary bile acids and water, while diminishing microbiome diversity, secondary bile acid formation, and small intestinal bile acid signaling. We identified new contributors to pathology of bile acid malabsorption in the forms of lipopolysaccharide-induced cholestasis and colonic crypt hyperplasia from reduced secondary bile acid signaling. Chemotherapy reduced markers of hepatic bile flow and bile acid synthesis, elevated markers of fibrosis and endotoxemia, and altered transcription of genes at all stages of bile acid metabolism. Primary hepatocytes exposed to lipopolysaccharide (but not chemotherapy) replicated chemotherapy-induced transcriptional differences, while gut microbial transplant into germ-free mice replicated very few differences. In the colon, chemotherapy-altered bile acid profiles (particularly higher tauromuricholic acid and lower hyodeoxycholic acid) coincided with crypt hyperplasia. Exposing primary colonoids to hyodeoxycholic acid reduced proliferation, while gut microbiota transplant enhanced proliferation. Together, these investigations reveal complex involvement of the entire microbiota-enterohepatic axis in chemotherapy-induced bile acid malabsorption. Interventions to reduce hepatic lipopolysaccharide exposure and enhance microbial bile acid metabolism represent promising co-therapies to cancer treatment.