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Abstract：
BACKGROUND: Hepatic encephalopathy (HE) is a severe neuropsychiatric complication of liver diseases characterized by neuroinflammation. The efficacies of nonabsorbable rifaximin (RIF) and lactulose (LAC) have been well documented in the treatment of HE. [18F]PBR146 is a translocator protein (TSPO) radiotracer used for in vivo neuroinflammation imaging. This study investigated anti-neuroinflammation effect of RIF or/and LAC in chronic HE rats by [18F]PBR146 micro-PET/CT.
METHODS: Bile duct ligation (BDL) operation induced chronic HE models, and this study included Sham+normal saline (NS), BDL+NS, BDL+RIF, BDL+LAC, and BDL+RIF+LAC groups. Behavioral assessment was performed to analyze the motor function, and fecal samples were collected after successfully established the chronic HE model (more than 28 days post-surgery). In addition, fecal samples collection and micro-PET/CT scans were performed sequentially. And we also collected the blood plasma, liver, intestinal, and brain samples after sacrificing the rats for further biochemical and pathological analyses.
RESULTS: The RIF- and/or LAC-treated BDL rats showed similar behavioral results with Sham+NS group, while the treatment could not reverse the biliary obstruction resulting in sustained liver injury. The RIF or/and LAC treatments can inhibit IFN-γ and IL-10 productions. The global brain uptake values of [18F]PBR146 in BDL+NS group was significantly higher than other groups (p < .0001). The brain regions analysis showed that the basal ganglia, hippocampus, and cingulate cortex had radiotracer uptake differences among groups (all p < .05), which were consistent with the brain immunohistochemistry results. Sham+NS group was mainly enriched in Christensenella, Coprobacillus, and Pseudoflavonifractor. BDL+NS group was mainly enriched in Barnesiella, Alloprevotella, Enterococcus, and Enterorhabdus. BDL+RIF+LAC group was enriched in Parabacteroides, Bacteroides, Allobaculum, Bifidobacterium, and Parasutterella.
CONCLUSIONS: RIF or/and LAC had anti-neuroinflammation in BDL-induced chronic HE rats with gut microbiota alterations. The [18F]PBR146 could be used for monitoring RIF or/and LAC treatment efficacy of chronic HE rats.
METHODS: Bile duct ligation (BDL) operation induced chronic HE models, and this study included Sham+normal saline (NS), BDL+NS, BDL+RIF, BDL+LAC, and BDL+RIF+LAC groups. Behavioral assessment was performed to analyze the motor function, and fecal samples were collected after successfully established the chronic HE model (more than 28 days post-surgery). In addition, fecal samples collection and micro-PET/CT scans were performed sequentially. And we also collected the blood plasma, liver, intestinal, and brain samples after sacrificing the rats for further biochemical and pathological analyses.
RESULTS: The RIF- and/or LAC-treated BDL rats showed similar behavioral results with Sham+NS group, while the treatment could not reverse the biliary obstruction resulting in sustained liver injury. The RIF or/and LAC treatments can inhibit IFN-γ and IL-10 productions. The global brain uptake values of [18F]PBR146 in BDL+NS group was significantly higher than other groups (p < .0001). The brain regions analysis showed that the basal ganglia, hippocampus, and cingulate cortex had radiotracer uptake differences among groups (all p < .05), which were consistent with the brain immunohistochemistry results. Sham+NS group was mainly enriched in Christensenella, Coprobacillus, and Pseudoflavonifractor. BDL+NS group was mainly enriched in Barnesiella, Alloprevotella, Enterococcus, and Enterorhabdus. BDL+RIF+LAC group was enriched in Parabacteroides, Bacteroides, Allobaculum, Bifidobacterium, and Parasutterella.
CONCLUSIONS: RIF or/and LAC had anti-neuroinflammation in BDL-induced chronic HE rats with gut microbiota alterations. The [18F]PBR146 could be used for monitoring RIF or/and LAC treatment efficacy of chronic HE rats.
摘要：
背景：肝性脑病（HE）是以神经炎症为特征的肝脏疾病的严重神经精神并发症。不可吸收的利福昔明(RIF)和乳果糖(LAC)在HE的治疗中的功效已被充分证明。[18F]PBR146是用于体内神经炎症成像的转运蛋白(TSPO)放射性示踪剂。本研究通过[18F]PBR146micro-PET/CT研究了RIF或/和LAC在慢性HE大鼠中的抗神经炎症作用。
方法：胆管结扎（BDL）手术诱导的慢性HE模型，本研究包括假盐水（NS），BDL+NS,BDL+RIF,BDL+LAC,和BDL+RIF+LAC组。进行行为评估以分析运动功能，成功建立慢性HE模型（术后28天以上）后收集粪便样本。此外,依次进行粪便样本收集和微PET/CT扫描。我们还收集了血浆，肝脏,肠,以及处死大鼠后的脑样本进行进一步的生化和病理分析。
结果：RIF和/或LAC处理的BDL大鼠表现出与ShamNS组相似的行为结果，而治疗不能逆转胆道梗阻导致持续肝损伤。RIF或/和LAC治疗可抑制IFN-γ和IL-10的产生。BDL+NS组[18F]PBR146的全脑摄取值显著高于其他组(p<.0001)。脑区分析显示基底神经节,海马体,和扣带皮质具有各组之间的放射性示踪剂摄取差异（所有p<0.05），结果与脑免疫组织化学结果一致。Sham+NS组主要富含Christenella,Copropacillus,和假黄酮。BDL+NS组主要富集于Barnesiella,Alloprevotella,肠球菌,和肠衣.BDL+RIF+LAC组富含副杆菌属，拟杆菌,Allobaculum,双歧杆菌,和Parasutterilla.
结论：RIF或/和LAC在BDL诱导的具有肠道菌群改变的慢性HE大鼠中具有抗神经炎症作用。[18F]PBR146可用于监测慢性HE大鼠的RIF或/和LAC治疗功效。
方法：胆管结扎（BDL）手术诱导的慢性HE模型，本研究包括假盐水（NS），BDL+NS,BDL+RIF,BDL+LAC,和BDL+RIF+LAC组。进行行为评估以分析运动功能，成功建立慢性HE模型（术后28天以上）后收集粪便样本。此外,依次进行粪便样本收集和微PET/CT扫描。我们还收集了血浆，肝脏,肠,以及处死大鼠后的脑样本进行进一步的生化和病理分析。
结果：RIF和/或LAC处理的BDL大鼠表现出与ShamNS组相似的行为结果，而治疗不能逆转胆道梗阻导致持续肝损伤。RIF或/和LAC治疗可抑制IFN-γ和IL-10的产生。BDL+NS组[18F]PBR146的全脑摄取值显著高于其他组(p<.0001)。脑区分析显示基底神经节,海马体,和扣带皮质具有各组之间的放射性示踪剂摄取差异（所有p<0.05），结果与脑免疫组织化学结果一致。Sham+NS组主要富含Christenella,Copropacillus,和假黄酮。BDL+NS组主要富集于Barnesiella,Alloprevotella,肠球菌,和肠衣.BDL+RIF+LAC组富含副杆菌属，拟杆菌,Allobaculum,双歧杆菌,和Parasutterilla.
结论：RIF或/和LAC在BDL诱导的具有肠道菌群改变的慢性HE大鼠中具有抗神经炎症作用。[18F]PBR146可用于监测慢性HE大鼠的RIF或/和LAC治疗功效。
