Kang Dae Joong, Betrapally Naga S, Ghosh Siddhartha A, Sartor R Balfour, Hylemon Phillip B, Gillevet Patrick M, Sanyal Arun J, Heuman Douglas M, Carl Daniel, Zhou Huiping, Liu Runping, Wang Xiang, Yang Jing, Jiao Chunhua, Herzog Jeremy, Lippman H Robert, Sikaroodi Masoumeh, Brown Robert R, Bajaj Jasmohan S
Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA.
Microbiome Analysis Center, George Mason University, Manassas, VA.
Hepatology. 2016 Oct;64(4):1232-48. doi: 10.1002/hep.28696. Epub 2016 Jul 29.
The mechanisms behind the development of hepatic encephalopathy (HE) are unclear, although hyperammonemia and systemic inflammation through gut dysbiosis have been proposed. The aim of this work was to define the individual contribution of hyperammonemia and systemic inflammation on neuroinflammation in cirrhosis using germ-free (GF) and conventional mice. GF and conventional C57BL/6 mice were made cirrhotic using CCl4 gavage. These were compared to their noncirrhotic counterparts. Intestinal microbiota, systemic and neuroinflammation (including microglial and glial activation), serum ammonia, intestinal glutaminase activity, and cecal glutamine content were compared between groups. GF cirrhotic mice developed similar cirrhotic changes to conventional mice after 4 extra weeks (16 vs. 12 weeks) of CCl4 gavage. GF cirrhotic mice exhibited higher ammonia, compared to GF controls, but this was not associated with systemic or neuroinflammation. Ammonia was generated through increased small intestinal glutaminase activity with concomitantly reduced intestinal glutamine levels. However, conventional cirrhotic mice had intestinal dysbiosis as well as systemic inflammation, associated with increased serum ammonia, compared to conventional controls. This was associated with neuroinflammation and glial/microglial activation. Correlation network analysis in conventional mice showed significant linkages between systemic/neuroinflammation, intestinal microbiota, and ammonia. Specifically beneficial, autochthonous taxa were negatively linked with brain and systemic inflammation, ammonia, and with Staphylococcaceae, Lactobacillaceae, and Streptococcaceae. Enterobacteriaceae were positively linked with serum inflammatory cytokines.
Gut microbiota changes drive development of neuroinflammatory and systemic inflammatory responses in cirrhotic animals. (Hepatology 2016;64:1232-1248).
肝性脑病（HE）发展背后的机制尚不清楚，尽管有人提出高氨血症和通过肠道菌群失调引起的全身炎症与之相关。这项研究的目的是利用无菌（GF）小鼠和常规小鼠确定高氨血症和全身炎症对肝硬化神经炎症的个体影响。通过四氯化碳灌胃使GF和常规C57BL/6小鼠发生肝硬化。将这些小鼠与其未发生肝硬化的对应小鼠进行比较。比较各组之间的肠道微生物群、全身和神经炎症（包括小胶质细胞和神经胶质细胞激活）、血清氨、肠道谷氨酰胺酶活性和盲肠谷氨酰胺含量。在四氯化碳灌胃4周（16周与12周）后，GF肝硬化小鼠出现了与常规小鼠相似的肝硬化变化。与GF对照相比，GF肝硬化小鼠的氨水平更高，但这与全身或神经炎症无关。氨是通过小肠谷氨酰胺酶活性增加以及肠道谷氨酰胺水平相应降低而产生的。然而，与常规对照相比，常规肝硬化小鼠存在肠道菌群失调以及全身炎症，伴有血清氨升高。这与神经炎症和神经胶质/小胶质细胞激活有关。常规小鼠的相关网络分析显示全身/神经炎症、肠道微生物群和氨之间存在显著联系。具体而言，有益的本土分类群与脑和全身炎症、氨以及葡萄球菌科、乳杆菌科和链球菌科呈负相关。肠杆菌科与血清炎症细胞因子呈正相关。
肠道微生物群变化驱动肝硬化动物神经炎症和全身炎症反应的发展。（《肝脏病学》2016年；64:1232 - 1248）
