Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire Veterans Affairs Medical Center, Richmond, Virginia, United States of America.
PLoS One. 2013;8(4):e60042. doi: 10.1371/journal.pone.0060042. Epub 2013 Apr 2.
Hepatic encephalopathy (HE) represents a dysfunctional gut-liver-brain axis in cirrhosis which can negatively impact outcomes. This altered gut-brain relationship has been treated using gut-selective antibiotics such as rifaximin, that improve cognitive function in HE, especially its subclinical form, minimal HE (MHE). However, the precise mechanism of the action of rifaximin in MHE is unclear. We hypothesized that modulation of gut microbiota and their end-products by rifaximin would affect the gut-brain axis and improve cognitive performance in cirrhosis. Aim To perform a systems biology analysis of the microbiome, metabolome and cognitive change after rifaximin in MHE.
Twenty cirrhotics with MHE underwent cognitive testing, endotoxin analysis, urine/serum metabolomics (GC and LC-MS) and fecal microbiome assessment (multi-tagged pyrosequencing) at baseline and 8 weeks post-rifaximin 550 mg BID. Changes in cognition, endotoxin, serum/urine metabolites (and microbiome were analyzed using recommended systems biology techniques. Specifically, correlation networks between microbiota and metabolome were analyzed before and after rifaximin.
There was a significant improvement in cognition(six of seven tests improved, p<0.01) and endotoxemia (0.55 to 0.48 Eu/ml, p = 0.02) after rifaximin. There was a significant increase in serum saturated (myristic, caprylic, palmitic, palmitoleic, oleic and eicosanoic) and unsaturated (linoleic, linolenic, gamma-linolenic and arachnidonic) fatty acids post-rifaximin. No significant microbial change apart from a modest decrease in Veillonellaceae and increase in Eubacteriaceae was observed. Rifaximin resulted in a significant reduction in network connectivity and clustering on the correlation networks. The networks centered on Enterobacteriaceae, Porphyromonadaceae and Bacteroidaceae indicated a shift from pathogenic to beneficial metabolite linkages and better cognition while those centered on autochthonous taxa remained similar.
Rifaximin is associated with improved cognitive function and endotoxemia in MHE, which is accompanied by alteration of gut bacterial linkages with metabolites without significant change in microbial abundance.
ClinicalTrials.gov NCT01069133.
对利福昔明治疗轻微型肝性脑病（MHE）前后的微生物组、代谢组和认知变化进行系统生物学分析。
20 例 MHE 肝硬化患者在基线和利福昔明 550mg bid 治疗 8 周后进行认知测试、内毒素分析、尿液/血清代谢组学（GC 和 LC-MS）和粪便微生物组评估（多标签焦磷酸测序）。采用推荐的系统生物学技术分析认知、内毒素、血清/尿液代谢物（和微生物组的变化。具体而言，在利福昔明治疗前后分析微生物组和代谢组之间的相关性网络。
利福昔明治疗后认知功能（七项测试中有六项改善，p<0.01）和内毒素血症（从 0.55 降至 0.48 Eu/ml，p = 0.02）显著改善。血清饱和（肉豆蔻酸、辛酸、棕榈酸、棕榈油酸、油酸和二十烷酸）和不饱和（亚油酸、亚麻酸、γ-亚麻酸和花生四烯酸）脂肪酸显著增加。除韦荣球菌科略有减少和真杆菌科增加外，未见明显微生物变化。利福昔明治疗后，相关网络的连接性和聚类显著降低。以肠杆菌科、卟啉单胞菌科和拟杆菌科为中心的网络表明，代谢物的致病性关联向有益性关联转变，认知功能改善，而以本土分类群为中心的网络则保持相似。
利福昔明与 MHE 患者认知功能和内毒素血症的改善有关，这与肠道细菌与代谢物的关联改变有关，而微生物丰度没有明显变化。
ClinicalTrials.gov NCT01069133。
