A longitudinal systems biology analysis of lactulose withdrawal in hepatic encephalopathy

被引:84
作者
Bajaj, Jasmohan S. [1 ,2 ]
Gillevet, Patrick M. [5 ]
Patel, Neeral R. [6 ]
Ahluwalia, Vishwadeep [2 ,4 ]
Ridlon, Jason M. [1 ,2 ,3 ]
Kettenmann, Birgit [2 ,4 ]
Schubert, Christine M. [2 ,7 ]
Sikaroodi, Masoumeh [5 ]
Heuman, Douglas M. [1 ,2 ]
Crossey, Mary M. E. [6 ]
Bell, Debulon E. [1 ,2 ]
Hylemon, Philip B. [1 ,2 ,3 ]
Fatouros, Panos P. [2 ,4 ]
Taylor-Robinson, Simon D. [6 ]
机构
[1] Virginia Commonwealth Univ, Div Gastroenterol Hepatol & Nutr, Richmond, VA 23249 USA
[2] McGuire VA Med Ctr, Richmond, VA 23249 USA
[3] Virginia Commonwealth Univ, Dept Microbiol, Richmond, VA 23249 USA
[4] Virginia Commonwealth Univ, Dept Radiol, Richmond, VA 23249 USA
[5] George Mason Univ, Microbiome Anal Ctr, Manassas, VA USA
[6] Univ London Imperial Coll Sci Technol & Med, Dept Med, Div Diabet Endocrinol & Metab, London, England
[7] Virginia Commonwealth Univ, Dept Biostat, Richmond, VA 23249 USA
关键词
Cirrhosis; Inflammation; Microbiome; Metabolomics; Systems biology; Magnetic resonance spectroscopy; GRADE CEREBRAL EDEMA; MAGNETIC-RESONANCE; CIRRHOTIC-PATIENTS; GUT FLORA; METABOLISM; SPECTROSCOPY; RATS; MICROBIOME; MODULATION; DIAGNOSIS;
D O I
10.1007/s11011-012-9303-0
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The pathogenesis of hepatic encephalopathy(HE) is unclear. However gut flora changes, inflammation and neuro-glial injury have been implicated. The aim was to evaluate factors that were associated with HE recurrence after lactulose withdrawal by analyzing the clinical phenotype, stool microbiome and systemic metabolome longitudinally. HE patients on a standard diet who were adherent on lactulose underwent characterization of their phenotype [cognition, inflammatory cytokines, in-vivo brain MR spectroscopy(MRS)], gut microbiome (stool Multitag Pyrosequencing) and metabolome (urine/serum MRS) analysis while on lactulose and on days 2, 14 and 30 post-withdrawal. Patients whose HE recurred post-withdrawal were compared to those without recurrence. We included seven men (53 +/- 8 years) who were adherent on lactulose after a precipitated HE episode were included. HE recurred in three men 32 +/- 6 days post-withdrawal. In-vivo brain MRS showed increased glutamine+glutamate (Glx) and decreased myoinositol with a reduction in stool spp., post-withdrawal. HE recurrence was predicted by poor baseline inhibitory control and block design performance and was associated with a shift of choline metabolism from tri-methylamine oxide formation towards the development of di-methylglycine, glycine and creatinine. This was accompanied by a mixed effect on the immune response (suppressed IL-10 and Th1/Th2/Th17 response). The correlation network showed to be linked to improved cognition and decreased inflammation in patients without HE recurrence. We conclude that lactulose withdrawal results in worsening cognition, mixed inflammatory response effect, lowered stool and increase in MR-measurable brain Glx. HE recurrence post-lactulose withdrawal can be predicted by baseline cognitive performance and is accompanied by disrupted choline metabolism.
引用
收藏
页码:205 / 215
页数:11
相关论文
共 47 条
[1]   Review article: the modern management of hepatic encephalopathy [J].
Bajaj, J. S. .
ALIMENTARY PHARMACOLOGY & THERAPEUTICS, 2010, 31 (05) :537-547
[2]   Inhibitory Control Test for the Diagnosis of Minimal Hepatic Encephalopathy [J].
Bajaj, Jasmohan S. ;
Hafeezullah, Muhammad ;
Franco, Jose ;
Varma, Rajiv R. ;
Hoffmann, Raymond G. ;
Knox, Joshua F. ;
Hischke, Darrell ;
Hammeke, Thomas A. ;
Pinkerton, Steven D. ;
Saeian, Kia .
GASTROENTEROLOGY, 2008, 135 (05) :1591-1600
[3]   Linkage of gut microbiome with cognition in hepatic encephalopathy [J].
Bajaj, Jasmohan S. ;
Ridlon, Jason M. ;
Hylemon, Phillip B. ;
Thacker, Leroy R. ;
Heuman, Douglas M. ;
Smith, Sean ;
Sikaroodi, Masoumeh ;
Gillevet, Patrick M. .
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 2012, 302 (01) :G168-G175
[4]   Rifaximin Improves Driving Simulator Performance in a Randomized Trial of Patients With Minimal Hepatic Encephalopathy [J].
Bajaj, Jasmohan S. ;
Heuman, Douglas M. ;
Wade, James B. ;
Gibson, Douglas P. ;
Saeian, Kia ;
Wegelin, Jacob A. ;
Hafeezullah, Muhammad ;
Bell, Debulon E. ;
Sterling, Richard K. ;
Stravitz, R. Todd ;
Fuchs, Michael ;
Luketic, Velimir ;
Sanyal, Arun J. .
GASTROENTEROLOGY, 2011, 140 (02) :478-U179
[5]   Spectrum of Neurocognitive Impairment in Cirrhosis: Implications for the Assessment of Hepatic Encephalopathy [J].
Bajaj, Jasmohan S. ;
Wade, James B. ;
Sanyal, Arun J. .
HEPATOLOGY, 2009, 50 (06) :2014-2021
[6]   Metabolic profiling, metabolomic and metabonomic procedures for NMR spectroscopy of urine, plasma, serum and tissue extracts [J].
Beckonert, Olaf ;
Keun, Hector C. ;
Ebbels, Timothy M. D. ;
Bundy, Jacob G. ;
Holmes, Elaine ;
Lindon, John C. ;
Nicholson, Jeremy K. .
NATURE PROTOCOLS, 2007, 2 (11) :2692-2703
[7]   Hepatic Encephalopathy: A Central Neuroinflammatory Disorder? [J].
Butterworth, Roger F. .
HEPATOLOGY, 2011, 53 (04) :1372-1376
[8]   Characterization of Fecal Microbial Communities in Patients with Liver Cirrhosis [J].
Chen, Yanfei ;
Yang, Fengling ;
Lu, Haifeng ;
Wang, Baohong ;
Chen, Yunbo ;
Lei, Dajiang ;
Wang, Yuezhu ;
Zhu, Baoli ;
Li, Lanjuan .
HEPATOLOGY, 2011, 54 (02) :562-572
[9]   Prevotella bryantii 25A used as a probiotic in early-lactation dairy cows:: Effect on ruminal fermentation characteristics, milk production, and milk composition [J].
Chiquette, J. ;
Allison, M. J. ;
Rasmussen, M. A. .
JOURNAL OF DAIRY SCIENCE, 2008, 91 (09) :3536-3543
[10]   The development of low-grade cerebral edema in cirrhosis is supported by the evolution of 1H-magnetic resonance abnormalities after liver transplantation [J].
Córdoba, J ;
Alonso, J ;
Rovira, A ;
Jacas, C ;
Sanpedro, F ;
Castells, L ;
Vargas, V ;
Margarit, C ;
Kulisewsky, J ;
Esteban, R ;
Guardia, J .
JOURNAL OF HEPATOLOGY, 2001, 35 (05) :598-604