Dataset Information

Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy.

ABSTRACT:

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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.

Methods

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.

Results

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.

Conclusions

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.

Trial registration

ClinicalTrials.gov NCT01069133.

SUBMITTER: Bajaj JS

PROVIDER: S-EPMC3615021 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy.

Bajaj Jasmohan S JS Heuman Douglas M DM Sanyal Arun J AJ Hylemon Phillip B PB Sterling Richard K RK Stravitz R Todd RT Fuchs Michael M Ridlon Jason M JM Daita Kalyani K Monteith Pamela P Noble Nicole A NA White Melanie B MB Fisher Andmorgan A Sikaroodi Masoumeh M Rangwala Huzefa H Gillevet Patrick M PM

PloS one 20130402 4

<h4>Unlabelled</h4>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 rifaxim ...[more]

PMID: 23565181

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Project description:Background & aimsPatients with cirrhosis are growing older. The overlap between minimal hepatic encephalopathy (MHE) and predementia mild cognitive impairment (MCI) could affect quality of life (QOL). We investigated the performance of elderly patients with cirrhosis on tests for MHE and MCI and their effects on QOL.MethodsWe recruited outpatients with cirrhosis (n = 109) and without cirrhosis (controls, n = 100), 65 years or older, at 4 centers (derivation cohort). All study participants were assessed for psychometric hepatic encephalopathy score (PHES), EncephalApp score, and QOL. MCI was tested in patients with cirrhosis using the repeatable battery for assessment of neuropsychological status and assigned to the following groups: unimpaired, MCI only, MHE only, and MCI+MHE. We created adjusted norms to detect MHE using PHES and EncephalApp scores from the controls. Findings were validated using data from a separate cohort of 77 patients with cirrhosis (mean age, 69.49 ± 4.36 y; 72% men) at the same study sites.ResultsControls were older but were more educated, performed better cognitively, and had better QOL. Among patients with cirrhosis, age, education, model for end-stage liver disease score, EncephalApp score, and QOL were similar, but PHES and repeatable battery for assessment of neuropsychological status differed among sites. In the derivation cohort, the presence of MHE, with or without MCI, was associated with poor QOL, which was lowest in the MCI+MHE group. When we adjusted for age, sex, and education, 49% of patients with cirrhosis had MHE based on the EncephalApp and 8% had MHE based on the PHES. A similar pattern (49% MHE based on EncephalApp and 6% MHE based on PHES) was found in a validation cohort.ConclusionsIn a multicenter study of patients with cirrhosis (>65 y) and controls, the presence of MHE, regardless of MCI, was associated with poor cognition and QOL. We created adjusted norms that defined the high sensitivity of EncephalApp for the detection of MHE in older individuals and validated it in a separate cohort.

Project description:Patients with hepatitis B virus (HBV)-related cirrhosis (HBV-RC) and minimal hepatic encephalopathy (MHE) exhibit alterations in homotopic inter-hemispheric functional connectivity (FC) and corpus callosum (CC) degeneration. However, the progression of inter-hemispheric dysconnectivity in cirrhotic patients from no MHE (NMHE) to MHE and its association with the progression of diseased-related cognitive impairment remain uncharacterized. We hypothesized that inter-hemispheric dysconnectivity exists in NMHE patients and further deteriorates at the MHE stage, which is associated with performance measured by psychometric hepatic encephalopathy scores (PHES) that can characterize cirrhotic patients with NMHE and MHE. Using inter-hemispheric homotopic FC and CC (and its subfields) volumetric measurements in 31 patients with HBV-RC (17 with NMHE and 14 with MHE) and 37 healthy controls, we verified that MHE patients had significant attenuated inter-hemispheric homotopic FC in the bilateral cuneus, post-central gyrus, inferior parietal lobule, and superior temporal gyms, as well as CC degeneration in total CC, CC2, CC3, and CC4 (each comparison had a corrected P < 0.05). In contrast, NMHE patients had relatively less severe inter-hemispheric homotopic FC and no CC degeneration. In addition, the degeneration of the CC and inter-hemispheric homotopic functional disconnections correlated with poor PHES performances in all cirrhotic patients (NMHE and MHE). Furthermore, impairment of inter-hemispheric homotopic FC partially mediated the association between CC degeneration and worse PHES performance. Notably, a combination of inter-hemispheric homotopic FC and CC volumes had higher discriminative values according to the area under the curve (AUC) score (AUC = 0.908, P < 0.001) to classify patients into MHE or NMHE groups when compared with either alone. Our findings shed light on the progression of inter-hemispheric dysconnectivity in relation to the progression of disease-related cognitive impairment in patients with HBV-RC.

Dataset Information

Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy.

Unlabelled

Methods

Results

Conclusions

Trial registration

Publications

Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy.

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