Abstract
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.MethodsTwenty 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.ResultsThere 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.ConclusionsRifaximin 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 RegistrationClinicalTrials.gov NCT01069133
Highlights
Dysfunction of the gut-liver-brain axis in cirrhosis can manifest as hepatic encephalopathy, the subclinical form of which is minimal hepatic encephalopathy (MHE) [1]
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 and unsaturated fatty acids postrifaximin
Summary
Dysfunction of the gut-liver-brain axis in cirrhosis can manifest as hepatic encephalopathy, the subclinical form of which is minimal hepatic encephalopathy (MHE) [1]. MHE affects several cognitive domains that can adversely impact patients in their daily function [2,3]. The treatment of MHE using gut-selective strategies can improve cognitive function and quality of life in patients; the precise mechanisms of their action are not clear [4,5,6]. The mechanism of action of rifaximin is presumed to modulate the concentration of gut microbiota, which has only been investigated in cirrhosis using culture-based techniques. The effect of rifaximin on gut flora using culture-independent techniques and its effect on gut-derived metabolites in the improvement of MHE has not been investigated
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