Modulation of the Metabiome by Rifaximin in Patients with Cirrhosis and Minimal Hepatic Encephalopathy

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

The role of microbiota in hepatic encephalopathy

“…[21][22][23][24] A systematic study of MHE therapy with rifaximin was performed by our group in which we found a significant improvement in cognitive performance. 25 This was accompanied by an enhanced working memory performance via facilitation of the functioning of subcortical structures, greater inhibitory control by modulation of fronto-parietal activation, and improved white matter integrity in MHE after rifaximin on multi-modal brain MR imaging. We also found improved neural network connectivity between frontal and parietal structures and, in particular, facilitation of the left parietal operculum.…”

Alzheimer’s disease and gut microbiota

“…These studies suggest that cognitive impairment in HE patients may be caused by gut microbiota disruption, because rifaximin and lactulose directly or indirectly act on gut microbiota, inhibiting the growth of ammonia-producing bacteria and reducing ammonia production in the gut. They improve the cognitive impairment of HE patients by changing the gut microbiota and metabolites (Bajaj et al, 2013). …”

Hepatobiliary Quiz Answers – 18 (2016)

“…Its use does not seem to significantly alter the stool microbiome or increase antibiotic resistance, and its use has been associated with lower incidence of development of SBP. [52][53][54] 9. Answers: B, C and E Cholangiocarcinoma (CCA) is the second most common type of primary liver cancer, and forms $3% of all gastrointestinal neoplasias.…”