title: 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.
  
  
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01069133.
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire Veterans Affairs Medical Center, Richmond, Virginia, United States of America. jsbajaj@vcu.edu
authors.forename: Jasmohan S
authors.initials: JS
authors.lastname: Bajaj
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Heuman
authors.forename: Arun J
authors.initials: AJ
authors.lastname: Sanyal
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Hylemon
authors.forename: Richard K
authors.initials: RK
authors.lastname: Sterling
authors.forename: R Todd
authors.initials: RT
authors.lastname: Stravitz
authors.forename: Michael
authors.initials: M
authors.lastname: Fuchs
authors.forename: Jason M
authors.initials: JM
authors.lastname: Ridlon
authors.forename: Kalyani
authors.initials: K
authors.lastname: Daita
authors.forename: Pamela
authors.initials: P
authors.lastname: Monteith
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Noble
authors.forename: Melanie B
authors.initials: MB
authors.lastname: White
authors.forename: Andmorgan
authors.initials: A
authors.lastname: Fisher
authors.forename: Masoumeh
authors.initials: M
authors.lastname: Sikaroodi
authors.forename: Huzefa
authors.initials: H
authors.lastname: Rangwala
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Gillevet
mesh_terms: D003071:Cognition / Q000187:drug effects; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000382:microbiology; D006501:Hepatic Encephalopathy / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000150:complications* / Q000378:metabolism*; D008297:Male; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D054892:Metagenome / Q000187:drug effects; D008875:Middle Aged; D012294:Rifamycins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000078262:Rifaximin
chemical_list: D012294:Rifamycins; D000078262:Rifaximin
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