Enhancement of functional connectivity, working memory and inhibitory control on multi-modal brain MR imaging with Rifaximin in Cirrhosis: implications for the gut-liver-brain axis

Metab Brain Dis. 2014 Dec;29(4):1017-25. doi: 10.1007/s11011-014-9507-6. Epub 2014 Mar 4.


Minimal hepatic encephalopathy (MHE) impairs daily functioning in cirrhosis, but its functional brain impact is not completely understood. To evaluate the effect of rifaximin, a gut-specific antibiotic, on the gut-liver-brain axis in MHE.

Hypothesis: Rifaximin will reduce endotoxemia, enhance cognition, increase activation during working memory(N-back) and reduce activation needed for inhibitory control tasks.

Methods: Cirrhotics with MHE underwent baseline endotoxin and cognitive testing, then underwent fMRI, diffusion tensor imaging and MR spectroscopy(MRS). On fMRI, two tasks; N-back (outcome: correct responses) and inhibitory control tests(outcomes: lure inhibition) were performed. All procedures were repeated after 8 weeks of rifaximin. RESULTS were compared before/after rifaximin.

Results: 20 MHE patients (59.7 years) were included; sixteen completed pre/post-rifaximin scanning with 92% medication compliance. Pre-rifaximin patients had cognitive impairment. At trial-end, there was a significantly higher correct 2-back responses, ICT lure inhibitions and reduced endotoxemia(p = 0.002). This was accompanied by significantly higher activation from baseline in subcortical structures (thalamus, caudate, insula and hippocampus) and left parietal operculum (LPO) during N-back, decrease in fronto-parietal activation required for inhibiting lures, including LPO during ICT compared to baseline values. Connectivity studies in N-back showed significant shifts in linkages after therapy in fronto-parietal regions with a reduction in fractional anisotropy (FA) but not mean diffusivity (MD), and no change in MRS metabolites at the end of the trial. A significant improvement in cognition including working memory and inhibitory control, and fractional anisotropy without effect on MD or MRS, through modulation of fronto-parietal and subcortical activation and connectivity was seen after open-label rifaximin therapy in MHE.

Publication types

  • Clinical Trial
  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / therapeutic use*
  • Bacterial Translocation
  • Brain / pathology*
  • Brain / physiopathology
  • Brain Chemistry / drug effects
  • Cognition Disorders / etiology
  • Cognition Disorders / microbiology
  • Cognition Disorders / prevention & control*
  • Connectome*
  • Diffusion Tensor Imaging
  • Female
  • Functional Neuroimaging*
  • Hepatic Encephalopathy / drug therapy*
  • Hepatic Encephalopathy / etiology
  • Hepatic Encephalopathy / microbiology
  • Hepatic Encephalopathy / pathology
  • Hepatic Encephalopathy / physiopathology
  • Humans
  • Inhibition, Psychological
  • Intestines / microbiology*
  • Liver / physiopathology
  • Liver Cirrhosis / complications
  • Liver Cirrhosis / drug therapy*
  • Liver Cirrhosis / microbiology
  • Liver Cirrhosis / pathology
  • Liver Cirrhosis / physiopathology
  • Magnetic Resonance Imaging*
  • Magnetic Resonance Spectroscopy
  • Male
  • Memory, Short-Term / drug effects*
  • Microbiota / drug effects
  • Middle Aged
  • Multimodal Imaging*
  • Neuropsychological Tests
  • Rifamycins / pharmacology
  • Rifamycins / therapeutic use*
  • Rifaximin


  • Anti-Bacterial Agents
  • Rifamycins
  • Rifaximin