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.

Abstract

UNLABELLED:

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.

• Authors: Vishwadeep Ahluwalia, James B Wade, Douglas M Heuman, Thomas A Hammeke, Arun J Sanyal, Richard K Sterling, R Todd Stravitz, Velimir Luketic, Mohammad S Siddiqui, Puneet Puri, Michael Fuchs, Micheal J Lennon, Kenneth A Kraft, HoChong Gilles, Melanie B White, Nicole A Noble, Jasmohan S Bajaj
• Journal: Metabolic brain disease (Metab Brain Dis) Vol. 29 Issue 4 Pg. 1017-25 (Dec 2014) ISSN: 1573-7365 [Electronic] United States
• PMID: 24590688 (Publication Type: Clinical Trial, Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Rifamycins
• Rifaximin

Topics

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