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

Objective Minimal hepatic encephalopathy (MHE) impairs daily functioning in cirrhosis, but its functional brain impact is not completely understood. Aim 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. Conclusion 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.

The role of microbiota in hepatic encephalopathy

“…20 Non-microbial studies using lactulose, probiotics, and rifaximin in MHE patients have shown varying degrees of cognitive improvement, reduction in endotoxemia, decreased brain swelling, and enhanced connectivity on multimodal MRI. [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. 26 However, despite these improvements and a reduction in endotoxemia after rifaximin, there was only a modest effect on relative bacterial abundance. This, however, was in line with prior studies in settings independent of cirrhosis in which a significant change in bacterial virulence and behavior rather than change in number with rifaximin were noted.…”

Gut Microbes and the Brain: Paradigm Shift in Neuroscience

“…For example, maternal separation, restraint conditions, crowding, heat stress, and acoustic stress all alter the composition of the gut microbiota (Bailey et al, 2011;De Palma et al, 2014;Moloney et al, 2014). In addition, a growing body of data suggests that the microbiota may be involved in controlling behaviors relevant to stress-related disorders.…”

Quantitative magnetic resonance imaging in patients with cirrhosis: a cross-sectional study

“…However, future studies which include concurrent functional MRI sequences (Ahluwalia et al, 2014) may also shed further light on the meaning and context of the changes observed with MTR and DWI.…”

“…However, future studies which include concurrent functional MRI sequences (Ahluwalia et al, 2014) Abbreviations: PoA= power of attention, CoA= continuity of attention, QoEM= quality of episodic memory, QoWM= quality of working memory, SoM= speed of memory *Z scores represent the number and direction of standard deviations in the patient data compared to those from the healthy controls ** Psychometric performance was classified as impaired if the total Z score for all domains was  -3 *significance value between healthy controls and the patient entire population with cirrhosis, corrected for multiple comparisons; ****** = p<0.0001;*** = p<0.005; * = p<0.05; NS = non-significant. There were no significant differences between the neuropsychometrically unimpaired and the neuropsychometrically impaired patients …”