P: 36 Antibiotic Rifaximin for Treatment of Chronic Liver Disease-Induced HE: A Longitudinal In Vivo 1H-MRS Study of Brain Metabolism on BDL Rats

Abstract

BACKGROUND: Rifaximin is a commonly-used antibiotic to treat hepatic encephalopathy (HE), a complex neuropsychiatric syndrome caused by hepatic dysfunction. Rifaximin aims at reducing the production of gut ammonia, an important toxin in HE pathogenesis. In a previous study using bile duct ligated (BDL) rats, we showed that rifaximin at the recommended human dose may help reduce brain Gln levels in early stages of HE.1 These findings raised the question of the efficacy of the dose used at later stages. Therefore we hypothesized that the effect of rifaximin on neurometabolic profile may be dose-related. In this study, the effects of a dose 6.2x that recommended in humans 2 were assessed in vivo and longitudinally in BDL rats. They were compared with non-treated rats (n = 17) and human-dose treated rats (15.7 mg/kg/day, n = 12).1 METHODS: Plasma measurements of NH4+, bilirubin and 1H-MRS scans were performed on adult Wistar rats (n = 8) before BDL ('week 0') and at weeks 2, 4, 6, 8 post-BDL. Rifaximin was administered twice daily (6x-human-dose = 97.3 mg/kg/day) starting two weeks after BDL-surgery ('week 2'). In vivo 1H-MRS was performed on a 9.4 Tesla MRI system. Changes in metabolites were studied in the hippocampus (2 × 2.8 × 2 mm3) using SPECIAL3 sequence (TE = 2.8 ms). Metabolite concentrations were estimated by LCModel using water as internal reference. Open field test was performed at week 4, 6 and 8 to evaluate motor activity.4 RESULTS: Plasma measurements of bilirubin confirmed the presence of CLD in all groups of rats. They displayed similar ammonium concentration across groups (Figure 1a). 1H-MRS revealed some significant differences between the 'high-dose rifaximin' rats and non-treated rats: glutamine increase was lower in the 'high-dose rifaximin' group at week 6 and at week 8, both in absolute value and relative to week 2 (+42% vs +118% at week 8, Figure 1b). Moreover, a decrease of glutamine was observed between week 4 and week 6 in the 'high-dose rifaximin' group (−10%), contrary to the non-treated group (Figure 1b). Also, in the 'high-dose rifaximin' group, decreases in the following metabolites were less pronounced during the time course of the study: myo-inositol, taurine, glutamate, ascorbate, creatine, total creatine (Figure 1c). CONCLUSIONS: While rifaximin at human dose appeared to have an effect only at the early stages of the disease, a higher dose gave stronger positive effects on the neurometabolic profile. Importantly, no differences between the groups were observed in behavioural tests, but the 'high-dose rifaximin' rats had the tendency to move less. It is therefore possible that such a high dose of antibiotics also leads to some undesirable side-effects such as electrolyte abnormalities or inherent drug toxicity.5,6