Type C hepatic encephalopathy (HE) is a neuropsychiatric disease caused by chronic liver disease. Management of type C HE remains an important challenge because treatment options are limited. Both the antibiotic rifaximin and probiotics have been reported to reduce the symptoms of HE, but longitudinal studies assessing their effects on brain metabolism are lacking and the molecular mechanisms underpinning their effects are not fully understood. Therefore, we evaluated in detail the effects of these different treatments on the neurometabolic changes associated with type C HE using a multimodal approach including ultra-high field in vivo 1H MRS. We analyzed longitudinally the effect of rifaximin alone or in combination with the probiotic Vivomixx on the brain metabolic profile in the hippocampus and cerebellum of bile duct ligated (BDL) rats, an established model of type C HE. Overall, while rifaximin alone appeared to induce no significant effect on the neurometabolic profile of BDL rats, its association with the probiotic resulted in more attenuated neurometabolic alterations in BDL rats followed longitudinally (i.e. a smaller increase in Gln and milder decrease in Glu and Cr levels). Given that both rifaximin and some probiotics are used in the treatment of HE, the implications of these findings may be clinically relevant.
Chronic liver disease leads to neuropsychiatric complications called hepatic encephalopathy (HE). Current treatments have some limitations in their efficacy and tolerability, emphasizing the need for alternative therapies. Modulation of gut bacterial flora using probiotics is emerging as a therapeutic alternative. However, knowledge about how probiotics influence brain metabolite changes during HE is missing. In the present study, we combined the advantages of ultra-high field in vivo 1H MRS with behavioural tests to analyse whether a long-term treatment with a multistrain probiotic mixture (VIVOMIXX) in a rat model of type C HE had a positive effect on behaviour and neurometabolic changes. We showed that the prophylactic administration of this probiotic formulation led to an increase in gut Bifidobacteria and attenuated changes in locomotor activity and neurometabolic profile in a rat model of type C HE. Both the performance in behavioural tests and the neurometabolic profile of BDL + probiotic rats were improved compared to the BDL group at week 8 post-BDL. They displayed a significantly lesser increase in brain Gln, a milder decrease in brain mIns and a smaller decrease in neurotransmitter Glu than untreated animals. The clinical implications of these findings are potentially far-reaching given that probiotics are generally safe and well-tolerated by patients.
Glucose is the primary fuel for the brain; its metabolism is linked with cerebral function. Different magnetic resonance spectroscopy (MRS) techniques are available to assess glucose metabolism, providing complementary information. Our first aim was to investigate the difference between hyperpolarized 13C-glucose MRS and non-hyperpolarized 2H-glucose MRS to interrogate cerebral glycolysis. Isoflurane anesthesia is commonly employed in preclinical MRS, but it affects cerebral hemodynamics and functional connectivity. A combination of low doses of isoflurane and medetomidine is routinely used in rodent fMRI and shows similar functional connectivity, as in awake animals. As glucose metabolism is tightly linked to neuronal activity, our second aim was to assess the impact of these two anesthetic conditions on the cerebral metabolism of glucose. Brain metabolism of hyperpolarized 13C-glucose and 2H-glucose was monitored in two groups of mice in a 9.4 T MRI system. We found that the very different duration and temporal resolution of the two techniques enable highlighting the different aspects in glucose metabolism. We demonstrate (by numerical simulations) that hyperpolarized 13C-glucose reports on de novo lactate synthesis and is sensitive to CMRGlc. We show that variations in cerebral glucose metabolism, under different anesthesia, are reflected differently in hyperpolarized and non-hyperpolarized X-nuclei glucose MRS.
The present work describes a quantitative analysis of lactate 13C-labeling pattern following the metabolism of hyperpolarized [2H7,U-13C6]-D-glucose. This lactate production results from 12 biochemical steps including glucose transport, 10 enzymatic steps of glycolysis, and LDH mediated pyruvate-to-lactate conversion. The 3-compartment model description was found a good compromise to interpret the hyperpolarized metabolic curves. This demonstrates the potential of hyperpolarized [2H7, U-13C6]-D-glucose as a new biochemical probe for brain energy metabolism.
BACKGROUND: Chronic hepatic encephalopathy (HE) is a severe complication of chronic liver disease (CLD), and finding the right treatment to reduce HE episodes before liver transplant remains a challenge. Both rifaximin (non-absorbable antibiotic) and probiotics are currently used to reduce HE symptoms, but their precise effect on brain metabolites has never been studied. Our aims were: 1) to assess in vivo and longitudinally the effect of the combination of probiotics and rifaximin on bile duct ligated (BDL) rats in different brain regions; and 2) to compare these results with both non-treated (n = 17) and rifaximin-only treated rats (n = 12).1,2 METHODS: In vivo 1H-MRS at 9.4 Tesla combined with biochemical tests (plasma NH4+, bilirubin) and microbiota analysis were performed on adult Wistar rats (n = 9) before BDL3,4 (week 0) and at weeks 2, 4, 6 and 8 after surgery. Evolution of metabolites was studied using the SPECIAL sequence (TE = 2.8 ms) in the hippocampus (2 × 2.8 × 2 mm3) and cerebellum (2.5 × 2.5 × 2.5 mm3). Metabolite concentrations were estimated using LCModel and water as internal reference. Probiotics administration (VIVOMIXX®, 60 billion bacteria/kg of rat) started two weeks before BDL-surgery until the end of the study. Rifaximin (15.7 mg/kg/day = 'human-dose') was administered twice daily starting two weeks after BDL-surgery. RESULTS: All rats displayed the characteristic rise in plasma bilirubin, regardless of treatment group, as well as a similar ammonium increase (Figure 1a). The characteristic pattern of chronic HE was observed (Figure 1e): a gradual increase of brain glutamine followed by a gradual decrease in the other brain osmolytes (myo-inositol, taurine, total choline) and a later decrease of glutamate and creatine. The combination of probiotics and rifaximin improved some of the neuro-metabolic changes associated with CLD at early stages of HE (week 4) in the cerebellum: the 'probiotics + rifaximin' group showed a lower rise of brain glutamine (+33% vs +66%, Figure 1c) and a smaller decrease of creatine (−4% vs −14%). In the hippocampus, rats receiving both probiotics and rifaximin exhibited a smaller increase in brain glutamine even at week 8 after BDL compared to non-treated rats (+99% vs +136%, Figure 1d) and a smaller decrease in brain myo-inositol and glutamate (−20% vs −30% and −7% vs −13%, respectively). Also, bifidobacteria concentration was slightly higher in the 'probiotics+rifaximin' group at week 8 (Figure 1b). Finally, the administration of rifaximin associated with this probiotic showed more beneficial effects than rifaximin only, and both could be used to maintain a balanced microbiota and may provide opportunities for reducing the spread of antibiotic resistances. CONCLUSIONS: To conclude, some promising changes were induced in the neurometabolic profile of BDL-rats who were treated with this specific probiotic and rifaximin (glutamine, myo-inositol, creatine and glutamate).
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
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