Probiotics combined with rifaximin influence the neurometabolic changes in a rat model of type C HE

Emmanuelle Flatt,Stefanita-Octavian Mitrea,Olivier Braissant,Paola Mastromarino,Katarzyna Pierzchala,Dario Sessa,Rolf Gruetter,Cristina Cudalbu,Valérie A Mclin

doi:10.1038/s41598-021-97018-8

Abstract

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.

Highlights

Type C hepatic encephalopathy (HE) is a neuropsychiatric disease caused by hepatic dysfunction secondary to chronic liver disease (CLD)
One recent study suggested that rifaximin (50 mg/kg/day) did not reduce inflammation (TNF-α levels) and fibrosis in bile duct ligated rats (BDL)[17], but there is a lack of knowledge about how rifaximin administration impacts changes in brain metabolites, which are frequently present in HE
The difference was pronounced at week 8 where the amount of bifidobacteria in the ‘rifaximin + probiotics’ group was on average twelve times higher compared to the ‘non-treated’ group

Summary

Introduction

Type C hepatic encephalopathy (HE) is a neuropsychiatric disease caused by hepatic dysfunction secondary to chronic liver disease (CLD). Type C HE is characterized by neurometabolic changes, in particular an increase in brain glutamine (Gln) due to cerebral ammonium (NH4+) removal by glutamine synthetase, causing osmotic stress and secondary disruption in astrocyte m etabolism[1]. Therapeutic approaches for treating HE have focused on reducing plasma ammonium levels either by decreasing its production or promoting its removal In patients, such treatments imply the usage of non-absorbable disaccharides such as lactulose, which is accepted to improve cognitive function in patients with minimal HE (mHE), the covert premise of type C HE8. Other therapeutic options include the non-absorbable antibiotic rifaximin or the administration of probiotics These therapies act on the modulation of gut flora, in line with the current evidence that gut flora plays an important role in type C HE. Further studies are needed to characterize the potential role and mechanisms of action of rifaximin in the setting of type C H E18

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