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

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.

Inhibition of urease-mediated ammonia production by 2-octynohydroxamic acid in hepatic encephalopathy

“…Previous studies on BDL rats showed that osmotic stress created by Gln accumulation might be in part offset by the decrease in other organic osmolytes 52 – 55 . Therefore, in the opposite case, the increase in main osmolytes as a response to decreased Gln was anticipated.…”

“…The metabolites were assessed in the cerebellum as this region was previously shown to exhibit more distinct changes (i.e. in Gln) compared to the hippocampus in HE in BDL rats 52 , 53 . A significant 28% decrease in brain Gln was observed in the group treated with 2-octynoHA-based solution compared to the negative control group (5.1 ± 1.1 vs. 7.1 ± 1.2 mmol/kg ww , multiplicity adjusted p = 0.0019) (Fig.…”

“…Interestingly, a 18% decrease trend in brain Gln was also observed in the enteric capsule group (5.8 ± 0.99 vs. 7.1 ± 1.2 mmol/kg ww , multiplicity adjusted p = 0.0643), while a 15% decrease trend in Gln was found in the suspension group compared to the negative control group (6.0 ± 0.9 vs. 7.1 ± 1.2 mmol/kg ww , multiplicity adjusted p = 0.1387). As Gln synthesis is the main pathway of ammonia detoxification in astrocytes, brain Gln levels are strongly correlated with circulating ammonia 9 , 52 . Therefore, the observed reduction in Gln might be related to inhibited urease activity and thereby ammonia production in the presence of 2-octynoHA.…”

“…Overall, alterations in brain osmolytes were more evident in the group treated with a 2-octynoHA solution. Although the underlying reason behind decreased osmolytes in the solution and enteric capsule group is unclear, possible explanations may involve delayed osmotic compensation for the Gln decline 56 – 58 , insufficient treatment duration 52 , 59 or additional osmotic stress driving the outflow of these osmolytes.…”

Neurometabolism and brain morphometry in an adolescent female with an extra‐hepatic congenital portosystemic shunt

“…Classically, it is held from high magnetic field spectroscopy studies in animals that administration of ammonium is associated with a rapid and linear increase in brain glutamine. 11 In type C HE animal models 15 , 16 , 28 , 29 , 30 and CPSS mice, 31 the Gln increase generates an osmolarity change in the brain, which in turn releases the main brain osmolytes (Ins, Tau, tCho) to counter the osmotic load. 15 , 18 These findings have been also observed in humans with type C HE.…”