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Permalink: http://hdl.handle.net/1866/24783

Genetically engineered E. coli Nissle attenuates hyperammonemia and prevents memory impairment in bile‐duct ligated rats

Article [Accepted Manuscript]
PDF
liv.14815.pdf (11.83Mb)
Under embargo until: 2022-02-06
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Liver international
Publisher(s)
Wiley
2021-02-06
Author(s)
Ochoa‐Sanchez, Rafael
Oliveira, Mariana M.
Tremblay, Mélanie
Petrazzo, Grégory
Pant, Asha
Bosoi, Cristina R.
Perreault, Mylene
Querbes, William
Kurtz, Caroline B.
Rose, Christopher
Affiliation
  • Université de Montréal. Faculté de médecine. Département de médecine
Keywords
  • Ammonia
  • Arginine
  • Bile‐duct ligature
  • Butyrate
  • Cirrhosis
  • E. coli Nissle
  • Hepatic encephalopathy
  • Inflammation
  • Memory
  • Probiotics
Abstract(s)
Hyperammonemia associated with chronic liver disease (CLD) is implicated in the pathogenesis of hepatic encephalopathy (HE). The gut is a major source of ammonia production that contributes to hyperammonemia in CLD and HE and remains the primary therapeutic target for lowering hyperammonemia. As an ammonia‐lowering strategy, Escherichia coli Nissle 1917 bacterium was genetically modified to consume and convert ammonia to arginine (S‐ARG). S‐ARG was further modified to additionally synthesize butyrate (S‐ARG+BUT). Both strains were evaluated in bile‐duct ligated (BDL) rats; experimental model of CLD and HE. Methods One‐week post‐surgery, BDLs received non‐modified EcN (EcN), S‐ARG, S‐ARG+BUT (3x1011 CFU/day) or vehicle until sacrifice at 3‐ or 5‐weeks. Plasma (ammonia/pro‐inflammatory/liver‐function), liver fibrosis (hydroxyproline), liver mRNA (pro‐inflammatory/fibrogenic/anti‐apoptotic) and colon mRNA (pro‐inflammatory) biomarkers were measured post‐sacrifice. Memory, motor‐coordination, muscle‐strength, and locomotion were assessed at 5‐weeks. Results In BDL‐Veh rats, hyperammonemia developed at 3‐ and further increased at 5‐weeks. This rise was prevented by S‐ARG and S‐ARG+BUT, whereas EcN was ineffective. Memory impairment was prevented only in S‐ARG+BUT vs BDL‐Veh. Systemic inflammation (IL‐10/MCP‐1/endotoxin) increased at 3‐ and 5‐weeks in BDL‐Veh. S‐ARG+BUT attenuated inflammation at both timepoints (except 5‐week endotoxin) vs BDL‐Veh, whereas S‐ARG only attenuated IP‐10 and MCP‐1 at 3‐weeks. Circulating (ALT/AST/ALP/GGT/albumin/bilirubin) and gene expression liver‐function markers (IL‐10/IL‐6/IL‐1β/TGF‐β/α‐SMA/collagen‐1α1/Bcl‐2) were not normalized by either strain. Colonic mRNA (TNF‐α/IL‐1β/occludin) markers were attenuated by synthetic strains at both timepoints vs BDL‐Veh. Conclusion S‐ARG and S‐ARG+BUT attenuated hyperammonemia, with S‐ARG+BUT additional memory protection likely due to greater anti‐inflammatory effect. These innovative strategies, particularly S‐ARG+BUT, have potential to prevent HE.
Other location(s)
https://doi.org/10.1111/liv.14815
Collections
  • Faculté de médecine – Travaux et publications [377]

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