2 research outputs found
Cibler le systĂšme digestif pour protĂ©ger le foie : Ă©valuation de lâefficacitĂ© prophylactique et thĂ©rapeutique de traitements de lâencĂ©phalopathie hĂ©patique dans un modĂšle murin de cholestase hĂ©patique par ligature de la voie biliaire
Introduction. LâencĂ©phalopathie hĂ©patique (HE) est une complication commune mais sĂ©vĂšre des insuffisances hĂ©patiques. La physiopathologie de lâHE provient essentiellement de lâammoniac dĂ©rivĂ© du mĂ©tabolisme des bactĂ©ries intestinales. Le traitement standard pour les patients qui subissent des Ă©pisodes manifestes dâHE est le lactulose mais son observance est faible du fait dâeffets secondaires inconfortables. La rifaximine est un candidat potentiel mais il nây a pas de donnĂ©es issues dâessais cliniques suffisamment robustes pour supporter sa seule utilisation. Les traitements anti-fibrotiques sont une autre piste de traitement dans le sens oĂč sâil est possible de prĂ©venir lâavancement de la dĂ©faillance hĂ©patique il est alors possible de diminuer la probabilitĂ© et la sĂ©vĂ©ritĂ© des Ă©pisodes. Deux Ă©tudes indĂ©pendantes ont Ă©tĂ© rĂ©alisĂ©es dans un modĂšle de ligature de la voie biliaire, la premiĂšre Ă©tude pour Ă©valuer lâefficacitĂ© de traitements thĂ©rapeutiques de lâHE (lactulose et rifaximine) utilisĂ©s seuls ou en combinaison pour rĂ©duire le taux dâammoniac et amĂ©liorer le statut de lâHE; et la seconde Ă©tude, pour Ă©valuer des traitements utilisĂ©s individuellement pour prĂ©venir lâĂ©tablissement de la fibrose (acide obĂ©ticholique, rapamycine, pirfĂ©nidone, acide ursodĂ©soxycholique).
MatĂ©riel et mĂ©thodes. Les deux projets utilisent un modĂšle murin de ligature de la voie biliaire. Pour lâĂ©valuation de la rifaximine, trois semaines aprĂšs la chirurgie, les animaux sont sĂ©parĂ©s en cinq groupes en fonction du traitement reçu quotidiennement et du modĂšle : SHAM-VEH, pour les animaux ayant subi un simulacre de chirurgie de ligature de la voie biliaire (SHAM) et traitĂ© par le vĂ©hicule (VEH); BDL-VEH, pour les animaux ayant subi la chirurgie de ligature de la voie biliaire et traitĂ© par le vĂ©hicule; BDL-RIF, pour les animaux traitĂ©s par la rifaximine (RIF); BDL-LAC, pour les animaux traitĂ©s par le lactulose (LAC); BDL-LAC+RIF, pour les animaux traitĂ©s par le lactulose et la rifaximin (LAC+RIF). Pour lâĂ©valuation des composĂ©s anti-fibrotiques, une semaine aprĂšs la chirurgie, les animaux sont sĂ©parĂ©s en six groupes en fonction du traitement reçu quotidiennement et du modĂšle : SHAM-VEH; BDL-VEH; BDL-OCA pour les animaux traitĂ©s par lâobĂ©ticholique acide (OCA); BDL-RPM, pour les animaux traitĂ©s par la rapamycine (RPM); BDL-UDCA, pour les animaux traitĂ©s par lâacide ursodĂ©soxycholique (UDCA); BDL-PFN pour les animaux traitĂ©s par la pirfenidone (PFN). Les animaux sont alors Ă©valuĂ©s au cours du modĂšle pour leur survie, leur consommation de nourriture et leur poids. Les paramĂštres biochimiques de la fonction hĂ©patiques sont Ă©valuĂ©s en fin de modĂšle. Plus particuliĂšrement, le projet sur les composĂ©s anti-fibrotiques comprend une analyse plus approfondie de la fibrose par histologie avec Ă©tablissement du score MĂTAVIR et par mesure du contenu hĂ©patique en hydroxyproline. Le projet rifaximine comprend des analyses comportementales pour Ă©valuer lâHE mais Ă©galement une mesure de lâĆdĂšme cĂ©rĂ©bral.
RĂ©sultats. Pour le projet rifaximine, aucun des deux composĂ©s testĂ©s (i.e. rifaximin et lactulose) seuls ou combinaison nâont pas eu dâeffets bĂ©nĂ©fiques globaux en termes de survie, de croissance, de consommation de nourriture, de tests comportementaux, dâĆdĂšme cĂ©rĂ©bral, de paramĂštres biochimiques incluant lâammoniac. Aucun des traitements pris sĂ©parĂ©ment ou en combinaison nâa montrĂ© dâefficacitĂ© pour le traitement de lâHE. Pour le projet des composĂ©s anti-fibrotiques, certains composĂ©s ont entrainĂ© une mortalitĂ© plus Ă©levĂ©e. Aucune diffĂ©rence entre les traitements ne fut observĂ©e en termes de croissance, de consommation de nourriture, de paramĂštres biochimiques, dâhistologie et de contenu en hydroxyproline.
Conclusions. Globalement, lâĂ©tude sur la rifaximine ne prĂ©sente pas de rĂ©sultats suffisamment concluants pour recommander lâutilisation de la rifaximine en remplacement ou en concomitance avec le lactulose. LâĂ©tude sur les composĂ©s anti-fibrotiques ne permet pas de mettre en Ă©vidence un composĂ© capable de limiter la progression de la fibrose.Introduction. Hepatic encephalopathy (HE) is a major but common complication of
liver failures diseases. The physiopathology of HE mainly involves intestinal bacteria
metabolism derived ammonia. The golden standard for patients who experience overt episodes
of HE is lactulose but its observance is poor due to uncomfortable side effects. On the other
hand, Rifaximin is a potent candidate but there is a lack of relevant data from clinical trials to
support its sole use. Antifibrotic drugs are another category of treatment that can be useful in
the setting of HE since it can prevent the onset of cirrhosis and thus of the liver failure, this can
decrease the appearance and severity of the episodes. The aim of this study is to evaluate in a
murine model of bile duct ligation the efficiency of therapeutic treatments (lactulose and
rifaximin) alone or in combination to decrease blood ammonia and ameliorate HE status; and of
prophylactic treatments (obeticholic acid, rapamycin, pirfenidone, ursodeoxycholic acid)
individually to prevent the onset of fibrosis.
Materials and methods. The two projects used a murine model of bile duct ligation.
For the evaluation of the efficiency of rifaximin, three weeks after surgery, the animals were
sorted into five groups according to the treatment they received daily and according to the model
: SHAM-VEH, for animals that underwent a mock surgery (SHAM) and were treated with
vehicle (VEH); BDL-VEH, for animals that underwent a bile duct ligation surgery (BDL) and
were treated with vehicle; BDL-RIF, for animals that were treated with rifaximin (RIF); BDLLAC,
for animals that were treated with lactulose (LAC); BDL-LAC+RIF for animals that were
treated with lactulose and rifaximin (LAC+RIF);. For the evaluation of the effect of antifibrotic
drugs, one week after surgery, the animals were sorted into six groups according to the treatment
they received daily and according to the model : SHAM-VEH, BDL-VEH, BDL-OCA for
animals that were treated with obeticholic acid (OCA); BDL-RPM, for animals that were treated
with rapamycine (RPM); BDL-UDCA, for animals that were treated with ursodeoxycholic acid
(UDCA); BDL-PFN, for animals that were treated with pirfenidone (PFN). All animals were
evaluated during the model for survival, food consumption and growth. The biological
parameters of the liver function were evaluated at the end of the model. More specifically, this
project includes a deeper analysis on fibrosis through histological analysis with establishment of the METAVIR score and measure of the content on hydroxyproline. The rifaximin project
includes behavioural analysis to evaluate the HE status and measurement of cerebral edema.
Results. Concerning the rifaximin project, no difference can be established between the
treatments in term of survival, growth, food consumption, behavioural tests, cerebral edema,
biochemistry parameters including ammonia. No treatment, taken alone or in combination,
showed efficacy to treat HE. Concerning the antifibrotic drug study, some compounds have
shown an increase in mortality, although no difference can be observed on growth, food
consumption, biochemistry parameters, histology or hydroxyproline content.
Conclusions. Overall, the study on rifaximin does not present strong and conclusive
results on the sole use of rifaximin. According to the study on the antifibrotic drugs, no
compounds show evidence of prevention of the onset of the fibrosis
Genetically engineered E. coli Nissle attenuates hyperammonemia and prevents memory impairment in bileâduct ligated rats
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 ammoniaâlowering strategy, Escherichia coli Nissle 1917 bacterium was genetically modified to consume and convert ammonia to arginine (SâARG). SâARG was further modified to additionally synthesize butyrate (SâARG+BUT). Both strains were evaluated in bileâduct ligated (BDL) rats; experimental model of CLD and HE.
Methods
Oneâweek postâsurgery, BDLs received nonâmodified EcN (EcN), SâARG, SâARG+BUT (3x1011 CFU/day) or vehicle until sacrifice at 3â or 5âweeks. Plasma (ammonia/proâinflammatory/liverâfunction), liver fibrosis (hydroxyproline), liver mRNA (proâinflammatory/fibrogenic/antiâapoptotic) and colon mRNA (proâinflammatory) biomarkers were measured postâsacrifice. Memory, motorâcoordination, muscleâstrength, and locomotion were assessed at 5âweeks.
Results
In BDLâVeh rats, hyperammonemia developed at 3â and further increased at 5âweeks. This rise was prevented by SâARG and SâARG+BUT, whereas EcN was ineffective. Memory impairment was prevented only in SâARG+BUT vs BDLâVeh. Systemic inflammation (ILâ10/MCPâ1/endotoxin) increased at 3â and 5âweeks in BDLâVeh. SâARG+BUT attenuated inflammation at both timepoints (except 5âweek endotoxin) vs BDLâVeh, whereas SâARG only attenuated IPâ10 and MCPâ1 at 3âweeks. Circulating (ALT/AST/ALP/GGT/albumin/bilirubin) and gene expression liverâfunction markers (ILâ10/ILâ6/ILâ1ÎČ/TGFâÎČ/αâSMA/collagenâ1α1/Bclâ2) were not normalized by either strain. Colonic mRNA (TNFâα/ILâ1ÎČ/occludin) markers were attenuated by synthetic strains at both timepoints vs BDLâVeh.
Conclusion
SâARG and SâARG+BUT attenuated hyperammonemia, with SâARG+BUT additional memory protection likely due to greater antiâinflammatory effect. These innovative strategies, particularly SâARG+BUT, have potential to prevent HE