Probiotic bacteria prevent hepatic damage and maintain colonic barrier function in a mouse model of sepsis.
A breakdown in intestinal barrier function and increased bacterial translocation are key events in the pathogenesis of sepsis and liver disease. Altering gut microflora with noninvasive and immunomodulatory probiotic organisms has been proposed as an adjunctive therapy to reduce the level of bacterial translocation and prevent the onset of sepsis. The purpose of this study was to determine the efficacy of a probiotic compound in attenuating hepatic and intestinal injury in a mouse model of sepsis. Wild-type and interleukin-10 (IL-10) gene-deficient 129 Sv/Ev mice were fed the probiotic compound VSL#3 for 7 days. To induce sepsis, the mice were injected with lipopolysaccharide (LPS) and D-galactosamine (GalN) in the presence and absence of the peroxisome proliferator-activated receptor gamma (PPARgamma) inhibitor GW9662. The mice were killed after 6 hours, and their colons were removed for the measurement of the cytokine production and epithelial function. The functional permeability was assessed by the mannitol movement and cyclic adenosine monophosphate-dependent chloride secretion in tissue mounted in Ussing chambers. The livers were analyzed for bacterial translocation, cytokine production, histological injury, and PPARgamma levels. The tissue levels of tumor necrosis factor alpha, interferon gamma, IL-6, and IL-12p35 ribonucleic acid were measured by semiquantitative reverse transcription polymerase chain reaction. Mice injected with LPS/GalN demonstrated a breakdown in colonic barrier function, which correlated with enhanced proinflammatory cytokine secretion, bacterial translocation, and significant hepatic injury. A pretreatment with oral probiotics prevented the breakdown in intestinal barrier function, reduced bacterial translocation, and significantly attenuated liver injury. The inhibition of PPARgamma with GW9662 abrogated the protection induced by probiotics.


CONCLUSIONS
Orally administered probiotics prevented liver and intestinal damage in a mouse model of sepsis through a PPARgamma-dependent mechanism.
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Julia
J
Ewaschuk
Ryan
R
Endersby
David
D
Thiel
Hugo
H
Diaz
Jody
J
Backer
Mang
M
Ma
Thomas
T
Churchill
Karen
K
Madsen
D000818:Animals; D003106:Colon / Q000276:immunology* / Q000382:microbiology*; D016207:Cytokines / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000502:physiology; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D017136:Ion Transport; D008099:Liver / Q000473:pathology; D008107:Liver Diseases / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008817:Mice, Mutant Strains; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000502:physiology; D019936:Probiotics / Q000627:therapeutic use*; D018805:Sepsis / Q000150:complications*
D016207:Cytokines; D047495:PPAR gamma; D016753:Interleukin-10