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Am J Transl Res 2012;4(2):187-197
Original Article
Cytokines and Toll-like receptor signaling pathways in the terminal
ileum of hypoxic/hyperoxic neonatal rats: benefits of probiotics
supplementation
Antoni D’Souza, Charles L Cai, Dharmendra Kumar, Fayme Cai, Lawrence Fordjour, Asma Ahmad, Gloria
Valencia, Jacob V Aranda, Kay D Beharry
Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York, Downstate
Medical Center, Brooklyn, NY; Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of
California, Irvine, Irvine, CA; *Change of affiliation (F.C.): Lawrence Fordjour, Department of Pediatrics, Division of
Neonatal-Perinatal Medicine, Beth Israel Medical Center, Manhattan, NY, USA.
Received December 5, 2011; accepted March 13, 2012; Epub April 10; Published April 30, 2012
Abstract: Background: Oxidative stress and inflammation are associated with the development of inflammatory
bowel diseases such as necrotizing enterocolitis. We tested the hypothesis that probiotics, prebiotics or
synbiotics (a combination of pre- and probiotics) is effective for prevention of inflammatory responses to formula-
feeding in the terminal ileum of neonatal rats. Methods: Neonatal rats were exposed to hyperoxia/hypoxia during
which they were either maternally-fed or hand-fed with formula supplemented with probiotics, prebiotics or
synbiotics. A non-supplemented formula group served as controls. Cytokines and genes associated with
oxidative stress and toll-like receptor signaling were determined in the terminal ileum. Data were compared to
room air littermates. Results: Exposure to hyperoxia/hypoxia reduced growth accretion in maternally-fed pups.
NEC-like symptoms and intestinal inflammatory markers were induced with formula feeding. Supplementation
with probiotics, prebiotics or synbiotics decreased pro-inflammatory cytokines and downregulated genes involved
in oxidative stress and toll-like receptor pathways, however, the effect was attenuated in hyperoxia/hypoxia.
Conclusions: The combination of suboptimal nutrition due to removal of breast milk and formula feeding with
hyperoxia/hypoxia may increase susceptibility to oxidative stress, inflammation, and NEC. Probiotics, prebiotics
and synbiotics are protective against oxidative stress and inflammation, but their efficacy may be reduced when
administered during hyperoxia/hypoxia insults. (AJTR1112001).
Keywords: Cytokines, Hypoxia/Hyperoxia, Prebiotics, Probiotics, Synbiotics, Toll-like receptors
Address all correspondence to:
Dr. Antoni D’Souza
Department of Pediatrics
Division of Neonatal-Perinatal Medicine
SUNY Downstate Medical Center
450 Clarkson Avenue, Box 49
Brooklyn, NY 11203, USA.
Tel: (718) 270-4236; Fax: (718) 270-1985
E-mail: ad’souza@ downstate. edu
Original Article
Cytokines and Toll-like receptor signaling pathways in the terminal
ileum of hypoxic/hyperoxic neonatal rats: benefits of probiotics
supplementation
Antoni D’Souza, Charles L Cai, Dharmendra Kumar, Fayme Cai, Lawrence Fordjour, Asma Ahmad, Gloria
Valencia, Jacob V Aranda, Kay D Beharry
Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York, Downstate
Medical Center, Brooklyn, NY; Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of
California, Irvine, Irvine, CA; *Change of affiliation (F.C.): Lawrence Fordjour, Department of Pediatrics, Division of
Neonatal-Perinatal Medicine, Beth Israel Medical Center, Manhattan, NY, USA.
Received December 5, 2011; accepted March 13, 2012; Epub April 10; Published April 30, 2012
Abstract: Background: Oxidative stress and inflammation are associated with the development of inflammatory
bowel diseases such as necrotizing enterocolitis. We tested the hypothesis that probiotics, prebiotics or
synbiotics (a combination of pre- and probiotics) is effective for prevention of inflammatory responses to formula-
feeding in the terminal ileum of neonatal rats. Methods: Neonatal rats were exposed to hyperoxia/hypoxia during
which they were either maternally-fed or hand-fed with formula supplemented with probiotics, prebiotics or
synbiotics. A non-supplemented formula group served as controls. Cytokines and genes associated with
oxidative stress and toll-like receptor signaling were determined in the terminal ileum. Data were compared to
room air littermates. Results: Exposure to hyperoxia/hypoxia reduced growth accretion in maternally-fed pups.
NEC-like symptoms and intestinal inflammatory markers were induced with formula feeding. Supplementation
with probiotics, prebiotics or synbiotics decreased pro-inflammatory cytokines and downregulated genes involved
in oxidative stress and toll-like receptor pathways, however, the effect was attenuated in hyperoxia/hypoxia.
Conclusions: The combination of suboptimal nutrition due to removal of breast milk and formula feeding with
hyperoxia/hypoxia may increase susceptibility to oxidative stress, inflammation, and NEC. Probiotics, prebiotics
and synbiotics are protective against oxidative stress and inflammation, but their efficacy may be reduced when
administered during hyperoxia/hypoxia insults. (AJTR1112001).
Keywords: Cytokines, Hypoxia/Hyperoxia, Prebiotics, Probiotics, Synbiotics, Toll-like receptors
Address all correspondence to:
Dr. Antoni D’Souza
Department of Pediatrics
Division of Neonatal-Perinatal Medicine
SUNY Downstate Medical Center
450 Clarkson Avenue, Box 49
Brooklyn, NY 11203, USA.
Tel: (718) 270-4236; Fax: (718) 270-1985
E-mail: ad’souza@ downstate. edu
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