Bifidobacterium adolescentis protects against necrotizing enterocolitis and upregulates TOLLIP and SIGIRR in premature neonatal rats

Abstract

BackgroundNecrotizing enterocolitis (NEC) is a serious gastrointestinal disorder that is often seen in premature infants. Probiotics decrease the risk of NEC; however, the mechanism by which probiotics work is not clear. The goal of this study was to evaluate the preventive effect of Bifidobacterium adolescentis in an NEC rat model.MethodsSprague-Dawley neonatal rats were obtained by caesarean section after 20-21 d gestation and randomly divided into the following 3 groups: dam fed (DF), formula fed (FF), and formula + B. adolescentis (FB). Those in the FF and FB groups developed NEC after exposure to asphyxia and cold stress. All rats were sacrificed 72 h after birth and intestinal injury and mRNA expression of TLR4, TOLLIP and SIGIRR were assessed.Results B. adolescentis significantly increased the 72-h survival rate from 56.3% in the FF group to 86.7% in the FB group. B. adolescentis significantly reduced the histological score from a median of 3.0 in the FF group to a median of 1.0 in the FB group,and significantly decreased the rate of NEC-like intestinal injury from 77.8% in the FF group to 23.1% in the FB group. The mRNA expression of TLR4 increased 3.6 fold in the FF group but decreased by 2 fold from B. adolescentis treatment. mRNA expression of TOLLIP and SIGIRR decreased 4.3 and 3.7 fold, respectively, in the FF group. B. adolescentis significantly increased mRNA expression of TOLLIP and SIGIRR by 3.7 fold and 2.6 fold, respectively.ConclusionsThis study demonstrated B. adolescentis prevents NEC in preterm neonatal rats and that the mechanism for this action might be associated with the alteration of TLR4, TOLLIP, and SIGIRR expression.

Glycine Relieves Intestinal Injury by Maintaining mTOR Signaling and Suppressing AMPK, TLR4, and NOD Signaling in Weaned Piglets after Lipopolysaccharide Challenge

“…Supplementation with glycine increased mRNA expression of ileal ERBB2IP. Previous studies showed that Tollip bound to IL-1 receptor-associated kinase (IRAK) and inhibited IRAK phosphorylation to downregulate TLR4 signaling [ 54 ]. This indicates that supplementation with glycine could suppress the activity of IRAK by increasing the mRNA expression of Tollip, resulting in impairing the signaling from TLR4 to downstream pathways, and reducing the synthesis of pro-inflammatory cytokines.…”

Glutamate alleviates intestinal injury, maintains mTOR and suppresses TLR4 and NOD signaling pathways in weanling pigs challenged with lipopolysaccharide

“…In order to prevent excessive inflammatory responses, many mechanisms can negatively control inflammatory signaling pathways. So far, several negative regulators of TLR4 (such as SOCS1 and Tollip) and NOD (such as ERBB2IP and ACAP1) signaling pathways have been identified and characterized 44 – 46 . Our data reflected that the LPS-challenged pigs had reduced mRNA expressions of ileal ERBB2IP and Tollip, which is in agreement with the study of Wang et al .…”

“…Wu et al . demonstrated that Tollip down-regulated the TLR4 signaling pathway via bounding to IL-1 receptor-associated kinase (IRAK) and inhibiting IRAK phosphorylation 44 . This indicates that supplementation with Glu could inhibit the activity of IRAK through increasing the gene expression of Tollip, leading to impair the signaling from TLR4 to downstream pathways and reduce the synthesis of pro-inflammatory cytokines.…”

Toll-Like Receptor–Mediated Intestinal Inflammatory Imbalance in the Pathogenesis of Necrotizing Enterocolitis

“…One of the most important pathways that mediates the balance between injury and repair in the premature intestine, and that plays a key role in NEC pathogenesis, is the Toll-like receptor (TLR) family of bacterial recognition receptors, specifically Toll-like receptor 4 (TLR4), which recognizes lipopolysaccharide (LPS) on gram-negative bacteria. 17 Key evidence linking TLR4 with the pathogenesis of NEC include the findings that the expression of TLR4 in the intestinal epithelium is increased in mice and human beings with NEC, 18 , 19 activating mutations in TLR4 signaling pathways are seen in human NEC, 20 , 21 , 22 , 23 and novel TLR4 inhibitors prevent and treat NEC in animal models and attenuate proinflammatory signaling in human NEC tissue ex vivo, 24 whereas mice lacking TLR4 in the intestinal epithelium are protected from NEC development. 25 It is noteworthy that there are other pathways that also play a role in the pathogenesis of NEC, many of which are downstream of TLR4, and these have been reviewed extensively by us recently elsewhere, 15 while other investigators have shown that the premature intestine is more prone to inflammation 26 in part through the expression of innate immune response genes including TLR4 and its gene family members, 27 which is supportive of this concept.…”