Breast milk protects against the development of necrotizing enterocolitis through inhibition of Toll-like receptor 4 in the intestinal epithelium via activation of the epidermal growth factor receptor

Good, Misty; Sodhi, Chhinder P.; Egan, Charlotte E.; Afrazi, Amin; Jia, Hongpeng; Yamaguchi, Yoshiaki; Lü, Peng; Branca, Maria F.; Ma, Congrong; Prindle, Thomas; Mielo, Samantha; Pompa, Anthony G; Hodzic, Zerina; Ozolek, John A.; Hackam, David J.

doi:10.1038/mi.2015.30

Cited by 180 publications

(211 citation statements)

References 54 publications

(97 reference statements)

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“…The addition of exogenous bacteria or LPS has been commonly described to enhance rodent NEC models. 16,51,52 We chose to use C. sakazakii in our experimental models of NEC because this bacteria has been implicated in human outbreaks of NEC. Furthermore, C. sakazakii is representative of the most common types of pathogens found in human NEC (Enterobacteriaceae).…”

Section: Discussionmentioning

confidence: 99%

A Role for cAMP and Protein Kinase A in Experimental Necrotizing Enterocolitis

Blackwood

Wood

Yuan

et al. 2017

The American Journal of Pathology

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Necrotizing enterocolitis (NEC) is a devastating intestinal disease that has been associated with Cronobacter sakazakii and typically affects premature infants. Although NEC has been actively investigated, little is known about the mechanisms underlying the pathophysiology of epithelial injury and intestinal barrier damage. Cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) are important mediators and regulators of apoptosis. To test the hypothesis that C. sakazakii increases cAMP and PKA activation in experimental NEC resulting in increased epithelial apoptosis, we investigated the effects of C. sakazakii on cAMP and PKA in vitro and in vivo. Specifically, rat intestinal epithelial cells and a human intestinal epithelial cell line were infected with C. sakazakii, and cAMP levels and phosphorylation of PKA were measured. An increase in cAMP was demonstrated after infection, as well as an increase in phosphorylated PKA. Similarly, increased intestinal cAMP and PKA phosphorylation were demonstrated in a rat pup model of NEC. These increases were correlated with increased intestinal epithelial apoptosis. The additional of a PKA inhibitor (KT5720) significantly ameliorated these effects and decreased the severity of experimental NEC. Findings were compared with results from human tissue samples. Collectively, these observations indicate that cAMP and PKA phosphorylation are associated with increased apoptosis in NEC and that inhibition of PKA activation protects against apoptosis and experimental NEC. (Am J Pathol 2017, 187: 401e417; http://dx

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Section: Discussionmentioning

confidence: 99%

A Role for cAMP and Protein Kinase A in Experimental Necrotizing Enterocolitis

Blackwood

Wood

Yuan

et al. 2017

The American Journal of Pathology

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“…Although the precise mechanisms by which breast milk protects against NEC are not yet fully understood, emerging experimental evidence suggests that breast milk inhibits TLR4 signalling by preventing glycogen synthase kinase 3β activity [77]. Consequently, breast milk-mediated downregulation of TLR4 signalling can reverse the inhibition of intestinal stem cell proliferation and mucosal healing, which are themselves inhibited by TLR4 [77] [78].…”

Section: The Use Of Breast Milkmentioning

confidence: 99%

New Frontiers of Necrotizing Enterocolitis: From Pathophysiology to Treatment

Zubarioglu¹,

Uslu²,

Bülbül³

2017

Health

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Necrotizing enterocolitis [NEC] is an inflammatory disease of intestine largely occuring in preterm infants with a wide range of damage from minimal injury limited to mucosa to extensive necrosis of bowel wall and perforation. Despite advancements in neonatal care, mortality remains high [30% -50%] and controversy still persists with regards to the most appropriate management of neonates with necrotizing enterocolitis. The main factors thought to be involved in the pathogenesis of NEC are: relatively hyper-reactive state of premature intestine, enteral feeding and bacterial colonization. In this review, we discuss current knowledge about the epidemiology, pathophysiology, imaging, medical and surgical management of necrotizing enterocolitis and describe novel strategies for prevention and treatment.

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“…Humans with NEC and rodent models of NEC both show elevated TLR4 expression that triggers enterocyte apoptosis and mucosal inflammation (38). EGF is highly abundant in both amniotic fluid as well as in breast milk; it inhibits TLR-4 signaling and prevents the development of NEC in animal models (39)(40)(41).…”

Section: Management Strategiesmentioning

confidence: 99%

Probiotics, Prebiotics, and Synbiotics for the Prevention of Necrotizing Enterocolitis

Johnson‐Henry

Abrahamsson

et al. 2016

Advances in Nutrition

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Necrotizing enterocolitis (NEC) is a devastating intestinal disease in preterm infants characterized by barrier disruption, intestinal microbial dysbiosis, and persistent inflammation of the colon, which results in high mortality rates. Current strategies used to manage this disease are not sufficient, although the use of human breast milk reduces the risk of NEC. Mother's milk is regarded as a fundamental nutritional source for neonates, but pasteurization of donor breast milk affects the composition of bioactive compounds. Current research is evaluating the benefits and potential pitfalls of adding probiotics and prebiotics to pasteurized milk so as to improve the functionality of the milk and thereby reduce the burden of illness caused by NEC. Probiotics (live micro-organisms that confer health to the host) and prebiotics (nondigestible oligosaccharides that stimulate the growth of healthy bacteria) are functional foods known to mediate immune responses and modulate microbial populations in the gut. Clinical research shows strain-and compoundspecific responses when probiotics or prebiotics are administered in conjunction with donor breast milk for the prevention of NEC. Despite ongoing controversy surrounding optimal treatment strategies, randomized controlled studies are now investigating the use of synbiotics to reduce the incidence and severity of NEC. Synbiotics, a combination of probiotics and prebiotics, have been proposed to enhance beneficial health effects in the intestinal tract more than either agent administered alone. This review considers the implications of using probiotic-, prebiotic-, and synbioticsupplemented breast milk as a strategy to prevent NEC and issues that could be encountered with the preparations. Adv Nutr 2016;7:928-37.

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Breast milk protects against the development of necrotizing enterocolitis through inhibition of Toll-like receptor 4 in the intestinal epithelium via activation of the epidermal growth factor receptor

Cited by 180 publications

References 54 publications

A Role for cAMP and Protein Kinase A in Experimental Necrotizing Enterocolitis

A Role for cAMP and Protein Kinase A in Experimental Necrotizing Enterocolitis

New Frontiers of Necrotizing Enterocolitis: From Pathophysiology to Treatment

Probiotics, Prebiotics, and Synbiotics for the Prevention of Necrotizing Enterocolitis

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