Necrotizing enterocolitis (NEC) is the most common intestinal disease of premature infants. Although increased mucosal permeability and altered epithelial structure have been associated with many intestinal disorders, the role of intestinal barrier function in NEC pathogenesis is currently unknown. We investigated the structural and functional changes of the intestinal barrier in a rat model of NEC. In addition, the effect of EGF treatment on intestinal barrier function was evaluated. Premature rats were divided into three groups: dam fed (DF), formula fed (NEC), or fed with formula supplemented with 500 ng/ml EGF (NEC + EGF); all groups were exposed to asphyxia/cold stress to develop NEC. Intestinal permeability, goblet cell density, mucin production, and composition of tight junction (TJ) proteins were evaluated in the terminal ileum, the site of NEC injury, and compared with the proximal jejunum, which was unaffected by NEC. Animals with NEC had significantly increased intestinal paracellular permeability compared with DF pups. Ileal goblet cell morphology, mucin production, and TJ composition were altered in animals with NEC. EGF treatment significantly decreased intestinal paracellular permeability, increased goblet cell density and mucin production, and normalized expression of two major TJ proteins, occludin and claudin-3, in the ileum. In conclusion, experimental NEC is associated with disruption of the intestinal barrier. EGF treatment maintains intestinal integrity at the site of injury by accelerating goblet cell maturation and mucin production and normalizing expression of TJ proteins, leading to improved intestinal barrier function.

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Bile acids are implicated as etiologic agents in cancer of the gastrointestinal (GI) tract, including cancer of the esophagus, stomach, small intestine, liver, biliary tract, pancreas and colon/rectum. Deleterious effects of bile acid exposure, likely related to carcinogenesis, include: induction of reactive oxygen and reactive nitrogen species; induction of DNA damage; stimulation of mutation; induction of apoptosis in the short term, and selection for apoptosis resistance in the long term. These deleterious effects have, so far, been reported most consistently in relation to esophageal and colorectal cancer, but also to some extent in relation to cancer of other organs. In addition, evidence is reviewed for an association of increased bile acid exposure with cancer risk in human populations, in specific human genetic conditions, and in animal experiments. A model for the role of bile acids in GI carcinogenesis is presented from a Darwinian perspective that offers an explanation for how the observed effects of bile acids on cells contribute to cancer development.

Khailova L, Dvorak K, Arganbright KM, Halpern MD, Kinouchi T, Yajima M, Dvorak B. Bifidobacterium bifidum improves intestinal integrity in a rat model of necrotizing enterocolitis.

Nuclear factor kappa B (NF-kappaB) is a redox-associated transcription factor that is involved in the activation of survival pathways. We have previously shown that deoxycholate (DOC) activates NF-kappaB in hepatocytes and colon epithelial cells and that persistent exposure of HCT-116 cells to increasing concentrations of DOC results in the constitutive activation of NF-kappaB, which is associated with the development of apoptosis resistance. The mechanisms by which DOC activates NF-kappaB in colon epithelial cells, and whether natural antioxidants can reduce DOC-induced NF-kappaB activation, however, are not known. Also, it is not known if DOC can generate reactive oxygen species within mitochondria as a possible pathway of stress-related NF-kappaB activation. Since we have previously shown that DOC activates the NF-kappaB stress-response pathway in HCT-116 cells, we used this cell line to further explore the mechanisms of NF-kappaB activation. We found that DOC induces mitochondrial oxidative stress and activates NF-kappaB in HCT-116 cells through multiple mechanisms involving NAD(P)H oxidase, Na+/K+-ATPase, cytochrome P450, Ca++ and the terminal mitochondrial respiratory complex IV. DOC-induced NF-kappaB activation was significantly (P < 0.05) inhibited by pre-treatment of cells with CAPE, EGCG, TMS, DPI, NaN3, EGTA, Ouabain and RuR. The NF-kappaB-activating pathways, induced by the dietary-related endogenous detergent DOC, provide mechanisms for promotion of colon cancer and identify possible new targets for chemoprevention.