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Probiotic Bacteria Induce Maturation of Intestinal Claudin 3 Expression and Barrier Function
Ravi Mangal Patel1, Loren S Myers1, Ashish R Kurundkar2, Akhil Maheshwari2, Asma Nusrat3 and Patricia W Lin1.
From the Department of Pediatrics1, Emory University School of Medicine, Atlanta, GA, Department of Pediatrics2, University of Alabama at Birmingham School of Medicine, Birmingham, AL, and the Department of Pathology3, Emory University School of Medicine, Atlanta, GA.
The American Journal of Pathology, Vol. 180, Issue 2, Pages 626-635, February 2012, DOI:10.1016/j.ajpath.2011.10.025
Impaired intestinal barrier function has been implicated in the pathogenesis of several intestinal diseases including infectious enteritis, inflammatory bowel disease, and necrotizing enterocolitis (NEC). These diseases impart a substantial morbidity and mortality to newborn infants and children. Understanding the factors that regulate gut barrier maturation may yield insight into strategies to prevent these intestinal diseases. Commensal bacteria, which normally colonize the murine gut during the first several weeks of postnatal life, induce expression of genes that improve intestinal barrier function, whereas abnormal bacterial colonization may disrupt this process and contribute to the development of host diseases. Infants with abnormal intestinal microbial composition are predisposed to intestinal disease as the result of a failure in postnatal maturation of this critical protective barrier, leading to intestinal inflammation and injury. Thus, Patel et al aimed to determine how commensal bacterial colonization may regulate the development of intestinal epithelial barrier function using a murine model of the immature intestine. Specifically, Patel et al investigated the claudin family of tight junction (TJ) proteins, which are known to play an important role in regulating epithelial paracellular permeability and gut barrier function.
In the present study, Patel et al report that intestinal epithelial barrier function matures at 3 weeks of life in the neonatal mouse. By measuring mRNA expression of a panel of TJ proteins, the authors identified claudin 3 as the most upregulated intestinal TJ protein at this time. Further, neonatal mice raised on antibiotics or those lacking the key TLR adaptor molecule, MyD88, exhibited impaired barrier function and decreased claudin 3 expression. These results indicate that commensal bacterial colonization induces intestinal barrier function maturation by promoting claudin 3 expression. Finally, Patel et al were able to demonstrate that enteral administration of the probiotic Lactobacillus rhamnosus GG (LGG) could accelerate intestinal barrier maturation and induce claudin 3 expression in neonatal mice.
While probiotics have shown promise in clinical trials as a potential therapy to prevent neonatal inflammatory bowel diseases such as NEC, their use has been limited by the concern for side-effects such as sepsis. The present report confirms these concerns since neonatal mice treated with live LGG had increased mortality. Importantly, this study reports for the first time that heat-killed preparations of probiotics (LGG) can also accelerate barrier function. Thus bacterial components present in heat-killed probiotics can improve epithelial barrier function in the immature intestine without increasing mortality.
Overall, Patel et al, provide evidence that commensal and probiotic bacteria play a key role in the developmental maturation of the intestinal epithelial barrier by regulating claudin 3 protein expression. More important, the authors demonstrate that probiotic administration can accelerate the maturation of both claudin 3 protein expression and intestinal barrier function in an immature gut. Specifically, bacterial components from heat-killed probiotics may be a promising therapy to prevent neonatal inflammatory bowel diseases by inducing intestinal epithelial barrier maturation without increasing mortality.