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Alanyl-glutamine Protects Against Damage Induced by Enteroaggregative Escherichia coli Strains in Intestinal Cells

Prata, Mara M.G.*; Cavalcante, Paloma A.*; da Silva, Antonio V. Alves*; de Medeiros, Pedro H.Q.S.*; de Assis Júnior, Eudmar M.*; Reyes, Mayra A.V.*; Quetz, Josiane da S.*; Clementino, Marco A.F.*; Ribeiro, Samilly A.*; Lima, Ila F.N.*; Lima-Junior, Roberto C.P.*; Havt, Alexandre*; Guerrant, Richard L.; Lima, Aldo A.M.*

Journal of Pediatric Gastroenterology and Nutrition: February 2019 - Volume 68 - Issue 2 - p 190–198
doi: 10.1097/MPG.0000000000002152
Original Articles: Gastroenterology

Background: Enteroaggregative Escherichia coli (EAEC) is an important pathogen causing enteric infections worldwide. This pathotype is linked to malnutrition in children from developing countries. Alanyl-glutamine (Ala-Gln) is an immune modulator nutrient that acts during intestinal damage and/or inflammation. This study investigated the effect of EAEC infection and Ala-Gln on cell viability, cell death, and inflammation of intestinal epithelium cells (IEC-6).

Methods: Cells were infected with an EAEC prototype 042 strain, an EAEC wild-type strain isolated from a Brazilian malnourished child, and a commensal E coli HS. Gene transcription and protein levels of caspases-3, -8, and -9 and cytokine-induced neutrophil chemoattractant 1 (CINC-1/CXCL1) were evaluated using RT-qPCR, western blot analysis, and ELISA.

Results: Infections with both EAEC strains decreased cell viability and induced apoptosis and necrosis after 24 hours. Ala-Gln supplementation increased cell proliferation and reduced cell death in infected cells. Likewise, EAEC strain 042 significantly increased the transcript levels of caspases-3, -8, and -9 when compared to the control group, and Ala-Gln treatment reversed this effect. Furthermore, EAEC induced CXCL1 protein levels, which were also reduced by Ala-Gln supplementation.

Conclusion: These findings suggest that EAEC infection promotes apoptosis, necrosis, and intestinal inflammation with involvement of caspases. Supplementation of Ala-Gln inhibits cell death, increases cell proliferation, attenuates mediators associated with cell death, and inflammatory pathways in infected cells.

*Department of Physiology and Pharmacology and INCT-Biomedicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil

Division of Infectious, Diseases and International Medicine, Center for Global Health, University of Virginia School of Medicine, Charlottesville, VA.

Address correspondence and reprint requests to Aldo A.M. Lima, PhD, Faculty of Medicine, Institute of Biomedicine, Federal University of Ceará, R. Cel. Nunes de Melo 1315, Rodolfo Teófilo, CEP 60.430-270, CE, Fortaleza, Brazil (e-mail:

Received 28 December, 2017

Accepted 9 September, 2018

The National Council for Scientific and Technological Development (CNPq Grants: 503442/2008-9 and 573928/2008-8) and Cearense Foundation for the Support of Scientific and Technological Development (FUNCAP) provided financial support for these studies.

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The authors report no conflicts of interest.

© 2019 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,