Using a Mathematical Model to Analyze the Role of Probiotics and Inflammation in Necrotizing Enterocolitis

PLOS ONE, Apr 2010

Background Necrotizing enterocolitis (NEC) is a severe disease of the gastrointestinal tract of pre-term babies and is thought to be related to the physiological immaturity of the intestine and altered levels of normal flora in the gut. Understanding the factors that contribute to the pathology of NEC may lead to the development of treatment strategies aimed at re-establishing the integrity of the epithelial wall and preventing the propagation of inflammation in NEC. Several studies have shown a reduced incidence and severity of NEC in neonates treated with probiotics (beneficial bacteria species). Methodology/Principal Findings The objective of this study is to use a mathematical model to predict the conditions under which probiotics may be successful in promoting the health of infants suffering from NEC. An ordinary differential equation model is developed that tracks the populations of pathogenic and probiotic bacteria in the intestinal lumen and in the blood/tissue region. The permeability of the intestinal epithelial layer is treated as a variable, and the role of the inflammatory response is included. The model predicts that in the presence of probiotics health is restored in many cases that would have been otherwise pathogenic. The timing of probiotic administration is also shown to determine whether or not health is restored. Finally, the model predicts that probiotics may be harmful to the NEC patient under very specific conditions, perhaps explaining the detrimental effects of probiotics observed in some clinical studies. Conclusions/Significance The reduced, experimentally motivated mathematical model that we have developed suggests how a certain general set of characteristics of probiotics can lead to beneficial or detrimental outcomes for infants suffering from NEC, depending on the influences of probiotics on defined features of the inflammatory response.

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Using a Mathematical Model to Analyze the Role of Probiotics and Inflammation in Necrotizing Enterocolitis

Rubin JE (2010) Using a Mathematical Model to Analyze the Role of Probiotics and Inflammation in Necrotizing Enterocolitis. PLoS ONE 5(4): e10066. doi:10.1371/journal.pone.0010066 Using a Mathematical Model to Analyze the Role of Probiotics and Inflammation in Necrotizing Enterocolitis Julia C. Arciero 0 G. Bard Ermentrout 0 Jeffrey S. Upperman 0 Yoram Vodovotz 0 Jonathan E. Rubin 0 Rory Edward Morty, University of Giessen Lung Center, Germany 0 1 Department of Mathematics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America, 2 Department of Surgery, University of Southern California, Los Angeles, California, United States of America, 3 Department of Surgery, University of Pittsburgh , Pittsburgh, Pennsylvania , United States of America Background: Necrotizing enterocolitis (NEC) is a severe disease of the gastrointestinal tract of pre-term babies and is thought to be related to the physiological immaturity of the intestine and altered levels of normal flora in the gut. Understanding the factors that contribute to the pathology of NEC may lead to the development of treatment strategies aimed at re-establishing the integrity of the epithelial wall and preventing the propagation of inflammation in NEC. Several studies have shown a reduced incidence and severity of NEC in neonates treated with probiotics (beneficial bacteria species). Methodology/Principal Findings: The objective of this study is to use a mathematical model to predict the conditions under which probiotics may be successful in promoting the health of infants suffering from NEC. An ordinary differential equation model is developed that tracks the populations of pathogenic and probiotic bacteria in the intestinal lumen and in the blood/tissue region. The permeability of the intestinal epithelial layer is treated as a variable, and the role of the inflammatory response is included. The model predicts that in the presence of probiotics health is restored in many cases that would have been otherwise pathogenic. The timing of probiotic administration is also shown to determine whether or not health is restored. Finally, the model predicts that probiotics may be harmful to the NEC patient under very specific conditions, perhaps explaining the detrimental effects of probiotics observed in some clinical studies. Conclusions/Significance: The reduced, experimentally motivated mathematical model that we have developed suggests how a certain general set of characteristics of probiotics can lead to beneficial or detrimental outcomes for infants suffering from NEC, depending on the influences of probiotics on defined features of the inflammatory response. - Funding: This work was supported by National Science Foundation Grant EMSW21-RTG 0739261 (http://www.nsf.gov/) and National Institutes of Health Grant P50-GM-53789 (http://www.nih.gov/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Necrotizing enterocolitis (NEC) is a severe disease of the gastrointestinal (GI) tract that is characterized by increased permeability of the intestine and is primarily observed in pre-term babies. Although the causes of this disease are not fully known, most studies conclude that prematurity is the greatest risk factor. NEC affects 7{10% of low birth weight (v1500 g) premature infants and is observed typically within 7 to 14 days of birth [1]. Symptoms of NEC mainly involve gastrointestinal dysfunction, such as abdominal distension and feeding intolerance. Current forms of treatment may be invasive, including surgical interventions, and are often insufficient due to the fragility of the patients and rapid progression of the disease. Mortality from NEC is nearly 30{50% for infants with surgical intervention [2]. Moreover, infants who recover from severe forms of the disease may experience complications and other bowel disorders later in life [38]. The severity of this disease, which stems from a complex inflammatory response and immaturity of organ architecture and physiology, coupled to a lack of effective therapy, suggests that systems approaches such as computational modeling may be necessary to gain a fuller insight into both mechanism and therapy. Possible factors contributing to NEC Although its pathophysiology is not entirely understood, NEC is thought to be related to the physiological immaturity of the GI tract and altered levels of normal flora in the intestines. A mature intestine contains many defense mechanisms that act as barriers to harmful bacteria. Many of these defense mechanisms, such as peristalsis and tight junctions between intestinal epithelial cells [1,3,4], are abnormal or decreased in an immature intestine, and thus bacteria normally confined to the intestinal lumen are able to reach systemic organs and tissues. Bacterial translocation triggers the activation (...truncated)


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Julia C. Arciero, G. Bard Ermentrout, Jeffrey S. Upperman, Yoram Vodovotz, Jonathan E. Rubin. Using a Mathematical Model to Analyze the Role of Probiotics and Inflammation in Necrotizing Enterocolitis, PLOS ONE, 2010, Volume 5, Issue 4, DOI: 10.1371/journal.pone.0010066