Using a Mathematical Model to Analyze the Role of Probiotics 1 and Inflammation in Necrotizing Enterocolitis

8 Background: Necrotizing enterocolitis (NEC) is a severe disease of the gastrointestinal tract of pre-term 9 babies and is thought to be related to the physiological immaturity of the intestine and altered levels of 10 normal flora in the gut. Understanding the factors that contribute to the pathology of NEC may lead to 11 the development of treatment strategies aimed at re-establishing the integrity of the epithelial wall and 12 preventing the propagation of inflammation in NEC. Several studies have shown a reduced incidence and 13 severity of NEC in neonates treated with probiotics (beneficial bacteria species). 14 15 Methodology/Principal Findings: The objective of this study is to use a mathematical model to 16 predict the conditions under which probiotics may be successful in promoting the health of infants suf17 fering from NEC. An ordinary differential equation model is developed that tracks the populations of 18 pathogenic and probiotic bacteria in the intestinal lumen and in the blood/tissue region. The permeabil19 ity of the intestinal epithelial layer is treated as a variable, and the role of the inflammatory response 20 is included. The model predicts that in the presence of probiotics health is restored in many cases that 21 would have been otherwise pathogenic. The timing of probiotic administration is also shown to determine 22 whether or not health is restored. Finally, the model predicts that probiotics may be harmful to the NEC 23 patient under very specific conditions, perhaps explaining the detrimental effects of probiotics observed 24 in some clinical studies. 25 26 Conclusions/Significance: The mathematical model developed in this study is able to predict phys27 iological outcomes consistent with experiment and can be used to suggest general characteristics of 28 probiotics necessary to ensure mainly beneficial effects as well as conditions under which probiotics may 29 be a successful treatment for infants suffering from NEC. 30