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Initial colonizing bacteria play a critical role in completing the development of the immune system in the gastrointestinal tract of infants. Yet, the interaction of colonizing bacterial organisms with the developing human intestine favors inflammation over immune homeostasis. This characteristic of bacterial-intestinal interaction partially contributes to the pathogenesis of necrotizing enterocolitis (NEC), a devastating premature infant intestinal inflammatory disease. However, paradoxically some unique pioneer bacteria (initial colonizing species) have been shown to have a beneficial effect on the homeostasis of the immature intestine and the prevention of inflammation. We have reported that one such pioneer bacterium, Bacteroides fragilis ( B. fragilis), and its surface component polysaccharide A (PSA) inhibit IL-1β-induced inflammation in a human primary fetal small intestinal cell line (H4 cells). In this study, using transcription profiling of H4 cellular RNA after pretreatment with or without PSA before an inflammatory stimulation of IL-1β, we have begun to further determine the cellular mechanism for anti-inflammation. We show that a developmentally regulated gene, zona pellucida protein 4 ( ZP4), is uniquely elevated after IL-1β stimulation and reduced with PSA exposure. ZP4 was known as a sperm receptor-mediating species-specific binding protein in the initial life of mammals. However, its intestinal epithelial function is unclear. We found that ZP4 is a developmentally regulated gene involved with immune function and regulated by both Toll-like receptor 2 and 4. Knockdown of ZP4-affected PSA inhibited IL-8 mRNA expression in response to IL-1β. This represents an initial study of ZP4 innate immune function in immature enterocytes. This study may lead to new opportunity for efficient treatment of NEC. NEW & NOTEWORTHY This study extends previous observations to define the cellular mechanisms of polysaccharide A-induced anti-inflammation in immature enterocytes using transcription profiling of enterocyte genes after preexposure to polysaccharide A before an inflammatory stimulus with IL-1β.

A topological data analysis approach is taken to the challenging problem of finding and validating the statistical significance of local modes in a data set. As with the SIgnificance of the ZERo (SiZer) approach to this problem, statistical inference is performed in a multi-scale way, that is, across bandwidths. The key contribution is a twoparameter approach to the persistent homology representation. For each kernel bandwidth, a sub-level set filtration of the resulting kernel density estimate is computed. Inference based on the resulting persistence diagram indicates statistical significance of modes. It is seen through a simulated example, and by analysis of the famous Hidalgo stamps data, that the new method has more statistical power for finding bumps than SiZer.