Abstract
Background and AimsIt is known that postnatal functional maturation of the small intestine is facilitated by microbial colonization of the gut. Preterm infants exhibit defects in gut maturation, weak innate immunity against intestinal infection and increased susceptibility to inflammatory disorders, all of which may be related to the inappropriate microbial colonization of their immature intestines. The earliest microbes to colonize the preterm infant gut encounter a naïve, immature intestine. Thus this earliest microbiota potentially has the greatest opportunity to fundamentally influence intestinal development and immune function. The aim of this study was to characterize the effect of early microbial colonization on global gene expression in the distal small intestine during postnatal gut development.MethodsGnotobiotic mouse models with experimental colonization by early (prior to two weeks of life) intestinal microbiota from preterm human infants were utilized. Microarray analysis was used to assess global gene expression in the intestinal epithelium.Results and ConclusionMultiple intestinal genes involved in metabolism, cell cycle regulation, cell-cell or cell-extracellular matrix communication, and immune function are developmental- and intestinal microbiota- regulated. Using a humanized gnotobiotic mouse model, we demonstrate that certain early preterm infant microbiota from prior to 2 weeks of life specifically induce increased NF-κB activation and a phenotype of increased inflammation whereas other preterm microbiota specifically induce decreased NF-κB activation. These fundamental differences correlate with altered clinical outcomes and suggest the existence of optimal early microbial communities to improve health outcomes.
Highlights
The human gastrointestinal tract is densely colonized with approximately 1014 resident bacteria [1] which provide many benefits to the host including supply of essential nutrients, metabolism of indigestible compounds, defense against colonization by pathogens and influence on the development of intestinal architecture [2,3,4,5,6,7,8]
Using a humanized gnotobiotic mouse model, we demonstrate that certain early preterm infant microbiota from prior to 2 weeks of life induce increased NF-κB activation and a phenotype of increased inflammation whereas other preterm microbiota induce decreased NF-κB activation
The differentially expressed genes were predominately associated with metabolism, as the top three scored Gene ontology (GO) categories were metabolic process, cellular metabolic, and single-organism metabolic process in Germ free (GF); single-organism metabolic, small molecule metabolic and metabolic process in specific pathogen free environment (SPF) mouse respectively (Fig 1A)
Summary
The human gastrointestinal tract is densely colonized with approximately 1014 resident bacteria [1] which provide many benefits to the host including supply of essential nutrients, metabolism of indigestible compounds, defense against colonization by pathogens and influence on the development of intestinal architecture [2,3,4,5,6,7,8]. Assembly of the gut microbiota has been linked to the terminal differentiation of intestinal structures [10] and the development of innate immune responses under optimal conditions [11,12]. This microbial colonization has been linked to disease states like necrotizing enterocolitis[13,14]. The earliest microbes to colonize the preterm infant gut encounter a naïve, immature intestine This earliest microbiota potentially has the greatest opportunity to fundamentally influence intestinal development and immune function. The aim of this study was to characterize the effect of early microbial colonization on global gene expression in the distal small intestine during postnatal gut development
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