Preterm infant gut microbiota affects intestinal epithelial development in a humanized microbiome gnotobiotic mouse model

Abstract

Changes in the microbiome early in life may affect host physiology across the life span. Early life interaction between host and luminal microbes was investigated using a mouse model in which germ-free mice were transfaunated with fecal lysates from human preterm infants. Our data demonstrate that microbial communities affect differentiation of intestinal epithelial cell lineages, which may lead to significant effects on developmental, defensive, and physiological processes of the gastrointestinal epithelium .

Abstract

Development of the infant small intestine is influenced by bacterial colonization. To promote establishment of optimal microbial communities in preterm infants, knowledge of the beneficial functions of the early gut microbiota on intestinal development is needed. The purpose of this study was to investigate the impact of early preterm infant microbiota on host gut development using a gnotobiotic mouse model. Histological assessment of intestinal development was performed. The differentiation of four epithelial cell lineages (enterocytes, goblet cells, Paneth cells, enteroendocrine cells) and tight junction (TJ) formation was examined. Using weight gain as a surrogate marker for health, we found that early microbiota from a preterm infant with normal weight gain (M _PI-H) induced increased villus height and crypt depth, increased cell proliferation, increased numbers of goblet cells and Paneth cells, and enhanced TJs compared with the changes induced by early microbiota from a poor weight gain preterm infant (M _PI-L). Laser capture microdissection (LCM) plus qRT-PCR further revealed, in M _PI-H mice, a higher expression of stem cell marker Lgr5 and Paneth cell markers Lyz1 and Cryptdin5 in crypt populations, along with higher expression of the goblet cell and mature enterocyte marker Muc3 in villus populations. In contrast, M _PI-L microbiota failed to induce the aforementioned changes and presented intestinal characteristics comparable to a germ-free host. Our data demonstrate that microbial communities have differential effects on intestinal development. Future studies to identify pioneer settlers in neonatal microbial communities necessary to induce maturation may provide new insights for preterm infant microbial ecosystem therapeutics.