S100A8 and S100A9 Are Important for Postnatal Development of Gut Microbiota and Immune System in Mice and Infants.

BACKGROUND & AIMS: After birth, the immune system matures via interactions with microbes in the gut. The S100 calcium binding proteins S100A8 and S100A9, and their extracellular complex form, S100A8-A9, are found in high amounts in human breast milk. We studied levels of S100A8-A9 in fecal samples (also called fecal calprotectin) from newborns and during infancy, and their effects on development of the intestinal microbiota and mucosal immune system. METHODS: We collected stool samples (n = 517) from full-term (n = 72) and preterm infants (n = 49) at different timepoints over the first year of life (days 1, 3, 10, 30, 90, 180, and 360). We measured levels of S100A8-A9 by enzyme-linked immunosorbent assay and analyzed fecal microbiomes by 16S sRNA gene sequencing. We also obtained small and large intestine biopsies from 8 adults and 10 newborn infants without inflammatory bowel diseases (controls) and 8 infants with necrotizing enterocolitis and measured levels of S100A8 by immunofluorescence microscopy. Children were followed for 2.5 years and anthropometric data and medical information on infections were collected. We performed studies with newborn C57BL/6J wild-type and S100a9-/- mice (which also lack S100A8). Some mice were fed or given intraperitoneal injections of S100A8 or subcutaneous injections of Staphylococcus aureus. Blood and intestine, mesenterial and celiac lymph nodes were collected; cells and cytokines were measured by flow cytometry and studied in cell culture assays. Colon contents from mice were analyzed by culture-based microbiology assays. RESULTS: Loss of S100A8 and S100A9 in mice altered the phenotypes of colonic lamina propria macrophages, compared with wild-type mice. Intestinal tissues from neonatal S100-knockout mice had reduced levels of CX3CR1 protein, and Il10 and Tgfb1 mRNAs, compared with wild-type mice, and fewer T-regulatory cells. S100-knockout mice weighed 21% more than wild-type mice at age 8 weeks and a higher proportion developed fatal sepsis during the neonatal period. S100-knockout mice had alterations in their fecal microbiomes, with higher abundance of Enterobacteriaceae. Feeding mice S100 at birth prevented the expansion of Enterobacteriaceae, increased numbers of T-regulatory cells and levels of CX3CR1 protein and Il10 mRNA in intestine tissues, and reduced body weight and death from neonatal sepsis. Fecal samples from term infants, but not preterm infants, had significantly higher levels of S100A8-A9 during the first 3 months of life than fecal samples from adults; levels decreased to adult levels after weaning. Fecal samples from infants born by cesarean delivery had lower levels of S100A8-A9 than from infants born by vaginal delivery. S100 proteins were expressed by lamina propria macrophages in intestinal tissues from infants, at higher levels than in intestinal tissues from adults. High fecal levels of S100 proteins, from 30 days to 1 year of age, were associated with higher abundance of Actinobacteria and Bifidobacteriaceae, and lower abundance of Gammaproteobacteria-particularly opportunistic Enterobacteriaceae. A low level of S100 proteins in infants' fecal samples associated with development of sepsis and obesity by age 2 years. CONCLUSION: S100A8 and S100A9 regulate development of the intestinal microbiota and immune system in neonates. Nutritional supplementation with these proteins might aide in development of preterm infants and prevent microbiota-associated disorders in later years.

Lithocholic Acid Improves the Survival of Drosophila Melanogaster.

SCOPE: Primary bile acids are produced in the liver, whereas secondary bile acids, such as lithocholic acid (LCA), are generated by gut bacteria from primary bile acids that escape the ileal absorption. Besides their well-known function as detergents in lipid digestion, bile acids are important signaling molecules mediating effects on the host's metabolism. METHODS AND RESULTS: Fruit flies (Drosophila melanogaster) are supplemented with 50 µmol L-1 LCA either for 30 days or throughout their lifetime. LCA supplementation results in a significant induction of the mean (+12 days), median (+10 days), and maximum lifespan (+ 11 days) in comparison to untreated control flies. This lifespan extension is accompanied by an induction of spargel (srl), the fly homolog of mammalian PPAR-γ co-activator 1α (PGC1α). In wild-type flies, the administration of antibiotics abrogates both the LCA-mediated lifespan induction as well as the upregulation of srl. CONCLUSION: It is shown that the secondary bile acid LCA significantly induces the mean, the median, and the maximum survival in D. melanogaster. Our data suggest that besides an upregulation of the PGC1α-homolog srl, unidentified alterations in the structure or metabolism of the gut microbiota contribute to the longevity effect mediated by LCA.

Regulation of polyp-to-jellyfish transition in Aurelia aurita.

BACKGROUND: The life cycle of scyphozoan cnidarians alternates between sessile asexual polyps and pelagic medusa. Transition from one life form to another is triggered by environmental signals, but the molecular cascades involved in the drastic morphological and physiological changes remain unknown. RESULTS: We show in the moon jelly Aurelia aurita that the molecular machinery controlling transition of the sessile polyp into a free-swimming jellyfish consists of two parts. One is conserved and relies on retinoic acid signaling. The second, novel part is based on secreted proteins that are strongly upregulated prior to metamorphosis in response to the seasonal temperature changes. One of these proteins functions as a temperature-sensitive "timer" and encodes the precursor of the strobilation hormone of Aurelia. CONCLUSIONS: Our findings uncover the molecule framework controlling the polyp-to-jellyfish transition in a basal metazoan and provide insights into the evolution of complex life cycles in the animal kingdom.