Transient neonatal antibiotic exposure increases susceptibility to late-onset sepsis driven by microbiota-dependent suppression of type 3 innate lymphoid cells

Abstract

extended early antibiotic exposure in the neonatal intensive care unit is associated with an increased risk for the development of late-onset sepsis (LoS). However, few studies have examined the mechanisms involved. We sought to determine how the neonatal microbiome and intestinal immune response is altered by transient early empiric antibiotic exposure at birth. neonatal mice were transiently exposed to broad-spectrum antibiotics from birth for either 3-(SE) or 7-days (LE) and were examined at 14-days-old. We found that mice exposed to either SE or LE showed persistent expansion of Proteobacteria (2 log difference, P < 0.01). Further, LE mice demonstrated baseline translocation of E. coli into the liver and spleen and were more susceptible K. pneumoniae-induced sepsis. Le mice had a significant and persistent decrease in type 3 innate lymphoid cells (ILC3) in the lamina propria. Reconstitution of the microbiome with mature microbiota by gavage in Le mice following antibiotic exposure resulted in an increase in ILC3 and partial rescue from LOS. We conclude that prolonged exposure to broad spectrum antibiotics in the neonatal period is associated with persistent alteration of the microbiome and innate immune response resulting in increased susceptibility to infection that may be partially rescued by microbiome reconstitution. Seventy five percent of preterm babies admitted to the neonatal intensive care unit (NICU) receive antibiotics empirically 1,2. Empiric antibiotics are generally broad-spectrum and prescribed based on risk assessment and not direct evidence of infection. The majority of infants in the NICU are exposed to transient antibiotics from birth that ranges from 2 to 7 days. Prolonged empiric antibiotics, lasting more than 2 days, are administered to approximately 35% to 50% of infants with a low gestational age 3. Many babies born prematurely are also exposed to antibiotics in utero just prior to birth. Several clinical studies have demonstrated that exposure to transient early antibiotics in the NICU can increase the risk for development of late-onset sepsis (LOS) 1,2,4,5. LOS is an important cause of morbidity and mortality in the NICU 5,6. Alteration of the intestinal microbiome and innate immune response may play an important role in increasing the risk for LOS in preterm infants. Early normal bacterial colonization is important for normal development of the gut 7 : strengthening and promoting gut barrier integrity 8,9 , protecting against pathogens 10 and regulating host immunity 11-13. Establishment of the microbiome during the neonatal period depends on multiple factors, including mode of delivery, breast versus formula feeding, gestational age, infant hospitalization, maternal diet and antibiotic use by the infant 14,15. While antibiotics are beneficial for treating human bacterial infections, even

Colonization at birth with human CST IV cervicovaginal microbiota alters development and increases neonatal mortality in mice

“…As early life microbiota composition can influence circulating immune cell composition and function, we next determined whether transplantation of CST I or CST IV microbiota influenced circulating immunity in P1 male offspring (Deshmukh et al, 2014; Gensollen et al, 2016; Niu et al, 2020; Olszak et al, 2012; Singer et al, 2019). We used an established model of perinatal antibiotic exposure whereby pregnant dams are exposed to ampicillin, vancomycin, and neomycin to deplete microbiota and thus prevents vertical transmission of maternal microbiota to offspring (Deshmukh et al, 2014).…”

Maternal Microbiota, Early Life Colonization and Breast Milk Drive Immune Development in the Newborn

“…Likewise, the maturation of the immune system is impaired due to its indispensable relationship with the microbiota. In a murine model, Niu et al could unravel the effects of antibiotic use and LOS on the innate immune system (83). Specific pathogen-free (SPF) dams were treated with antibiotics either shortly (3 d) or for a prolonged period (7 d) while they were nursing their neonates, resulting in antibiotic exposure of the neonates through their mother.…”

“…This was dependent on the transfer of maternal microbiota-derived aryl hydrocarbon receptor (AhR) ligands ( 81 ), which stimulated the proliferation of innate lymphoid cells type 3 (ILC3s) ( 77 ). ILC3s are crucial for maintaining the gut epithelial barrier and host defense by the production of IL-22 and IL-17 and subsequently inducing the secretion of AMPs ( 82 , 83 ). Moreover, the expression of genes involved in epithelial cell differentiation, integrity, and homeostasis was altered in small intestinal epithelial cells of the offspring born to mothers who had experienced reversible colonization during pregnancy ( 77 ).…”

“…Since microbiota restoration reestablished ILC3s and rescued the antibiotic-treated pups from sepsis, this innate immune population contributes to the important protection of the neonate after birth. However, changes in the abundance of ILC3s through neonatal antibiotic exposure by treating the dams might also be explained by changes in the maternal microbiota or breast milk itself ( 83 ). The importance of maternal microbiota-induced intestinal ILC3s in regulating early life colonization was also demonstrated by our group as discussed earlier ( 77 ).…”

Associations between the Gut Microbiota, Immune Reconstitution, and Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation

“…to Escherichia coli sepsis [44]. Impaired ILC type 3 development in antibiotic exposed neonatal mice also directly impairs mucosal immunity and increases susceptibility to Klebsiella pneumoniae [61].…”