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Background: Broad-spectrum antibiotics in preterm infants have been associated with necrotizing enterocolitis (NEC), but the exact mechanisms that explain this association remain poorly defined.

Objective: To examine the impact of peripartum antibiotics on gut microbiota and intestinal inflammation in the developing gut.

Design/Methods: C57BL6 dams were administered broad spectrum antibiotics mixed with sterile drinking water from E15 to postnatal day (P)14 (Fig 1). Gut microbiota were analyzed by targeted 16S PCR for total bacterial density and relative abundance of major bacterial phyla. Effects of antibiotics on inflammatory TLR-signaling and injury in the neonatal gut were evaluated with PCR and histology.

Results: Peripartum antibiotics reduced gut bacterial density (Fig 2A) and diversity (Fig 2B) of treated dams compared to untreated controls. Decreased gut bacterial density was also evident among pups of antibiotic-treated dams starting at P8 and persisting to P21 (Fig 2C). Investigation of TLR signaling by PCR showed that at P8, pups of antibiotic-treated dams have significant upregulation of TLR4 signaling (TLR4, IRAK1) and inflammatory cytokines (KC, ICAM1) in the gut compared to pups of untreated controls (Fig 3A). Increased gut TLR4 inflammatory signaling persisted to P21 despite discontinuation of antibiotics by P14 (Fig 3B). Histologic evaluation of terminal ileum revealed that antibiotics alone were insufficient to elicit intestinal injury consistent with NEC (Fig 4).

Conclusion(s): Antibiotic exposure during the early critical period after birth induces gut dysbiosis and negatively impacts the developing gut towards a pro-inflammatory state. These results support ongoing efforts of antibiotic stewardship to avoid routine antibiotics in preterm infants without risk factors for sepsis. Future experimentation is ongoing to assess the effects of shorter antibiotic duration and addition of noxious stimuli on TLR signaling and other markers of intestinal injury.

Presented at the 2021 PAS Virtual Conference



Peripartum Antibiotics Induce Dysbiosis and Predispose the Neonatal Gut Towards Inflammation

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