SUN-736 - Investigating the Effects of Early Life Short Term Subtherapeutic Antibiotic Exposure on the Gut Microbiome and Bone Metabolism

The gut microbiome plays a central role in host physiology, extending beyond digestion to influence immunity, metabolism, and overall development. Evidence suggests that early life disturbances to the microbiome from antibiotic exposure have consequences for host growth and metabolism. This project investigates the effects of early life short term subtherapeutic antibiotic treatment (ELST-STAT) in mice on the establishment of the gut microbiome and bone development, with the goal of better understanding the gut-bone axis. Pregnant dams were given a low dose (6.67mg/L) of penicillin (LDP) of in autoclaved water or antibiotic-free autoclaved water (control) beginning on embryonic day 18 through postnatal day 7 (P7). During treatment, developing pups were exposed to antibiotics in utero and via lactation after birth. Pups were euthanized at P7, P14, P21, and P56 to provide a developmental timeline to evaluate both transient and lasting effects of the early antibiotic exposure. Body weight of the pups was measured weekly from P7 to P56, and at each euthanasia time point, body length was measured. Analyses of body weight and length measurements showed no phenotype. Bone mineral density (BMD) and bone mineral content (BMC) were measured non-invasively using dual-energy X-ray absorptiometry (DEXA-PIXImus) directly before euthanasia. DEXA-PIXImus analysis showed a decrease in tibial BMD only at P56 in males. Gastrointestinal microbiome samples from the colon, ileum, cecum, and feces were collected for compositional analysis by 16S rRNA gene sequencing. Femurs, tibiae, and lumbar vertebrae were collected to analyze the influence of LDP on the bones. Gene expression was assessed in tibiae by quantitative PCR (qPCR). Expression of genes involved in osteoblast formation (Runx2, Alpl, Col1a1, Bsp, Bglap, Sost, RankL, Opg), mature osteoclasts (Ctsk, Acp5), and chondrocyte regulation (Mmp13, Col2a1) was quantified using qPCR. Sexual dimorphism was observed in several osteoblastic genes. At early time points (P7 and P21) LDP increased expression of Runx2, Alpl, and RankL in males, with little to no difference in females. At P56, LDP induced increased expression of Runx2, Alpl, Bsp, Sost, RankL, and Opg in females. In males, LDP induced decreased expression of Alpl, RankL, and Opg, consistent with decreased tibial BMD at P56. We conclude that ELST-STAT exposure altered the trajectory of the expression of genes related to bone development in a sex-dependent manner. Findings from this study will contribute to a deeper understanding of the gut-bone axis and its sensitivity to early life disruptions.

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