Abstract Background: Early-onset colorectal cancer (EOCRC) is rising for reasons not fully explained by genetics. Pediatric antibiotic prescriptions are medically ubiquitous, and nearly 1/3rd of all prescribed pedeatric antibiotics are retrospectively unnescessary. We hypothesized that brief pediatric penicillin courses ignite transient blooms of colibactin-producing (pks+) Enterobacteriaceae that seed colibactin-specific DNA damage and accelerate colon tumorigenesis. Methods: We developed an early-life exposure model (3–8 weeks) combining either corn starch, lard (HFD), or fiber-based diets with three 5-day oral penicillin pulses and colonization by a human pks+ Escherichia coli isolate (SP15), quantified bacterial dynamics (culture/qPCR), epithelial responses (RNA-seq, γH2AX), and neoplasia (AOM/DSS). We then analyzed infant metagenomes for time-locked pks+ spikes after intrapartum antibiotics (IAP) or childhood antibiotics. Results: Early-life penicillin triggered ≥100-fold, transient pks+ E. coli blooms, peaking during exposure and contracting afterward in mice across diets. In colonocytes of mice harboring pks+ E. coli, oral penicillin enriched DNA-damage response, EMT, and hyperproliferative programs and reduced homeostatic oxidative phosphorylation in a diet dependent manner. Preliminary mesenteric lymph node (MLN) flow cytometry data indicate antibiotics and pks+ (but not mutant) E. coli synergize as a critical driver of a signifcant pro-tumor TNF-rich pan-T-lymphocyte immune state across memory, effector and naive subsets that persists after AOM/DSS induction 9 weeks later. In the AOM/DSS cancer model, early-life penicillin promoted colorectal cancer in pks+-colonized HFD mice, which had increased tumor incidence, multiplicity, and burden (two-sided tests, P0. 05), directionally supported in the corn starch-diet mice as well (p∼0. 1). Across infant cohorts, we observed congruent signals: time-locked pks+ spikes after antibiotics and higher early pks+ abundance with intrapartum penicillin exposure (p0. 05), consistent with transient antibiotic-induced blooms in humans. Conclusions/impact: Brief, clinically modeled penicillin courses in early life create a permissive luminal niche that blooms pks+ E. coli, perturbs epithelial programs, and accelerates colon tumorigenesis, with diet dependent effects. These data nominate precision antibiotic stewardship and colibactin-targeted interception as actionable strategies to reduce EOCRC risk, and motivate human studies pairing antibiotic timing with pks+ burden, dA-CLB, and SBS88/ID18 readouts along with first-in-human colibactin inhibitor trials. Citation Format: Max R. Van Belkum, Tamara Machado, Julia Lane, Doug P. Mortlock, Catie Shelton, Nic G. Shealy, Camila de Brito, Mariana X. Byndloss. Early-life penicillin blooms colibactin-positive Escherichia coli and drives DNA damage and tumorigenesis abstract. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31 (23Suppl): Abstract nr PR010.
Belkum et al. (Wed,) studied this question.