Abstract PR010: Early-life penicillin blooms colibactin-positive Escherichia coli and drives DNA damage and tumorigenesis
Bibliographic record
Abstract
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, P<0.05), 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 (p<0.05), 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(23_Suppl):Abstract nr PR010.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".