Work

Developmental Programming of Drug Response: Microbiota as a Missing Dimension in Perinatal Drug Discovery

Year: 2026

Type: article

Abstract: Drug exposure during pregnancy and early life is typically considered a short-term clinical intervention rather than a determinant of long-term pharmacological outcomes. Consequently, the developmental context is largely absent from drug discovery and drug development paradigms, where efficacy, safety and target engagement are evaluated predominantly in adult, steady-state systems. This disconnect may contribute to unexplained variability in drug response and toxicity later in life. Pregnancy is accompanied by dynamic remodeling of the maternal gut microbiota and its metabolic output, generating bioactive microbial metabolites that regulate immune tone, metabolic homeostasis and the expression of drug-metabolizing enzymes and transporters. These microbial signals intersect with pharmacological interventions across gestation, shaping maternal pharmacokinetics, placental regulation and fetal drug exposure during developmentally sensitive windows. Importantly, microbiota-drug interactions initiated during pregnancy do not terminate at birth. Instead, they extend into infancy through vertical microbial transmission, breast milk-mediated metabolic signaling, and the immaturity of neonatal drug-handling systems, collectively contributing to developmental programming of drug responsiveness beyond early life. In this review, we propose a microbiota-informed framework that reframes perinatal drug exposure as a developmentally embedded signal operating across a maternal-placental-infant continuum. This perspective introduces a missing developmental dimension into drug discovery and highlights new opportunities to improve translational predictability and precision pharmacotherapy across the life course.

Source: International Journal of Molecular Sciences

DOI: 10.3390/ijms27114667

Authors: Yanan Zhang, Liangkun Ma, Yan Wang

Institutions: Chinese Academy of Medical Sciences & Peking Union Medical College, Peking Union Medical College Hospital

Language: English

Topic: Gut microbiota and health

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,499