Periodic Reporting for period 1 - PRO-MOM (Postbiotic Restoration Of the Metabolome Of Moms)
Periodo di rendicontazione: 2024-01-01 al 2025-12-31
Antibiotics are among the most frequently prescribed medicines during pregnancy. While they are often essential for maternal health, antibiotics can also disrupt the mother’s gut microbiota at a time when microbial signals and microbe-derived metabolites help support healthy fetal and infant development. Emerging evidence suggests that early-life microbial disruption may have long-term consequences, including effects on brain development and behavior later in life.
This project set out to develop a practical, pregnancy-compatible way to protect mothers and infants from antibiotic-associated microbial perturbations. The core idea is a postbiotic approach: using defined, non-living microbial components and/or microbe-derived metabolites (small molecules), rather than live bacteria, to help restore key metabolic functions while antibiotics are being taken and shortly after the treatment course. The overall objectives were to (1) test promising candidate postbiotics in a controlled preclinical model, (2) determine whether supplementation can reduce later behavioral changes in offspring, and (3) generate an evidence package to guide next-stage development (formulation, regulatory path, and follow-up funding).
This project set out to develop a practical, pregnancy-compatible way to protect mothers and infants from antibiotic-associated microbial perturbations. The core idea is a postbiotic approach: using defined, non-living microbial components and/or microbe-derived metabolites (small molecules), rather than live bacteria, to help restore key metabolic functions while antibiotics are being taken and shortly after the treatment course. The overall objectives were to (1) test promising candidate postbiotics in a controlled preclinical model, (2) determine whether supplementation can reduce later behavioral changes in offspring, and (3) generate an evidence package to guide next-stage development (formulation, regulatory path, and follow-up funding).
A multi-arm mouse pilot study was performed to model maternal antibiotic exposure during pregnancy and to evaluate candidate interventions. Two microbe-derived metabolites, 3-indolepropionic acid (3-IPA) and 5-aminovaleric acid betaine (5-AVAB), were tested alongside an inactivated bacterial strain (Desulfovibrio piger). Offspring behavior was assessed in adulthood using a standard aggression paradigm (resident–intruder test), and biological readouts included microbiota profiling, brain gene expression profiles and blood metabolomic profiling.
The pilot produced clear prioritization signals. Maternal supplementation with 3-IPA significantly lowered aggression levels in adult offspring across trials. 5-AVAB showed a weaker effect (a trend towards reduced aggression), suggesting that dose and exposure may need optimization. The inactivated bacterial preparation did not improve outcomes and was associated with increased anxiety-like behavior in treated adult females, supporting discontinuation of this candidate.
Molecular profiling indicated that interventions can produce durable biological changes: brain transcriptome patterns in offspring exposed to metabolites clustered closer to controls than to the antibiotic-only group, consistent with partial rescue of gene expression. Microbiota measures and serum metabolite profiles also shifted with intervention, providing mechanistic support for the behavioral patterns we observed.
The pilot produced clear prioritization signals. Maternal supplementation with 3-IPA significantly lowered aggression levels in adult offspring across trials. 5-AVAB showed a weaker effect (a trend towards reduced aggression), suggesting that dose and exposure may need optimization. The inactivated bacterial preparation did not improve outcomes and was associated with increased anxiety-like behavior in treated adult females, supporting discontinuation of this candidate.
Molecular profiling indicated that interventions can produce durable biological changes: brain transcriptome patterns in offspring exposed to metabolites clustered closer to controls than to the antibiotic-only group, consistent with partial rescue of gene expression. Microbiota measures and serum metabolite profiles also shifted with intervention, providing mechanistic support for the behavioral patterns we observed.
Most microbiota-support approaches used during or after antibiotic exposure rely on live probiotics, which can have variable colonization success and pose additional safety challenges in sensitive populations and manufacturing constraints. This project advances an alternative, more controllable strategy: using defined postbiotics that can be formulated like conventional supplements and are less likely to interfere with natural microbiota re-establishment.
Scientifically, the work links maternal antibiotic exposure, microbiota-related metabolic changes, and long-term offspring behavioral outcomes within one integrated preclinical framework, supported by behavioral, microbiota, metabolomic, and transcriptomic readouts. The results provide early proof that specific metabolites can modulate later-life behavior and brain molecular signatures following prenatal antibiotic exposure.
Expected impacts and key needs for further uptake
If translated successfully, a metabolite-based supplement could provide a low-risk, shelf-stable, and scalable add-on to standard antibiotic therapy in pregnancy, with the long-term goal of supporting healthier neurodevelopment and reducing later behavioral dysregulation in childhood and throughout life. Beyond this specific indication, the approach could create a broader blueprint for developing postbiotic interventions targeted to critical windows in early life.
Key next steps to enable uptake include: selecting the most scalable metabolite(s) (including alternatives within the same pathway if needed), optimizing dose/ratio and delivery format to achieve reliable exposure levels, confirming stability in a capsule or beverage-compatible formulation, repeating efficacy testing with the final formulation in a powered preclinical study, and completing early safety and tolerability work in a clinical setting. In parallel, early dialogue with regulators is needed to clarify the most appropriate product category and allowable claims, followed by first-in-human studies to confirm exposure and tolerability and to prepare for clinical proof-of-concept.
Scientifically, the work links maternal antibiotic exposure, microbiota-related metabolic changes, and long-term offspring behavioral outcomes within one integrated preclinical framework, supported by behavioral, microbiota, metabolomic, and transcriptomic readouts. The results provide early proof that specific metabolites can modulate later-life behavior and brain molecular signatures following prenatal antibiotic exposure.
Expected impacts and key needs for further uptake
If translated successfully, a metabolite-based supplement could provide a low-risk, shelf-stable, and scalable add-on to standard antibiotic therapy in pregnancy, with the long-term goal of supporting healthier neurodevelopment and reducing later behavioral dysregulation in childhood and throughout life. Beyond this specific indication, the approach could create a broader blueprint for developing postbiotic interventions targeted to critical windows in early life.
Key next steps to enable uptake include: selecting the most scalable metabolite(s) (including alternatives within the same pathway if needed), optimizing dose/ratio and delivery format to achieve reliable exposure levels, confirming stability in a capsule or beverage-compatible formulation, repeating efficacy testing with the final formulation in a powered preclinical study, and completing early safety and tolerability work in a clinical setting. In parallel, early dialogue with regulators is needed to clarify the most appropriate product category and allowable claims, followed by first-in-human studies to confirm exposure and tolerability and to prepare for clinical proof-of-concept.