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Updated: Nov 28, 2025
Assessment of Gut Barrier Integrity in Mice Using Fluorescein-Isothiocyanate-Labeled Dextran
Published on: November 18, 2022
The enhanced intestinal permeability of infant mice enables oral protein and macromolecular absorption without
John P Gleeson1, Katherine C Fein1, Namit Chaudhary1
1Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, United States.
Insights
Infant intestines are more permeable, allowing for potential oral delivery of biologic drugs like insulin without special enhancers. This research explores this unique window for pediatric drug development.
Area of Science:
- Pharmacology
- Gastroenterology
- Pediatric Medicine
Background:
- Oral drug delivery is preferred for patient convenience, but challenges remain for macromolecular drugs, especially in infants.
- Infants have distinct intestinal physiology compared to adults, necessitating specific research into their drug absorption capabilities.
- Current methods for oral delivery of biologics often require permeation enhancers, which are not ideal for pediatric use.
Purpose of the Study:
- To assess intestinal permeability in neonatal and infant mice to determine the feasibility of oral peptide and protein drug delivery.
- To investigate the impact of age on intestinal barrier function and macromolecular transport in young mammals.
- To evaluate the in vivo oral absorption and efficacy of model drugs and insulin in infant versus adult mice.
Main Methods:
- Utilized the non-everted gut sac model to measure macromolecular permeability using fluorescently labeled dextrans (FD4, FD70) of varying sizes.
- Analyzed the expression of tight junction proteins involved in intestinal barrier formation and pore regulation.
- Conducted in vivo studies measuring oral absorption of FITC-Dextran and lactoferrin, and assessed the glucose-lowering effect of oral insulin in infant and adult mice.
Main Results:
- Macromolecular permeability was significantly higher in infant intestinal tissue compared to adult tissue, influenced by molecular size and age.
- Increased age correlated with enhanced expression of barrier-forming tight junction proteins and decreased expression of pore-forming proteins.
- Oral absorption of model drugs and lactoferrin was higher in younger mice, and oral insulin demonstrated a notable glucose-lowering effect in infants but not adults.
Conclusions:
- The infantile intestine exhibits significantly higher permeability to macromolecules than the adult intestine.
- This increased permeability in infants may enable the oral delivery of peptide and protein drugs without the need for advanced delivery technologies.
- These findings support the potential for developing oral biologic therapies for infants, leveraging their unique intestinal physiology.
Abstract:
Oral delivery of macromolecular drugs is the most patient-preferred route of administration because it is painless and convenient. Over the past 30 years, significant attention has been paid to oral protein delivery in adults. Unfortunately, there is an outstanding need for similar efforts in infants, a patient population with distinct intestinal physiology and treatment needs. Here, we assess the intestinal permeability of neonatal and infant mice to determine the feasibility of orally delivering peptide and protein drugs without permeation enhancers or other assistance. Using the non-everted gut sac model, we found that macromolecular permeability depended on molecular size, mouse age, and intestinal tissue type using model dextrans. For example, the apparent permeability of 70 kDa FITC-Dextran (FD70) in infant small intestinal tissue was 2-5-fold higher than in adult tissue. As mice aged, the expression of barrier-forming and pore-forming tight junction proteins increased and decreased, respectively. The in vivo oral absorption of 4 kDa FITC-Dextran (FD4) and FD70 was significantly higher in younger mice, and there was a fourfold increase in oral absorption of the 80 kDa protein lactoferrin compared to adults. Oral gavage of insulin (5 IU/kg) reduced blood glucose levels in infants by >20% at 2 and 3 h but had no effect in adults. Oral insulin had 35% and <1% of the pharmacodynamic effect of a 1 IU/kg subcutaneous dose in infants and adults, as measured by area above the curve. These data indicate that the uniquely leaky nature of the infantile intestine may support the oral delivery of biologics without the need for traditional oral delivery technology.
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