The developing gut–lung axis: postnatal growth restriction, intestinal dysbiosis, and pulmonary hypertension in a rodent model

• Published in: Pediatric research 2020-02, Vol.87 (3), p.472-479
• Main Authors: Wedgwood, Stephen, Warford, Cris, Agvatisiri, Sharleen R., Thai, Phung N., Chiamvimonvat, Nipavan, Kalanetra, Karen M., Lakshminrusimha, Satyan, Steinhorn, Robin H., Mills, David A., Underwood, Mark A.
• Format: Article
• Language: English
• Subjects: Animal Nutritional Physiological Phenomena; Animals; Animals, Newborn; Basic Science Article; Caloric Restriction - adverse effects; Cecum - microbiology; Disease Models, Animal; Dysbiosis; Female; Gastrointestinal Microbiome; Hyperoxia; Hyperoxia - complications; Hypertension, Pulmonary - etiology; Hypertension, Pulmonary - microbiology; Hypertension, Pulmonary - physiopathology; Hypertension, Pulmonary - prevention & control; Hypertrophy, Right Ventricular - etiology; Hypertrophy, Right Ventricular - microbiology; Hypertrophy, Right Ventricular - physiopathology; Hypertrophy, Right Ventricular - prevention & control; Intestine, Small - microbiology; Limosilactobacillus reuteri - physiology; Litter Size; Lung - blood supply; Medicine; Medicine & Public Health; Microbiota; Nutritional Status; Pediatric Surgery; Pediatrics; Pregnancy; Probiotics; Probiotics - administration & dosage; Pulmonary hypertension; Rats, Sprague-Dawley
• ISSN: 0031-3998; 1530-0447
• DOI: 10.1038/s41390-019-0578-2

Background Postnatal growth restriction (PNGR) in premature infants increases risk of pulmonary hypertension (PH). In a rodent model, PNGR causes PH, while combining PNGR and hyperoxia increases PH severity. We hypothesized that PNGR causes intestinal dysbiosis and that treatment with a probiotic attenuates PNGR-associated PH. Method Pups were randomized at birth to room air or 75% oxygen (hyperoxia), to normal milk intake (10 pups/dam) or PNGR (17 pups/dam), and to probiotic Lactobacillus reuteri DSM 17938 or phosphate-buffered saline. After 14 days, PH was assessed by echocardiography and right ventricular hypertrophy (RVH) was assessed by Fulton’s index (right ventricular weight/left ventricle + septal weight). The small bowel and cecum were analyzed by high-throughput 16S ribosomal RNA gene sequencing. Results PNGR with or without hyperoxia (but not hyperoxia alone) altered the microbiota of the distal small bowel and cecum. Treatment with DSM 17938 attenuated PH and RVH in pups with PNGR, but not hyperoxia alone. DSM 17938 treatment decreased α-diversity. The intestinal microbiota differed based on oxygen exposure, litter size, and probiotic treatment. Conclusion PNGR causes intestinal dysbiosis and PH. Treatment with DSM 17938 prevents PNGR-associated RVH and PH. Changes in the developing intestine and intestinal microbiota impact the developing lung vasculature and RV.