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

Stephen Wedgwood, Cris Warford, Sharleen R. Agvatisiri, Phung N. Thai, Nipavan Chiamvimonvat, Karen M. Kalanetra, Satyan Lakshminrusimha, Robin H. Steinhorn, David A. Mills, Mark A. Underwood

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalPediatric research
DOIs
StateAccepted/In press - Jan 1 2019

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Dysbiosis
Pulmonary Hypertension
Rodentia
Hyperoxia
Growth
Right Ventricular Hypertrophy
Probiotics
Cecum
Lactobacillus reuteri
16S Ribosomal RNA
Oxygen
RNA Sequence Analysis
Therapeutics
Weights and Measures
Litter Size
Microbiota
rRNA Genes
Premature Infants
Heart Ventricles
Intestines

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

Cite this

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

In: Pediatric research, 01.01.2019.

Research output: Contribution to journalArticle

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. / The developing gut–lung axis : postnatal growth restriction, intestinal dysbiosis, and pulmonary hypertension in a rodent model. In: Pediatric research. 2019.
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abstract = "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.",
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AU - Warford, Cris

AU - Agvatisiri, Sharleen R.

AU - Thai, Phung N.

AU - Chiamvimonvat, Nipavan

AU - Kalanetra, Karen M.

AU - Lakshminrusimha, Satyan

AU - Steinhorn, Robin H.

AU - Mills, David A.

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