Complex Sugars and Microbiome in Mother’s Milk Influence Neonatal Rotavirus Infection

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Using a multidisciplinary approach, an international team of researchers, including scientists at University of California San Diego School of Medicine, reports that complex interactions between complex sugars and the microbiome in breast milk influence neonatal rotavirus infection.

Published in the November 27 online issue of Nature Communications, the authors say the study provides new understanding of rotavirus (gastrointestinal) infections in newborns and identifies breast milk components that could improve the performance of live, attenuated rotavirus vaccines.

“Rotavirus infection causes diarrhea and vomiting, primarily in children younger than five, with the exception of neonates — babies younger than 28 days of age, who usually have no symptoms. However, in some places, infections in newborns are associated with severe gastrointestinal problems,” said first and corresponding author Sasirekha Ramani, PhD, assistant professor of molecular virology and microbiology at Baylor College of Medicine.  

“What factors mediate differences between newborns with and without symptoms are not clearly understood. We began our investigation years ago by determining that a particular strain of rotavirus was associated with both asymptomatic infections and clinical symptoms in newborns.”

Ramani and colleagues first looked for answers from the perspective of the virus. They investigated whether factors, such as the amount of virus in newborns or the genome of the virus, could be linked to the presence of symptoms in newborns, but found no connections among those factors. The researchers then looked from the perspective of the newborn: Were there factors in newborns that could explain why this virus infects neonates and why there are differences in clinical presentation?

Lars Bode, PhD, associate professor of pediatrics at UC San Diego School of Medicine.

In the lab, the team, which included Lars Bode, PhD, associate professor of pediatrics at UC San Diego School of Medicine and director of the Larsson-Rosenquist Foundation Mother-Milk-Infant Center of Research Excellence, investigated whether components of breast milk might inhibit infection of MA104 cells, a well-established model for rotavirus studies, with the particular strain of rotavirus they had identified in the neonatal nurseries in India. Unexpectedly, they discovered that specific complex sugars present in mother’s milk, called human milk oligosaccharides, enhanced infection of cells in culture with the neonatal rotavirus strain.

“We were surprised by these results,” Ramani said. “Breast milk is known to enhance newborn protection against rotavirus infection and complex sugars in breast milk can reduce infectivity of other rotaviruses, but here we found the opposite for this particular strain of the virus.”

The researchers went back into the field to determine whether they could validate the lab results in a cohort of mother-infant pairs. Using the powerful analytical platform in Bode’s lab at UC San Diego, they found some of the same specific complex sugars in breast milk that increase infectivity of cells in culture were more abundant in the milk of mothers of newborns with symptomatic infection.

They also found an association between the microbiome in the mothers’ milk and gastrointestinal symptoms in newborns, prompting new and yet-to-be-answered questions about how the microbiome — all of the microorganisms found in a particular environment — contributed to differences in gastrointestinal symptoms.

“These discoveries are a prime example of the urgent need to improve our understanding of the composition and variation in breast milk components,” said Bode. “Understanding how rotavirus and other pathogens can take advantage of breast milk components will guide the development of new vaccination strategies to stay ahead in the host-pathogen arms-race.”

The researchers also discovered that the complex sugars in mother’s milk increased replication of the attenuated rotavirus in the live vaccine, which is similar to the neonatal virus they were studying. That finding may have therapeutic benefit.

“Enhanced viral replication can potentially translate into a more effective immune response against the virus, which would lead to better protection for the infant,” said Ramani. “This is something we want to explore in the future because it could illuminate strategies to improve the effectiveness of rotavirus vaccines in parts of the world where they do not do well.”

“One of the most important things to us is that these unexpected findings are tightly linked to public health,” said co-author Mary K. Estes, PhD, Distinguished Service Professor and Cullen Endowed Chair of Human and Molecular Virology at Baylor College of Medicine and emeritus founding director of the Texas Medical Center Digestive Diseases Center.

“The multidisciplinary nature of our team of researchers has allowed us to answer questions about how this unique rotavirus strain infects neonates, confirm the findings in the field and open possibilities to improve the effectiveness of rotavirus vaccines where they are needed the most.”

Co-authors include: Christopher J. Stewart, Baylor College and Newcastle University; Daniel R. Laucirica, Nadim J. Ajami, Liya Hu, Josephine C. Ferreon and Joseph F. Petrosino, Baylor College; Bianca Robertson, Chloe A. Autran and Dhairyasheel Shinge, UC San Diego; Sandya Rani, Sasirekha Anandan and Kurien A. Kuruvilla, Christian Medical College, India; B. V. Venkataram Prasad, Baylor College and Christian Medical College; and Gagandeep Kang, Christian Medical College and Translational Health and Science Technology Institute, India.

Research for this work came, in part, from the National Institutes of Health (R01AI105101, AI36040), the Center for Metagenomics and Microbiome Research and the Larsson-Rosenquist Foundation.