Research in mice by scientists at Harvard Medical School has shown that at least part of the protective effect of mother’s milk against infection in their newborns comes from the microbes that reside in the maternal gastrointestinal (GI) tract. The studies found that maternal antibodies made in response to commensal Pantoea species in the mother’s GI tract are passed on to the offspring both via milk and through the placenta, and protect newborn pups from infection by potentially lethal enterotoxigenic E. coli bacteria. Importantly, the results indicate that, in mice at least, maternal intestinal microbiota can offer immune protection even when the mother has had no prior encounters with the infection to generate and pass on protective antibodies to their offspring.

If the results of the reported work can be validated in additional studies, they could help scientists develop microbial therapies against serious infections such as E. coli, as well as other disease-causing organisms. “Albeit preliminary, we are hopeful these insights could inform the development of vaccines derived from commensal microbial molecules as a way to prevent infectious diseases,” said senior study investigator Dennis Kasper, MD, professor of immunology in the Blavatnik Institute at Harvard Medical School. “Another therapeutic avenue could be the use of commensal microbes as probiotics that protect against diarrheal disease.”

The findings add to a growing body of evidence pointing to the important roles that mammalian microbiota—including the microbial communities in the gut, skin, mouth, and other parts of the bodies—play in disease and health. Kasper and colleagues reported their findings in Nature, in a paper titled, “Microbiota-targeted maternal antibodies protect neonates from enteric infection.”

Infectious diarrhea is the second leading cause of malnutrition and death globally in children under five years of age. Most commonly caused by E. coli or rotavirus, the condition claims more than 520,000 lives a year worldwide, according to the World Health Organization figures. “Neonates are highly susceptible to microbial infections, not only because their immature immune system is less capable of generating adaptive immune effectors such as antibodies, but also because they lack a diverse commensal microbiota that can antagonize pathogens independently of host responses,” the authors explained.

Without any prior exposure to microbes, a newborn’s immune system is effectively a blank slate. For the first three weeks after birth, immune protection in neonates is derived entirely from maternal antibodies either passed to the fetus during pregnancy via the placenta, or transferred during birth via the birth canal, and shortly after birth via breastfeeding. Although the benefits of maternal antibodies passed to newborns are widely accepted, “few studies have addressed whether maternal natural antibodies (mNabs)—that is, antibodies acquired without known exposure to the pathogen or through immunization—can help neonates to defend against pathogens,” the authors noted.

For their current study, the researchers worked with newborn mice that were genetically engineered to lack antibody-producing B cells. Some of the newborn mice were raised by mothers that had also been born without antibody-making B cells, and so lacked protective antibodies. The control group of newborn mice was raised by mothers that had normal immune systems.

The studies showed that mice exposed to protective IgG antibodies from their mothers were far more resistant to E. coli infection than were mice that had not been exposed to maternal antibodies. In contrast, mouse pups that were not exposed to these protective antibodies developed disseminated E. coli disease. The intestines of mice exposed to protective maternal antibodies carried 33 times fewer E. coli bacteria than newborn mice lacking maternal antibodies. “By challenging pups that were fostered by either maternal antibody-sufficient or antibody-deficient dams, we found that IgG derived from breast milk was crucial for protection against mucosal disease induced by enterotoxigenic E. coli,” the authors wrote. “IgG also provides protection against systemic infection by E. coli.

Further studies indicated that Pantoea, a member of the Enterobacteriaceae family of bacteria, was the specific organism responsible for protective immunity against E. coli. It was this organism that induced the formation of the protective antibodies in the mother that cross-reacted against E. coli. Pantoea bacteria naturally reside in the intestines of mice and other mammals, including humans.

“Our results help explain why newborns are protected from certain disease-causing microbes despite their underdeveloped immune systems and lack of prior encounters with these microbes,” said Kasper, who is also the William Ellery Channing professor of medicine at Brigham and Women’s Hospital. “Moreover, they raise the possibility that mothers can confer immune protection to their offspring even to pathogens that they haven’t themselves encountered in the past.”

The team’s experiments, in addition, showed that maternal antibodies were transferred to the intestines and bloodstream of newborns via the neonatal Fc receptor, a molecular channel on the placenta that helps to ferry protective antibodies from the mother to the fetus. It was already known that the Fc receptor transferred antibodies through the placenta, but the new experiments by Kasper’s team showed that the same receptor also absorbs antibodies derived from milk and further ferries them from the newborn mouse intestine, into the blood, to provides wider, systemic protection beyond the gut. “In addition to acquisition through the placenta, pups can assimilate IgG mNabs directly from ingested milk into serum by a neonatal Fc receptor (FcRn)-dependent process,” the investigators commented. Studies showed that adult mice, in which this neonatal receptor loses its function with age, did not transfer protective antibodies from their gut to the bloodstream.

The investigators acknowledged that while the relevance to humans of their results in mice has yet to be determined, they could point to new ways of protecting human infants from potentially deadly infections. “We have not addressed whether this milk-mediated gastrointestinal pathway for introducing therapeutic or preventive IgG into the bloodstream is applicable to human neonatal infants,” they wrote. “Characterizing this transport pathway in humans is a future priority because vaccination of women may generate high-affinity IgG, protecting breast-fed neonates long after antibodies received through the placenta have waned from the bloodstream … If efficient and practical, this noninvasive approach offers advantages over conventional passive-immunization strategies by avoiding needle use in newborns, a practice that carries additional risk of disease transmission.”

 

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