Probiotic Supplementation Regulates Newborn Immune System

Supplementing breastfed infants with bifidobacteria promotes development of a well-regulated immune system, theoretically reducing risk of immune-mediated conditions like allergies and asthma, according to investigators.

These findings support the importance of early gut colonization with beneficial microbes, an event that may affect the immune system throughout life, reported lead author Bethany M. Henrick, PhD, director of immunology and diagnostics at Evolve Biosystems, Davis, Calif., and adjunct assistant professor at the University of Nebraska, Lincoln, and colleagues.

“Dysbiosis of the infant gut microbiome is common in modern societies and a likely contributing factor to the increased incidences of immune-mediated disorders,” the investigators wrote in Cell. “Therefore, there is great interest in identifying microbial factors that can support healthier immune system imprinting and hopefully prevent cases of allergy, autoimmunity, and possibly other conditions involving the immune system.”

Prevailing theory suggests that the rising incidence of neonatal

intestinal dysbiosis – which is typical in developed countries – may be caused by a variety of factors, including cesarean sections; modern hygiene practices; antibiotics, antiseptics, and other medications; diets high in fat and sugar; and infant formula.

According to Henrick and colleagues, a healthy gut microbiome plays the greatest role in immunological development during the first 3 months post partum; specifically, a lack of bifidobacteria during this time has been linked with increased risks of autoimmunity and enteric inflammation, although underlying immune mechanisms remain unclear.

Bifidobacteria also exemplify the symbiotic relationship between mothers, babies, and beneficial microbes. The investigators pointed out that breast milk contains human milk oligosaccharides (HMOs), which humans cannot digest, but are an excellent source of energy for bifidobacteria and other beneficial microbes, giving them a “selective nutritional advantage.”

Bifidobacteria should therefore be common residents within the infant gut, but this is often not now the case, leading Henrick and colleagues to zero in on the microbe, in hopes of determining the exactly how beneficial bacteria shape immune development.

It is only recently that the necessary knowledge and techniques to perform studies like this one have become available, the investigators wrote, noting a better understanding of cell-regulatory relationships, advances in immune profiling at the systems level, and new technology that allows for profiling small-volume samples from infants.

The present study involved a series of observational experiments and a small interventional trial.

First, the investigators conducted a wide array of blood- and fecal-based longitudinal analyses from 208 infants in Sweden to characterize immune cell expansion and microbiome colonization of the gut, with a focus on bifidobacteria.

Their results showed that infants lacking bifidobacteria, and HMO-utilization genes (which are expressed by bifidobacteria and other beneficial microbes), had higher levels of systemic inflammation, including increased T helper 2 (Th2) and Th17 responses.

“Infants not colonized by Bifidobacteriaceae or in cases where these microbes fail to expand during the first months of life there is evidence of systemic and intestinal inflammation, increased frequencies of activated immune cells, and reduced levels of regulatory cells indicative of systemic immune dysregulation,” the investigators wrote.

The interventional part of the study involved 60 breastfed infants in California. Twenty-nine of the newborns were given 1.8 x 1010 colony-forming units (CFUs) of B. longum subsp. infantis EVC001 daily from postnatal day 7 to day 28, while the remaining 31 infants were given no supplementation.

Fecal samples were collected on day 6 and day 60. At day 60, supplemented infants had high levels of HMO-utilization genes, plus significantly greater alpha diversity (P = .0001; Wilcoxon), compared with controls. Infants receiving EVC001 also had less inflammatory fecal cytokines, suggesting that microbes expressing HMO-utilization genes cause a shift away from proinflammatory Th2 and Th17 responses, and toward Th1.

“It is not the simple presence of bifidobacteria that is responsible for the immune effects but the metabolic partnership between the bacteria and HMOs,” the investigators noted.

According to principal investigator Petter Brodin, MD, PhD, professor of pediatric immunology at Karolinska Institutet, Solna, Sweden, the findings deserve further investigation.

“Our data indicate that substitution with beneficial microbes efficiently metabolizing HMOs could open a way to prevent cases of immune-mediated diseases, but larger, randomized trials aimed at this will be required to determine this potential,” Brodin said in an interview.

Carolynn Dude, MD, PhD, assistant professor in the division of maternal-fetal medicine at Emory University, Atlanta, agreed that more work is needed.

“While this study provides some insight into the mechanisms that may set up a newborn for poor health outcomes later in life, the data is still very limited, and more long-term follow-up on these infants is needed before recommending any sort of bacterial supplementation to a newborn,” Dude said in an interview.

Brodin and colleagues are planning an array of related studies, including larger clinical trials; further investigations into mechanisms of action; comparisons between the present cohort and infants in Kenya, where immune-mediated diseases are rare; and evaluations of vaccine responses and infectious disease susceptibility.

The study was supported by the European Research Council, the Swedish Research Council, the Marianne & Marcus Wallenberg Foundation, and others. The investigators disclosed relationships with Cytodelics, Scailyte, Kancera, and others. Dude reported no relevant conflicts of interest.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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