In the realm of neonatal medicine, the quest to safeguard the delicate neurological development of preterm infants has reached a compelling new frontier. Emerging research has illuminated the powerful role of human milk oligosaccharides (HMOs) as critical agents in protecting the enteric nervous system—the so-called “enteric brain”—of these vulnerable newborns. This complex nervous system, embedded within the gut, governs not only digestive functions but also profoundly influences systemic developmental processes. The groundbreaking study by Barbian and Sampath, soon to be published in Pediatric Research (2025), offers a pioneering perspective on harnessing HMOs to enhance neuroprotection and optimize long-term outcomes for preterm infants.
Understanding the enteric nervous system is essential to appreciating the full significance of this research. Often referred to as the “second brain,” the enteric nervous system consists of an intricate network of neurons lining the gastrointestinal tract. It operates autonomously from the central nervous system but closely communicates with it via bidirectional pathways. In preterm infants, this system is especially susceptible to damage due to interrupted in utero development, exposure to oxidative stress, and inflammatory challenges. Impairment here has been increasingly linked to lifelong gastrointestinal disorders and even neurodevelopmental delays, underlining the urgency of protective interventions.
Human milk oligosaccharides, complex carbohydrates unique to breast milk, have long been celebrated for their prebiotic and immunomodulatory properties. However, their neuroprotective potential is only now coming to the fore. These oligosaccharides escape digestion in the upper gastrointestinal tract and reach the colon intact, where they modulate the gut microbiome and engage with enteric neurons and immune cells. Barbian and Sampath’s research delves deep into the molecular interplay between HMOs and the enteric nervous system, revealing mechanisms by which HMOs mitigate inflammation, promote neuronal survival, and foster synaptic plasticity within the gut milieu.
One of the pivotal discoveries emphasized in the study is the anti-inflammatory capacity of specific HMOs, such as 2’-fucosyllactose and lacto-N-neotetraose. These molecules counteract the pro-inflammatory cytokine cascades frequently elevated in preterm infants due to both microbial imbalances and the immature immune system. Chronic enteric inflammation is a documented precursor to neuro-enteric dysfunction, and by attenuating this inflammation, HMOs help maintain the integrity of enteric neurons and glial cells, crucial for sustaining neurodevelopmental trajectories.
Moreover, the intricate design of HMOs allows them to interact selectively with receptors expressed on enteric neurons. Barbian and Sampath underscore the engagement of HMOs with toll-like receptors (TLRs) and C-type lectin receptors, which modulate neural signaling pathways implicated in neurogenesis and neuroprotection. By binding to these receptors, HMOs trigger intracellular cascades that reduce oxidative stress and enhance anti-apoptotic signaling—critical factors in reducing neuronal loss and fostering a healthier enteric environment.
The protective scope of HMOs extends beyond the gut’s confines. The enteric nervous system’s intimate crosstalk with the central nervous system suggests that intact gut neurophysiology influences brain development and systemic health. Dysregulation of gut neuronal signaling has been implicated in developmental disorders, including autism spectrum disorder and attention deficit hyperactivity disorder. This novel link positions HMOs not only as gut protectors but as potential modulators of holistic infant neurodevelopment.
Barbian and Sampath’s research also casts new light on the timing and dosing of HMO administration. Recognizing that preterm infants often face challenges in receiving adequate amounts of maternal breastmilk, the authors advocate for targeted supplementation strategies. Their experimental models demonstrate that exogenous HMO supplementation during critical early windows of development significantly enhances enteric neuronal resilience and systemic immune homeostasis.
Technological advances in mass spectrometry and neuroimaging have been instrumental in supporting these findings. Detailed HMO profiling in breastmilk samples, coupled with visualization of enteric neuronal networks in neonatal animal models, allowed precise correlation between HMO exposure and neuronal health indicators. Such cutting-edge methodologies underscore the translational potential of this research into clinical practice, promising personalized neonatal nutritional interventions that optimize neural outcomes.
However, the study also acknowledges several complexities and challenges. The heterogeneous composition of HMOs varies among individuals and stages of lactation, complicating standardization of supplementation protocols. Furthermore, the multifactorial nature of enteric nervous system development means that HMOs are likely one piece in a larger puzzle that includes genetic, environmental, and microbial factors. Nevertheless, the identification of specific HMO structures with potent neuroprotective effects is a critical step toward precision nutrition in neonatal care.
Importantly, this research adds momentum to the growing consensus that human milk is an unparalleled nutritional source, offering bioactive molecules that extend beyond basic nourishment. HMOs exemplify nature’s sophisticated design in shaping neonatal development, supporting not only physical growth but intricate neural architecture that underpins lifelong health. This understanding calls for sustained efforts to promote breastfeeding and to develop bioengineered formula supplements that retain these neuroprotective benefits where breastfeeding is not possible.
The implications of protecting the enteric brain in preterm infants resonate on multiple levels. Clinically, the reduction of gut-derived inflammation and neuronal injury can lessen the incidence of necrotizing enterocolitis, a devastating condition with high morbidity and mortality. Neurologically, safeguarding early enteric circuits may translate into improved cognitive and behavioral outcomes, reducing the burden of neurodevelopmental impairments common in preemies.
Furthermore, this research challenges conventional paradigms that segregate neurological and gastrointestinal health. The concept of the gut-brain axis gains enriched nuance as the enteric nervous system emerges as a pivotal neurodevelopmental interface influenced by nutrition. HMOs serve as molecular mediators in this axis, exemplifying how targeted biochemical interventions can harmonize systemic physiology.
Looking forward, Barbian and Sampath suggest future studies to unravel the full spectrum of HMOs’ neuroprotective functions, investigating synergistic effects with probiotics and other bioactive milk components. Clinical trials in preterm infant cohorts will be critical to validate these findings in human populations and to optimize therapeutic regimens. The integration of genomic and metabolomic data promises to personalize care, aligning nutritional strategies with individual risk profiles.
In sum, the groundbreaking exploration of human milk oligosaccharides in protecting the enteric nervous system of preterm infants offers a transformative vision for neonatal neurology and nutrition. This research heralds a new era where specialized milk components are recognized as vital neuroprotectants, capable of mitigating vulnerability and enhancing resilience during the most critical phases of early life development. As science continues to decode the complex language of breast milk, the hope is that more preterm infants will benefit from nature’s intrinsic neuroprotection, rewritten by human ingenuity.
Subject of Research: Neuroprotection of the enteric nervous system in preterm infants via human milk oligosaccharides
Article Title: Protecting the enteric brain (nervous system) in preterm infants: human milk oligosaccharides to the rescue
Article References:
Barbian, M.E., Sampath, V. Protecting the enteric brain (nervous system) in preterm infants: human milk oligosaccharides to the rescue. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04243-2
Image Credits: AI Generated
