One of the central questions the authors tackle is where the bacteria in milk actually come from. For years, researchers debated whether the milk microbiome is simply contamination from skin or sampling equipment. The review lays out several proposed sources that are not mutually exclusive: the maternal skin and nipple areola, the infant’s own oral cavity during feeding, environmental exposure, and a more provocative route known as the entero-mammary pathway, in which gut bacteria or their components are hypothesized to migrate through maternal immune circulation to the mammary gland. Each proposed origin carries different implications for how milk microbes might be influenced, or even therapeutically modulated, before they ever reach the infant gut.

The composition of the milk microbiome is not fixed. The review identifies a series of determinants that shift its profile, including the stage of lactation, mode of delivery, maternal antibiotic exposure, maternal diet, maternal obesity, and prematurity. These factors matter because they can alter which bacterial species are delivered to the infant during exactly the period when the gut is being seeded. A baby born by cesarean section, for example, may receive a different microbial inoculum than one born vaginally, and preterm infants in neonatal intensive care units face compounded disruptions from antibiotics, separated feeding, and donor milk that has typically been pasteurized, a process that reduces microbial viability.

Mechanistically, the review describes several plausible routes by which milk-associated microbes could influence the developing brain. The first is straightforward colonization: bacteria swallowed with milk take up residence in the infant gut, where they shape the maturation of the gut barrier and the immune system. Secretory immunoglobulin A delivered in milk helps coat and calibrate these early microbial communities, fostering regulatory T cell development and immune tolerance. Because the immune system and the brain are in constant dialogue during development, inflammatory signals such as interleukin-1 beta and interleukin-6, and signaling cascades like nuclear factor kappa B, sit at the interface between gut microbes and neural outcomes.

A second route runs through microbial metabolites. Gut bacteria ferment dietary substrates, including human milk oligosaccharides, into short-chain fatty acids such as those detected via receptors like FFA2 and FFA3 on immune and enteroendocrine cells. These metabolites can strengthen the gut barrier, cross into circulation, influence the blood–brain barrier, and even act as histone deacetylase inhibitors, meaning they can directly modulate gene expression in developing cells. The review also highlights tryptophan metabolism as a key pathway: bacterial processing of this essential amino acid generates metabolites that engage the aryl hydrocarbon receptor and the kynurenine pathway, both of which have documented links to neurodevelopment and mood regulation.

Neural and neuroendocrine signaling provides a third channel of communication. The enteric nervous system, sometimes called the body’s second brain, is in direct contact with the gut lumen and its microbial residents, and the vagus nerve offers a hard-wired line to the brainstem. Enteroendocrine cells release hormones such as glucagon-like peptide-1 and peptide YY in response to microbial and metabolic cues, while serotonin signaling through receptors including 5-HT4 and 5-HT7 links gut activity to central nervous system function. The hypothalamic–pituitary–adrenal axis, the body’s central stress system, is also sensitive to early microbial inputs, and animal studies in germ-free mice have repeatedly shown that the absence of microbes disrupts brain development, myelination, and behavior.

Human milk oligosaccharides deserve special mention because they are among the most abundant components of milk after fat and lactose, yet the infant cannot digest them. Their purpose, most researchers now agree, is to feed specific bacteria, particularly Bifidobacterium species. The review discusses individual HMOs such as 2′-fucosyllactose, 3′-sialyllactose, and 6′-sialyllactose, noting that sialylated variants in particular have been associated with sialic acid availability for brain development, including ganglioside synthesis and myelin formation via myelin basic protein. In this sense, the milk microbiome and its preferred substrates function as a matched pair: the oligosaccharides select for bacteria, and those bacteria in turn produce the metabolites that may support neural maturation.

What does the clinical evidence actually show? The review evaluates observational and experimental studies linking breastfeeding and milk-associated microbial exposures to cognitive, behavioral, and neurodevelopmental outcomes, with particular attention to preterm and medically vulnerable infants. Breastfeeding has been associated in numerous cohorts with modest advantages in IQ scores and with reduced odds of conditions such as attention-deficit/hyperactivity disorder and, in some studies, autism spectrum disorder, although the review is careful to stress that causality remains unresolved, since breastfeeding correlates with many socioeconomic and parental factors. Tools such as the Bayley Scales of Infant and Toddler Development, Third Edition, are commonly used to track outcomes, and the authors call for studies that pair microbiome profiling with metabolomics, immune phenotyping, neuroimaging, and validated neurodevelopmental assessments rather than relying on any single measure.

The authors are equally candid about the field’s methodological headaches. Milk is a low-biomass sample, meaning the small number of microbial cells present makes it exquisitely vulnerable to contamination from reagents, skin, and laboratory handling, and differences in DNA extraction and analytical pipelines have produced inconsistent findings across studies. Questions also persist about whether the microbes in milk are alive and metabolically active, whether they stably colonize the infant gut or pass through transiently, and whether observed associations reflect genuine microbial effects or confounding. The review endorses reporting standards such as STORMS, Strengthening the Organization and Reporting of Microbiome Studies, as a way to improve comparability and reproducibility across laboratories.

Despite these caveats, the translational opportunities are considerable. If specific milk microbes or their metabolites prove causally important for neurodevelopment, they could inform the design of probiotic or postbiotic supplements for infants who cannot receive mother’s own milk, particularly very low birth weight and preterm babies whose disrupted colonization has been linked to higher risks of neurodevelopmental impairment. Donor human milk banks, optimized HMO supplementation in infant formula, and microbiome-aware neonatal nutrition protocols all stand to benefit from a clearer mechanistic map of the milk–gut–brain axis. The review, which was supported by United Arab Emirates University UPAR grants and published open access on 31 August 2026, ultimately frames human milk as a modulator of early-life brain programming whose microbial dimension is only beginning to be understood, and it sets a research agenda that will require longitudinal, mechanistically informed studies to convert biological plausibility into clinical practice.

Subject of Research: The role of the human milk microbiome in modulating the early-life gut–brain axis and neurodevelopment

Article Title: Human milk microbiome as a modulator of the early-life gut–brain axis: mechanisms and translational opportunities for neurodevelopment

Article References: Alnuaimi, F., Yassin, L. K., Alketbi, S., Skrabulyte-Barbulescu, J., Almazrouei, S., Alremeithi, D., Alahbabi, N., Almarzooqi, S., Alkuwaiti, S. H., & Hamad, M. I. K. (2026). Human milk microbiome as a modulator of the early-life gut–brain axis: mechanisms and translational opportunities for neurodevelopment. Journal of Translational Medicine, 24(1), Article 1125. https://doi.org/10.1186/s12967-026-08844-1

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08844-1

Keywords: human milk microbiome, milk–gut–brain axis, infant gut microbiota, human milk oligosaccharides, breastfeeding, microbial metabolites, short-chain fatty acids, neurodevelopment, preterm infants, gut–brain axis, entero-mammary pathway, neonatal nutrition