Early life is a critical window for immune and metabolic development, with the infant gut representing a dynamic and rapidly establishing ecosystem. The maturation of the gut microbiome during the first six months of life is a foundational process, playing a key role in metabolic programming and training of the immune system1. Current research into these processes has largely focused on cohorts in high-income countries2, leaving the developmental patterns of key signaling molecules critically underexplored in populations from low- and middle-income countries (LMICs).
To address this critical gap, an observational, longitudinal study profiled the developing gut microbiome and metabolome in 55 mother-infant pairs in Dhaka, Bangladesh, across the first six months of life3. The overall aim was to understand how maternal and environmental factors—specifically delivery mode, maternal milk composition, and household water treatment—shape this foundational postnatal development.
Multi-Omics Approach and Metabolite Annotation
A research team around Lars Bode, Pieter C. Dorrestein, and Rob Knight (University of California, San Diego) conducted a comprehensive multi-omics approach, combining metagenomics, untargeted liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) metabolomics and Human Milk Oligosaccharide (HMO) profiling. The metabolomics analysis yielded 13,871 detected features across biofluids. Systematic analysis of this large dataset was achieved using sophisticated informatics tools, particularly SIRIUS, which was essential for classification and metabolite annotation.
Rapid Functional Maturation of the Infant Gut
A key finding was the demonstration of rapid functional maturation within the infant gut, evidenced by a significant and swift increase in microbially derived metabolites with infant age. In the fecal metabolome the abundance of free di- and tri-hydroxylated bile acids increased steadily over the first weeks of life. Conversely, host-derived taurine and glycine conjugates decreased. Microbially modified bile acids, including various amino acid conjugates and oxo bile acids, showed a marked increase. This pattern reflects the maturing microbiome’s growing functional capacity to modify host-derived bile acids. Similarly, short-chain N-acyl lipids, specifically those with acetate and propionate chains, increased across different head groups with infant age.
Maternal Milk and Secretor Status
Maternal Secretor Status4 refers to whether a mother is a “secretor” or “non-secretor”. “Secretors” produce certain types of special sugar molecules called Human Milk Oligosaccharides (HMOs) in their breast milk. These HMOs are bioactive molecules that are not digested by the baby but act as fertilizer for specific, beneficial gut bacteria fostering the growth of the infant gut microbiota and influencing health outcomes. Mothers classified as secretors (67% in this cohort) produce fucosylated HMOs, which promote the early growth of beneficial microorganisms like Bifidobacterium.
The difference in HMO profiles between secretor and non-secretor milk drove a corresponding association with the infant fecal metabolome in the first months of life. A cross-biofluid molecular network confirmed that HMOs abundant in secretor milk were enriched in the feces of their respective infants. The discriminant fecal features associated with maternal secretor status were putatively classified using SIRIUS as saccharides, steroids, sphingolipids, and aminosugars. SIRIUS also aided in the characterization of a candidate trihydroxy bile acid that was consistently elevated in the feces of infants born to secretor mothers, predicted to be a bile acid derivative.
Environmental and Maternal Imprints on Infant Gut
The study established that environmental and maternal living circumstances significantly influence gut metabolic development through the microbiome.
Fecal Seeding and Delivery Mode: Delivery mode represents one of the most immediate and profound determinants of initial newborn microbiota colonization5. In vaginally born infants, colonization is initiated by exposure to the maternal fecal and vaginal microbiota. Conversely, infants born via Cesarean section (C-section) are primarily colonized by microorganisms associated with the maternal skin and hospital environment. Given that C-section rates have increased significantly across many LMICs, including Bangladesh, over the past decade, understanding its lasting impact is crucial. In this cohort, the association between delivery mode and the infant fecal metabolome was confirmed. Infants born via C-section exhibited transiently elevated levels of several microbially derived metabolites, including bile amidates, N-acyl lipids, and short-chain acylcarnitines, specifically during the first month of life.
Microbial source tracking also highlighted a substantial and increasing contribution to the infant gut microbiome from non-maternal sources, potentially environmental, that increased substantially over the study period. This suggests that non-maternal environmental factors—such as household conditions, water, or contact with non-maternal caretakers—play a larger and increasingly dominant role in shaping the infant microbiome’s long-term development in this setting.
Household Water Treatment: Household drinking water treatment practices (boiling and/or filtering) were used as an indirect proxy for household hygiene and sanitation. Untreated drinking water was associated with different fecal metabolic profiles throughout the study period. The most prominent finding was a consistent enrichment of multiple acylcarnitines in the untreated water group, peaking during the first week of life. This metabolic shift coincided with the enrichment of Clostridium species, which are known to metabolize carnitines.
Summary
This longitudinal multi-omics study on a cohort in an LMIC setting reveals that early environmental and maternal factors profoundly influence the trajectory of gut metabolic development. The integrative data analysis, enabled by computational tools such as SIRIUS for deep metabolite annotation, demonstrated that the fecal metabolome is a more sensitive reporter of environmental and clinical perturbations than simple overall microbial composition.
References
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- Kvitne KE, Allaband C, Onuora JC, Perry D, Zuffa S, Patel L, Charron-Lamoureux V, Mohanty I, Sejane K, Patan A, Mahmud AA, Ahmed T, Bassani DG, González A, Hamer DH, Haque R, Ho B, Hossain MI, Islam MS, McDonald D, Pell LG, Qamar H, Roth DE, Saha S, Shah PS, Siddiqui MM, Sarker SA, Sultana S, Thomas S, Burnett LA, Tsunoda SM, Bode L, Dorrestein PC, Knight R. Environmental and maternal imprints on infant gut metabolic development. Cell Host Microbe. 2025 Nov 26:S1931-3128(25)00456-1. https://doi.org/10.1016/j.chom.2025.11.002 ↩︎
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