Open research questions in Infant Nutrition and Health

What the literature leaves open

• The complexity of lactoferrin's regulatory effects on bone metabolism. The need for further research into the mechanisms of lactoferrin's regulation of bone metabolism. The challenge of developing effective delivery systems for lactoferrin-derived peptides.

  Direct and indirect regulation of bone metabolism by lactoferrin · 2025 · DOI

• In-depth research into lactoferrin-derived peptides and their complexes for slow-release systems may open new avenues for treating orthopedic diseases, - Research into the role of lactoferrin in the regulation of bone metabolism

  Direct and indirect regulation of bone metabolism by lactoferrin · 2025 · DOI

• There is a notable lack of research directly evaluating the cognitive outcomes of HMOs using MRI or standardized developmental assessment tools. The paper identifies a gap in understanding the effects of HMOs on adults with or without medical conditions.

  Clinical evidence and mechanistic pathways of human milk oligosaccharide supplementation for health benefits: an updated review · 2025 · DOI

• The review highlights the need for data on the postprandial AA profile in infants from well-designed clinical trials, - Further research is needed to confirm preliminary results on the effects of supplementing IF with β-casein or α-LA, - The variation of the NPN fraction in CM is often attributed to the variation of the urea level

  Human milk vs. cow-milk based infant formula proteins: structure, digestion and physiological impacts · 2025 · DOI

• There is a lack of understanding of the mechanisms of protein digestion and amino acid absorption in infants. The non-protein nitrogen fraction is often neglected in milks, despite accounting for one fifth of the total nitrogen in human milk. There is a need for data on the postprandial amino acid profile in infants from well-designed clinical trials.

  Human milk vs. cow-milk based infant formula proteins: structure, digestion and physiological impacts · 2025 · DOI

• Most assessments of human milk microbiota have been done in small cohorts and/or in single geographical locations. The study of non-bacterial microbes in human milk, such as archaea and fungi, is relatively understudied. There is a need for global-scale studies to understand the human microbiome and its role in maternal and infant health.

  The human milk bacteriome and mycobiome and their inter-kingdom interactions viewed across geography · 2025 · DOI

• Abstract Background Variation in nutrition delivery contributes to poor growth in preterm infants in the neonatal intensive care unit (NICU); however, few studies have examined how clinicians develop nutrition plans.

  Food for thought: a mixed methods analysis of nutrition decision making during bedside rounds in the neonatal intensive care unit · 2026 · DOI

• The exact cause of NEC remains unclear, but it is believed to involve a combination of immune dysregulation, intestinal injury, and microbiota imbalance.

  The role of myeloid cells in the pathogenesis of necrotizing enterocolitis; a scoping review · 2026 · DOI

• Future research should focus on translating immune-modulating therapies to clinical practice, as such interventions may reduce NEC incidence and severity and offer new hope for vulnerable neonates.

  The role of myeloid cells in the pathogenesis of necrotizing enterocolitis; a scoping review · 2026 · DOI

• Background Epidemiological data focusing on clinical practices for necrotizing enterocolitis (NEC) in China remains scarce.

  Necrotizing enterocolitis in very preterm infants: an epidemiological study in Jiangsu, China · 2026 · DOI

• Breastfeeding is known to support infant health, but the contributions of the numerous breastmilk components to gut microbiota and immune maturation remain unclear.

  Human milk IgA promotes normal immune development by limiting Th17-inducing Erysipelatoclostridium ramosum in the infant gut · 2025 · DOI

• the complex composition of human milk remains poorly understood, - the collective biological functions and variation of human milk components are not well characterized, - there is a need for a comprehensive harmonized analysis of human milk from diverse settings

  Protocol: the International Milk Composition (IMiC) Consortium - a harmonized secondary analysis of human milk from four studies · 2025 · DOI

• Introduction: Human milk (HM) contains a multitude of nutritive and nonnutritive bioactive compounds that support infant growth, immunity and development, yet its complex composition remains poorly understood.

  Protocol: the International Milk Composition (IMiC) Consortium - a harmonized secondary analysis of human milk from four studies · 2025 · DOI

• However, the variability in dosage, participant groups, intervention duration, and outcomes, along with the limited studies on the mechanistic pathways of HMOs, makes it difficult to draw definitive conclusions, underscoring the need for well-designed clinical trials across diverse health conditions to better understand the full potential of HMO supplementation.

  Clinical evidence and mechanistic pathways of human milk oligosaccharide supplementation for health benefits: an updated review · 2025 · DOI

• Background The human milk microbiota is one of the biologically active components of human milk, and factors affecting it and the effect size are not well understood.

  The human milk bacteriome and mycobiome and their inter-kingdom interactions viewed across geography · 2025 · DOI

• The pathogenesis of NEC remains complex and not fully elucidated; thus, the screening and validation of biomarkers with high specificity, high sensitivity, and clinical applicability constitutes a core strategy to enhance the efficacy of early diagnosis and accuracy of prognostic assessment for this disease.

  Predictive value of biomarkers in neonatal necrotizing enterocolitis · 2025 · DOI

• External validation in multicenter cohorts is warranted to confirm generalizability.

  Machine learning prediction of feeding intolerance in preterm infants: a pre-feeding risk stratification model · 2025 · DOI

• Prospective multicenter validation with standardized thresholds and imaging strategies is warranted.

  Metabolic bone disease in extremely preterm infants: incidence, risk factors, and outcomes from a structured bone health program · 2025 · DOI

• However, the regulatory roles of LNnT and GOS in early intestinal development are not yet fully understood.

  Human Milk Oligosaccharide LNnT Promotes Intestinal Epithelial Growth and Maturation During the Early Life of Infant Mice · 2025 · DOI

• 2′-Fucosyllactose has been identified as a regulator of gut microbiota homeostasis, however, its effectiveness in addressing autism spectrum disorder remains unclear.

  Supplementation of 2′-Fucosyllactose during the Growth Period Improves Neurodevelopmental Disorders in Offspring Mice Induced by Maternal Immune Activation · 2025 · DOI

• However, the importance of iron saturation has been largely overlooked in LF production and research due to the lack of standardized protocols.

  Critical Importance of Iron Saturation in Lactoferrin: Effects on Biological Activity, Nutritional Functions, and Applications · 2025 · DOI

• Studies have shown that LF has a protective effect against liver injury, but the mechanism of action remains incompletely understood.

  Lactoferrin Alleviates LPS-Induced Oxidative Stress and Necroptosis in Liver by Promoting Mitophagy · 2025 · DOI

• However, which surgery-related factors exacerbate neonatal brain damage remains insufficiently investigated.

  Analysis of risk factors and establishment of a predictive model for brain injury in neonates with surgical necrotizing enterocolitis: a retrospective study · 2025 · DOI

• DISCUSSION: The etiology of transfusion-associated neonatal enterocolitis (TANEC) remains unclear and may result from multiple factors.

  Significance of ultrasound combined with near-infrared spectroscopy in monitoring transfusion-associated intestinal injury in extremely preterm infants: a study protocol for a prospective, observational study · 2025 · DOI

• Cold exposure, including feeding at low temperatures, has been associated with increased risks of NEC, yet the direct relationship between feeding temperature and NEC development remains underexplored.

  Milk temperature reducing necrotizing enterocolitis in very preterm infants: study protocol for a randomized controlled trial · 2025 · DOI

Most-cited papers in Infant Nutrition and Health

• Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study · The Lancet · 2013 · 3,196 citations
• Necrotizing Enterocolitis · New England Journal of Medicine · 2011 · 1,971 citations
• Factors Influencing the Composition of the Intestinal Microbiota in Early Infancy · PEDIATRICS · 2006 · 1,800 citations
• Breast milk and neonatal necrotising enterocolitis · The Lancet · 1990 · 1,281 citations
• Effects of Early Nutritional Interventions on the Development of Atopic Disease in Infants and Children: The Role of Maternal Dietary Restriction, Breastfeeding, Timing of Introduction of Complementary Foods, and Hydrolyzed Formulas · PEDIATRICS · 2007 · 837 citations
• An Exclusively Human Milk-Based Diet Is Associated with a Lower Rate of Necrotizing Enterocolitis than a Diet of Human Milk and Bovine Milk-Based Products · The Journal of Pediatrics · 2009 · 809 citations
• Gut microbiota of healthy Canadian infants: profiles by mode of delivery and infant diet at 4 months · Canadian Medical Association Journal · 2013 · 777 citations
• Human milk is a source of lactic acid bacteria for the infant gut · The Journal of Pediatrics · 2003 · 641 citations
• Postnatal Malnutrition and Growth Retardation: An Inevitable Consequence of Current Recommendations in Preterm Infants? · PEDIATRICS · 2001 · 627 citations
• Feeding Strategies for Premature Infants: Beneficial Outcomes of Feeding Fortified Human Milk Versus Preterm Formula · PEDIATRICS · 1999 · 566 citations

Most recent work

• Promoting Human Milk and Breastfeeding for the Very Low Birth Weight Infant: Clinical Report · PEDIATRICS · 2026
• High-Level Production of 2′-Fucosyllactose in Escherichia coli by Systematic Metabolic Engineering · Journal of Agricultural and Food Chemistry · 2026
• Nexus of Whey Proteins, Gut Dysbiosis, and Colonic Health · Food Science & Nutrition · 2026
• The role of myeloid cells in the pathogenesis of necrotizing enterocolitis; a scoping review · Frontiers in Pediatrics · 2026
• Risk Factors Associated with Extrauterine Growth Restriction (EUGR) Among Hospitalised Preterm Neonates <34 Weeks of Gestational Age: A Prospective Cohort Study · The Indian Journal of Pediatrics · 2026
• Neonatal Lactic Acidosis Associated With Antiretroviral Exposure: A Case Report · Cureus · 2026
• Standardised reporting framework for nutrition and growth in preterm nutrition studies: the NutriGrow Delphi study · Pediatric Research · 2026
• A systematic review and meta-analysis of the omega-3 and omega-6 long-chain polyunsaturated fatty acid composition of donor human milk for preterm infants · Prostaglandins, Leukotrienes and Essential Fatty Acids · 2026
• Nutrient Composition of Pasteurized Donor Human Milk and Short-Term Growth Outcomes in Infants · Indian Journal of Pediatrics · 2026
• Probiotic-Associated Invasive Infection Among Preterm Infants · JAMA Network Open · 2026

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