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These findings suggest an important role for human milk in supporting intestinal health, and may inform strategies for reducing the risk of necrotizing enterocolitis (NEC) in preterm infants, lead author Lauren Smith, MD, of Yale School of Medicine, New Haven, Connecticut, and colleagues, reported.
“Compelling evidence has revealed that the largest risk factor for NEC apart from prematurity is formula feeding, while conversely, parental milk (PM) confers protection, with a 6- to 10-fold lower incidence of NEC among PM-fed infants compared to formula,” the investigators wrote in Gastro Hep Advances. “It is unknown whether this is due to the many known protective factors in PM or as a result of an injurious component present in formula or a combination of both.”
To learn more, the investigators studied organoids cultured in a three-dimensional matrix and exposed to one of four dietary conditions: PM, donor human milk (DHM), standard formula (SF), or extensively hydrolyzed formula (HF). Organoids were grown in growth media supplemented with these diets for 5 days, followed by differentiation media for an additional 5 days. Growth, differentiation, and immune-related factors were analyzed using advanced imaging, RNA sequencing, and cytokine profiling.
The results demonstrated that human milk–fed organoids significantly outperformed formula-fed organoids in several measures. By the fifth day of growth media exposure, organoids supplemented with PM or DHM were larger and exhibited higher rates of proliferation, as evidenced by Ki67 staining. Organoids exposed to SF were the smallest and had the lowest proliferation and highest levels of apoptosis, while HF-fed organoids showed intermediate growth performance.
During the differentiation phase, organoids exposed to human milk developed more complex structures, forming buds with greater length and diameter compared to formula-fed organoids. PM was particularly effective, though DHM also promoted substantial differentiation. RNA sequencing revealed that organoids cultured with human milk upregulated genes involved in fatty acid metabolism and Wnt signaling, which are critical for cellular energy production and epithelial proliferation. In contrast, formula-fed organoids exhibited downregulation of cell-cycle-promoting genes and showed an inflammatory gene signature.
Cytokine profiling further underscored the benefits of human milk. Organoids exposed to PM and DHM secreted higher levels of immune-regulating cytokines, such as thymic stromal lymphopoietin (TSLP) and macrophage colony-stimulating factor (M-CSF). In contrast, formula-fed organoids produced lower levels of these beneficial cytokines and higher levels of pro-inflammatory markers, including interleukin-18 (IL-18).
These findings suggest that human milk supports intestinal growth, differentiation, and immune regulation in ways that formula does not, and the investigators emphasized the importance of identifying specific bioactive factors in human milk.
“If the factors responsible for this effect can be identified, there could be significant clinical value in supplementing these components in DHM and formula to help prevent NEC and foster normal intestinal development in preterm infants,” they concluded.
Future research will aim to isolate and supplement key components of human milk to enhance the nutritional and protective value of donor milk and formula. In addition, the investigators noted the need to explore potential sex-based differences in intestinal development, as the current study used only male-derived samples.The research was supported by the Yale School of Medicine Medical Student Research Fellowship. The investigators disclosed no conflicts of interest.
These findings suggest an important role for human milk in supporting intestinal health, and may inform strategies for reducing the risk of necrotizing enterocolitis (NEC) in preterm infants, lead author Lauren Smith, MD, of Yale School of Medicine, New Haven, Connecticut, and colleagues, reported.
“Compelling evidence has revealed that the largest risk factor for NEC apart from prematurity is formula feeding, while conversely, parental milk (PM) confers protection, with a 6- to 10-fold lower incidence of NEC among PM-fed infants compared to formula,” the investigators wrote in Gastro Hep Advances. “It is unknown whether this is due to the many known protective factors in PM or as a result of an injurious component present in formula or a combination of both.”
To learn more, the investigators studied organoids cultured in a three-dimensional matrix and exposed to one of four dietary conditions: PM, donor human milk (DHM), standard formula (SF), or extensively hydrolyzed formula (HF). Organoids were grown in growth media supplemented with these diets for 5 days, followed by differentiation media for an additional 5 days. Growth, differentiation, and immune-related factors were analyzed using advanced imaging, RNA sequencing, and cytokine profiling.
The results demonstrated that human milk–fed organoids significantly outperformed formula-fed organoids in several measures. By the fifth day of growth media exposure, organoids supplemented with PM or DHM were larger and exhibited higher rates of proliferation, as evidenced by Ki67 staining. Organoids exposed to SF were the smallest and had the lowest proliferation and highest levels of apoptosis, while HF-fed organoids showed intermediate growth performance.
During the differentiation phase, organoids exposed to human milk developed more complex structures, forming buds with greater length and diameter compared to formula-fed organoids. PM was particularly effective, though DHM also promoted substantial differentiation. RNA sequencing revealed that organoids cultured with human milk upregulated genes involved in fatty acid metabolism and Wnt signaling, which are critical for cellular energy production and epithelial proliferation. In contrast, formula-fed organoids exhibited downregulation of cell-cycle-promoting genes and showed an inflammatory gene signature.
Cytokine profiling further underscored the benefits of human milk. Organoids exposed to PM and DHM secreted higher levels of immune-regulating cytokines, such as thymic stromal lymphopoietin (TSLP) and macrophage colony-stimulating factor (M-CSF). In contrast, formula-fed organoids produced lower levels of these beneficial cytokines and higher levels of pro-inflammatory markers, including interleukin-18 (IL-18).
These findings suggest that human milk supports intestinal growth, differentiation, and immune regulation in ways that formula does not, and the investigators emphasized the importance of identifying specific bioactive factors in human milk.
“If the factors responsible for this effect can be identified, there could be significant clinical value in supplementing these components in DHM and formula to help prevent NEC and foster normal intestinal development in preterm infants,” they concluded.
Future research will aim to isolate and supplement key components of human milk to enhance the nutritional and protective value of donor milk and formula. In addition, the investigators noted the need to explore potential sex-based differences in intestinal development, as the current study used only male-derived samples.The research was supported by the Yale School of Medicine Medical Student Research Fellowship. The investigators disclosed no conflicts of interest.
These findings suggest an important role for human milk in supporting intestinal health, and may inform strategies for reducing the risk of necrotizing enterocolitis (NEC) in preterm infants, lead author Lauren Smith, MD, of Yale School of Medicine, New Haven, Connecticut, and colleagues, reported.
“Compelling evidence has revealed that the largest risk factor for NEC apart from prematurity is formula feeding, while conversely, parental milk (PM) confers protection, with a 6- to 10-fold lower incidence of NEC among PM-fed infants compared to formula,” the investigators wrote in Gastro Hep Advances. “It is unknown whether this is due to the many known protective factors in PM or as a result of an injurious component present in formula or a combination of both.”
To learn more, the investigators studied organoids cultured in a three-dimensional matrix and exposed to one of four dietary conditions: PM, donor human milk (DHM), standard formula (SF), or extensively hydrolyzed formula (HF). Organoids were grown in growth media supplemented with these diets for 5 days, followed by differentiation media for an additional 5 days. Growth, differentiation, and immune-related factors were analyzed using advanced imaging, RNA sequencing, and cytokine profiling.
The results demonstrated that human milk–fed organoids significantly outperformed formula-fed organoids in several measures. By the fifth day of growth media exposure, organoids supplemented with PM or DHM were larger and exhibited higher rates of proliferation, as evidenced by Ki67 staining. Organoids exposed to SF were the smallest and had the lowest proliferation and highest levels of apoptosis, while HF-fed organoids showed intermediate growth performance.
During the differentiation phase, organoids exposed to human milk developed more complex structures, forming buds with greater length and diameter compared to formula-fed organoids. PM was particularly effective, though DHM also promoted substantial differentiation. RNA sequencing revealed that organoids cultured with human milk upregulated genes involved in fatty acid metabolism and Wnt signaling, which are critical for cellular energy production and epithelial proliferation. In contrast, formula-fed organoids exhibited downregulation of cell-cycle-promoting genes and showed an inflammatory gene signature.
Cytokine profiling further underscored the benefits of human milk. Organoids exposed to PM and DHM secreted higher levels of immune-regulating cytokines, such as thymic stromal lymphopoietin (TSLP) and macrophage colony-stimulating factor (M-CSF). In contrast, formula-fed organoids produced lower levels of these beneficial cytokines and higher levels of pro-inflammatory markers, including interleukin-18 (IL-18).
These findings suggest that human milk supports intestinal growth, differentiation, and immune regulation in ways that formula does not, and the investigators emphasized the importance of identifying specific bioactive factors in human milk.
“If the factors responsible for this effect can be identified, there could be significant clinical value in supplementing these components in DHM and formula to help prevent NEC and foster normal intestinal development in preterm infants,” they concluded.
Future research will aim to isolate and supplement key components of human milk to enhance the nutritional and protective value of donor milk and formula. In addition, the investigators noted the need to explore potential sex-based differences in intestinal development, as the current study used only male-derived samples.The research was supported by the Yale School of Medicine Medical Student Research Fellowship. The investigators disclosed no conflicts of interest.
FROM GASTRO HEP ADVANCES