Comparing early life nutritional sources and human milk feeding practices: personalized and dynamic nutrition supports infant gut microbiome development and immune system maturation

Figures & data

Figure 1. Associations between human milk components and physiological processes that influence infant immune development: epigenetics, microbiome, and gut integrity.

Table 1. Milk components associated with infant immune system and/or gut microbiome development, and their relative concentrations in different nutritional sources: parents own milk (POM, distinguishing between colostrum and mature milk), frozen expressed POM (EPOM), donor human milk (DHM), and commercial infant formula.

	Parents’ Own Milk (POM)			Donor Human Milk (DHM)^a	Commercial Infant Formula^b	Reference
Components	Colostrum (<5 days)	Mature Milk (>14 days)	Expressed & Frozen^c
Immune Cells
Macrophages	+++	++ >	Exp, Frz	-	-	38,39,40
Monocytes	+++	++ >	Frz	-	-	39,40
Dendritic Cells	+++	++ >	Frz	?	-	39,40
Neutrophils	+++	++ >	Frz	-	-	39,40
Lymphocytes	+++	++ >	Frz	-	-	39,40
Immunoglobulins
SIgA	+++	++ <	Unaffected	+ ~	-	39,41,42,43
IgG	+++	++ <	Unaffected	+ ~	+ (B)	39,41,42,43,44
IgM	+++	++	Unaffected	+ ~	-	39,41,42,43
Signaling Proteins and Bioactive Enzymes
TGF-ß1	+++	++ >	Unaffected	++ ~	-	39,45,46,47
TGF-ß2	+++	++ >	Unaffected	++ ~	-	39,45,47
IL-10	+++	++ >	Unaffected	+ ~	-	45,48,49
IL-6	+++	++ >	Unaffected	+ ~	-	45,48,50
IL-1ß	+++	++ >	?	+ ~	-	48,50
IGF-1	+++	++ >	?	+ ~	-	39,51
IL-7	+++	++ >	?	?	-	52
TNF-α	+++	++ >	Exp	+ ~	-	38,45,50
GCSF	+++	++ >	?	++ ~	-	48,53
EGF	+++	++ >	Unaffected	++ ~	-	39,45,54,55
Lactoferrin	++++	+++ >	Unaffected	+ ~	+ (B, S)	33,41,42,56
Microbes	++	+++ <	Frz	-	- (S)	39,42,57,58
Prebiotic Oligosaccharides	+++	++ >	Unaffected	++ ~	- (S)	59–62
Fatty Acids
Short-Chain	+	++ <	Frz	++ ~	+ (B)	60,63–66
Medium-Chain	+	++ <	Frz	++ ~	++ (B, S)	63,64,66,67
Essential Long-Chain (e.g. DHA, ARA)	++	+ >	Frz	++ ~	+ (B, S)	60,63–66
Postbiotics^d	++	+++ <	Frz	++++ ~	+ (B)	57,63,68,69
MicroRNAs	++++	+++ >	Unaffected	++ ~	+ (B)	70–73

^aDifference when frozen at −20°C for 3 months.

^bRefers to formula made from cow’s milk; the most common type of commercial formula.

^cRefers to the combination of non-viable microbes and microbial metabolites.

^dAssuming Holder Pasteurization (62.5°C for 30 minutes).

Symbols: (?), unknown; (+ to ++++) relative concentrations from lowest to highest; (-) not detected or not functional; (>) concentration generally decreases over time; (<) concentration generally increases over time; (Exp) affected by expression and/or lack of suckling); (Frz), affected by freezing; (~) concentration varies depending on lactation stage of donated milk; (B) bovine origin, structurally different from human versions; (S) some formulas contain these components as supplemental additives, often in lower concentrations than what is found in human POM.

Abbreviations: Ig, immunoglobulin; TGF, transforming growth factor; IL, interleukin; IGF, insulin-like growth factor; TNF; tumor necrosis factor; GCSF, granulocyte colony-stimulating factor; EGF, epidermal growth factor, DHA; docosahexaenoic acid, ARA; arachidonic acid.

Figure 2. Suggested mechanisms of action and interactions among parents’ own milk (POM) components, infant gut microbiota, and the infant immune system. Adapted from “intestinal immune system (small intestine)”, by Biorender.Com (2023). Retrieved from https://app.biorender.com/biorender-templates.

Figure 3. Approximate changes in milk composition and other factors associated with the weaning reaction over time, in mice. Adapted from Hornef and Torow (2019).¹

Box 1. Priority areas for future research on early life nutrition, gut microbiota and immune development.

Characterizing the full extent of POM components and applying a systems biology approach to determine their independent and collective functions in the infant How do these functions change over lactation? How do these functions contribute to immune system development? How do different POM components interact with each other? Priority components: miRNAs, HMOs, SIgA, EGF

Understanding the viability and function of immune cells and microbes in POM Are they viable? Do they survive digestion? Do they act locally in the gut and/or systemically? What are their functional roles in the infant? Do these roles change over time as the infant gut matures?

Continuing research on the short and long-term effects of adding different POM components to infant formula. Which POM components and combinations are most important to include? How do these components influence microbiome development? How do these components influence immune system development? What composition and dose are safe and efficacious for infant health and development? Is it possible and beneficial to mimic the dynamism and chronobiology of POM?

Improving our understanding of how POM adapts to infant needs, and how direct POM feeding facilitates this adaptability. What POM components can adapt according to infant needs? What infant needs stimulate POM adaptation? What mechanisms contribute to the hypothesized bi-directional signalling pathway between lactating parent and suckling infant? To what extent does EPOM feeding interfere with this process?

Determining the extent to which weaning reaction research applies to human infant development and lifelong health. How does human milk EGF-mediated GAP inhibition influence immune system development? Is a lack of EGF associated with immune system development disruption? Is a lack of human milk EGF associated with the increased risk of NEC in brief periods of neonatal formula feeding? Characterizing epigenetic signatures of POM feeding at different life stages and identifying critical time windows of POM-mediated epigenetic imprinting. Improving processing technology and storage protocols to maximize the preservation of immunomodulatory POM functions in EPOM and DHM

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