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Human milk oligosaccharide: As growth promoter of infant gut microbiota
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Tuesday, 08 June, 2021, 08 : 00 AM [IST]
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Davana, T.V., Bhavana, A., and Akshay R Patil
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Mother’s own milk is considered to be the best source of nutrition for the infants. The World Health Organisation recommends that infants should be exclusively breastfed for the first six months of life. Human milk contains an abundance of structurally diverse oligosaccharides, collectively known as Human Milk Oligosaccharides (HMOs)/Human Milk Glycan, is essential for potential benefits to infants.
As infants gut is sterile and colonisation of beneficial bio bacteria starts when fed with breast milk and potential benefits likes preventing pathogens adhesion, protection against intestinal or extra-intestinal infections, modulation of several immune responses and also for brain development (Ballard and Morrow, 2013).
The human milk is a rich and complete fluid that nourishes the baby, is essential for the Correct Development of the infant’s gut microbiota, that delivers bioactive components for the growth and development of the intestinal and immune systems (Ballard and Morrow, 2013).
Exclusive human milk feeding for the first 6 months of life, with continued breastfeeding for 1 to 2 years of life or longer, is recognised as the normative standard for infant feeding, (Pubmeb, et al., 2012).
Human milk contains an abundance of structurally diverse oligosaccharides, collectively known as human milk oligosaccharides (HMOs), which represent the third largest solid component of human milk after lactose and lipids.
It has been long noted that breastfeeding protects newborns against infections. Infant formula has been developed over many decades into adequate nutrition for those infants who cannot receive human milk. However, even modern infant formulas lack many components tailor made by each mother for the immune imprinting of her baby, such as speci?c antibodies (based on the immunologic history of the mother) and human milk oligosaccharides (HMOS) (based on the mother’s speci?c genetic makeup regarding e.g., Lewis (Le) blood group and secretor (Se) status).
Exclusive breastfeeding until the age of 4 months followed by partial breastfeeding is associated with a reduction in respiratory and gastrointestinal infectious diseases.
Human milk oligosaccharides (HMOs) are a family of structurally diverse unconjugated glycans that are highly abundant in and unique to human milk. Originally, HMOs were discovered as a prebiotic “bifidus factor” that serves as a metabolic substrate for desired bacteria and shapes an intestinal microbiota composition with health benefits for the breast-fed neonate.
Stage of lactation
Colostrum
Colostrum is the thick, yellowish ?uid secreted by the mammary gland a few days before and after parturition (1-4days), contains as much as 20–25 g/L of HMO, higher amount of protein, less fat and a number of immunising factors for the newborn.
Transitional milk
It is the transition from colostrum to mature milk, where lactation is established and production of milk begins in the breast tissue. Transitional milk is produced from approximately day 8 – 20.
Mature milk
Mature milk is produced from 20 days after birth, onwards. It can vary in and between individuals and the energy can vary between 270 and 315 kJ per 100mL. This is largely due to the variation in the fat content, as the fat of the milk received by the infant increases as the feed progresses. Mature milk continues to provide immune factors and other important non-nutritional components to the infant.
Hormones responsible for milk production:
Prolactin is produced by anterior pituitary gland which is responsible for milk secretion by mammary gland cells
Oxytocin is produced by posterior pituitary is responsible for contraction of myoepithelium around the glands leading to ejection of milk from glands into lacteal sinuses and ducts.
Nutrients in breast milk:
Breast milk contains all the nutrients the infant needs for proper growth and development.
These nutrients include:-
• Free water
• Proteins: - Protein accounts for 75% of the nitrogen-containing compounds and the non-protein nitrogen substances include urea, nucleotides, peptides, free amino acids and DNA.
• Fats: - Essential fatty acids and long-chain polyunsaturated fatty acids.
• Carbohydrates: - The principal carbohydrate of human milk is lactose.
• Minerals, vitamins, and trace elements.
Breast milk also contains important non-nutritional components, such as antimicrobial factors, digestive enzymes, hormones and growth factors that are important for passive protection against infections and immune-mediated diseases and modulate immunological development.
Immune-related components and growth factors include:
• Secretory IgA: -Predominant immunoglobulin in breast milk.
• Bioactive Cytokines: - Including transforming growth factor-b (TGF-b) 1 and 2 and interleukin-10 (IL-10)].
• Others: - Leukocytes, oligosaccharides, lysozyme, lactoferrin, adiponectin, interferon-g, epidermal growth factor (EGF) and insulin-like growth factor (IGF)-1.
Human Milk Oligosaccharides.
Human milk oligosaccharides (HMO, also known as human milk glycan’s) are sugar molecules, that are part of the oligosaccharides group and which can be found in high concentrations exclusively in human breast milk.
Three classes of oligosaccharides in human milk:-
• Neutral fucosylated (including 2'fucosyllactose, 2'FL),
• Neutral nonfucosylated (including lacto-N-neotetraose, LNnT),
• Acidic (including 3'sialyllactose, 3'SL, and 6'sialyllactose, 6'SL)
Human milk oligosaccharides (HMOs) are a family of structurally diverse unconjugated glycan's that are highly abundant in and unique to human milk, These diverse glycan structures are indigestible to the infant and can reach the large intestine, they can often be found in the stool.
These glycan’s serve many functions, including protection and development ranging from selectively enriching gut bifido-bacteria, promoting the immune system and enhancing intestinal epithelial barrier function. Milk glycan functions shape the intestinal micro-biome, from the sterile uterine environment through the chaotic introduction of environmental bacteria at birth, through a stable milk-oriented micro-biome.
HMOs selectively promote growth of beneficial bacteria such as Bifidobacterium longum subspecies infantis, while suppressing growth of pathogens like Escherichia coli and Clostridium perfringens. The breakdown products of HMOs from B. infantis, lactate and SCFAs, also inhibit E. coli and C. perfringens growth.
Kerala and Karnataka shows decline in number compared to others according to national health and family survey.
HMOs are composed out of 5 di?erent monosaccharide's, which are used as building blocks for HMOS are Glucose (Glc), Galactose (Gal), N-Acetyl-Glucosamine (GlcNAc), Fucose (Fuc) and Sialic acid (Neu5Ac), Each HMOS structure starts with a lactose unit “Gal (ß1-4) Glc” which results from formation of a ß1-4 glycosidic linkage between galactose and glucose.
Several tri-saccharides can be synthesized by either galactose or fucose to the reducing or non-reducing end of the lactose residue, which is performed through galactosyl- or fucosyl-transferase activity. Resulting components are e.g., 3'-galactosyllactose, 4'-galactosyllactose, 6'-galactosyllactose, 2-fucosyllactose (2-FL), and 3-fucosyllactose (3-FL) . If Sialic acids are connected to the non-reducing end of lactose via sialyl-transferases, 3'-sialyllactose (3'-SL) and 6'-sialyllactose (6'-SL) are formed.
Uniqueness of Human milk:
Human milk composition is altered based on maternal genetic factor - the Secretor (Se) and lewies (Le) blood group system, which is determined by the activity of two gene a1-2-fucoslyltransferase FUT2 (encoded by the Se gene) and the a1-3/4-fucosyltransferase FUT3 (encoded by the Le gene).
Individuals with an active Se locus are classi?ed as Secretors. Milk of Secretor women is abundant in 2'-fucosyllactose (2'FL), LNFP I and other a1-2-fucosylated HMOs. In contrast, non-Secretor lack a functional FUT2 enzyme and their milk does not contain a1-2-fucosylated HMO, Individuals with an active Le locus are classi?ed as Le positive. They express FUT3, which contain a1-4-fucosylated HMOs.
If both FUT2 and FUT3 are expressed, milk contains HMO with Le b antigens (highlighted). If only FUT3 is expressed, milk contains HMO with Le a antigens (highlighted). If FUT3 is not expressed, HMOs contain neither Le a (or) Le b antigens.
Infants consuming milk produced by women who are non-secretors exhibit delayed colonisation of bifido bacteria, higher abundance of Streptococcus taxa, and have functional differences in the metabolic activity of their microbiota. Infants fed milk from non-secretor mothers are at higher risk for diarrheal disease.
Potential Benefits of HMOs
• HMOs are prebiotics that serve as metabolic substrates for bene?cial bacteria (green) and provides them with a growth advantage over potential pathogens (purple).
• HMOs are antiadhesive antimicrobials that serve as soluble glycan receptor decoys and prevent pathogen attachment.
• HMOs directly affect intestinal epithelial cells and modulate their gene expression, which leads to changes in cell surface glycan’s and other cell responses.
• HMOs modulate lymphocyte cytokine production, potentially leading to a more balanced Th1/Th2 response.
• HMOs reduce selectin-mediated cell–cell interactions in the immune system and decrease leukocyte rolling on activated endothelial cells, potentially leading to reduced mucosal leukocyte in?ltration and activation.
• HMOs provide Sialic acid as potentially essential nutrients for brain development and cognition.
Infant Gut Microbiota.
• A healthy microbiota has been de?ned as the intestinal microbial community that assists the host to maintain a healthy status under certain environmental conditions (Peso Echarri et al., 2011).
• Is teeming with microbes – up to 70% of the body’s total number
• It is an extremely complex ecosystem harboring more than 100 trillion microorganisms
• There are thought to be around 30 – 40 different species of bacteria.
• Gut colonisation of the newborn begins with facultative anaerobes, such as entero-bacteria and streptococci and continues with anaerobic genera, such as Bi?do-bacterium, Bacteroides, and Clostridium (Mackie et al., 1999; Fanaro et al., 2003).
• Many of these have a symbiotic relationship with us – and help to keep less beneficial strains at bay.
• A healthy gut in an adult human has somewhere in the region of 2 kg of these bacteria in the gut.
• They play a vital role in the body – without them we would not survive
Gut Microbiota or Gut Flora
The word microbiota represents a ensembles of microorganisms that resides in a previously established environment. Human beings have clusters of bacteria in different parts of the body such as in the surface or deep layers of skin (skin microbiota), the mouth (oral microbiota), the vagina (vaginal microbiota), and so on.
Gut microbiota is harbored in the intestine, one of the main areas in our bodies that comes into contact with the external environment (other examples are the skin and the lungs).
Importance of Gut Microbiota or Gut Flora
• It helps the body to digest certain foods that the stomach and small intestine have not been able to digest.
• It helps with the production of some vitamins (B and K).
• It helps us combat aggressions from other microorganisms, maintaining the wholeness of the intestinal mucosa.
• It plays an important role in the immune system, performing a barrier effect.
• A healthy and balanced gut microbiota is key to ensuring proper digestive functioning.
Essential or beneficial flora
These bacteria are referred to as our indigenous friendly bacteria. The main members of this group are: Lacto bacteria, Lactobacillus plantarum Bifidobacteria, Lactobacteria, Propionobacteria, Peptostreptococci and Enterococci.
Beneficial or good bacteria is also called probiotic. They are the housekeepers of the gut. These bacteria fulfil a myriad of vital functions in the body
Advantages of Breast feeding:
• Stronger immune systems.
• Less diarrhea, constipation, gastroenteritis, gastro esophageal reflux, and preterm necrotizing enterocolitis (NEC)
• Fewer colds and respiratory illnesses like pneumonia, respiratory syncytial virus (RSV) and whooping cough
• Fewer ear infections, especially those that damage hearing
• Fewer case of bacterial meningitis
• Better vision and less retinopathy of prematurity
• Lower rates of infant mortality
• Lower rates of Sudden Infant Death Syndrome (SIDS)
• Less illness overall and less hospitalisation
Maternal health benefits:
Human milk confers multiple layers of protection to the new-born by providing bioactive components that protect the infant from pathogenic infection, facilitate intestinal and immune development, and support healthy gut microbes. So, human milk has been referred to as the “gold standard” of infant nutrition.
(Davana is assistant professor, Food Science and Nutrition, College of Sericulture, Chintamani. She can be contacted at davanatv94@gmail.com.
Bhavana is a scientist, Home Science, ICAR- Krishi Vigyan Kendra, Chintamani-563125, She can be contacted at bhavana7243@gmail.com.
Patil is a Ph.D scholar, Food Science and Technology, Indian Institute of Food Processing Technology (IIFPT), Ministry of Food Processing Industries, Government of India, Pudukkottai road, Thanjavur. He can be reached at akshaynayaka1111@gmail.com)
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