Human milk oligosaccharides


Human milk oligosaccharides (HMO) are with concentrations between 1 ‑ 15 g/l the third largest fraction of components in human milk (Donovan and Comstock. 2016). They comprise approx. 200 individual oligosaccharide isoforms. The high concentration coupled with structural diversity are characteristic for human milk. Lactose, the most abundant and dietary carbohydrate in human milk is also an integral component of HMO. In contrast to lactose, HMO are indigestible and do not contribute to energy intake. They reach the colon intact, exert their effects often via gut microbiota and are absorbed in low concentrations, only (Bode. 2012).

  1. Evidence indicates that HMO play a remarkable role in the observed short- and long-term benefits of breastfeeding, especially its immune protection and support of cognitive development. HMO are promoting growth of specific bacteria (Bode. 2012); and individual HMO isoforms are prebiotic candidates that possibly affect health (Gibson et al. 2017⁠; Sakanaka et al. 2019).
  2. HMO bind intestinal pathogens reducing susceptibility for infections (Triantis et al. 2018);
  3. By shaping gut microbiota, HMO modulate the systemic and mucosal immune system indirectly, for example by reducing use of medication (Puccio et al. 2017), reducing mortality (Kuhn et al. 2015) or reducing risk of respiratory and enteric diseases (Stepans et al. 2006⁠; Triantis et al. 2018).
  4. Certain HMO isoforms may be potential substrates for neurological cells (Wang. 2009) and suspected to influence cognitive development in infancy favourably (Berger et al. 2020).

Although laboratory research on the isolated HMO fraction from mother's milk has been ongoing for many decades, technological advances from the last decade are now allowing production of individual HMO isoforms on industrial scale. To date, the European Union allows four HMO to be added to infant food: 2'‑fucosyllactose (2'FL), lacto-N-neo-tetraose (LNnT), difucosyllactose (DiFL), and lacto‑N‑tetraose (LNT) (EU/2016/375⁠; EU/2016/376⁠; EU/2019/1979⁠; EU/2020/484). Whether these isolated components are capable of mimicking the diverse HMO fraction present in breast milk remains to be determined. Nevertheless, HMO either as natural fraction or industrially generated isolated isoforms hold the potential to play a key role for healthy infant development (Bode. 2012).

  • Human milk oligosaccharide terminology


    The literature on human milk oligosaccharides is diverse and stretches over many decades. Certain terms are used synonymously. We summarised these terms here:

    • The oligosaccharide fraction of human milk
    • consists of 200+ HMO species or isoforms or molecules or types.
    • Together, these form a HMO profile (e.g. HPLC analysis) or cluster or conglomerate.
    • The cluster/profile/conglomerate can be split into three HMO categories
    • in which HMO with a specific structure are sorted or grouped by their residues.
    • These structures are all built from the same three to five residues or molecules or monomers or building blocks that are monosaccharides and
    • differ in the combination of building blocks and glycosidic bond i.e. connection type.
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  • Structural diversity – Human milk oligosaccharide building blocks


    All human milk oligosaccharides (HMO) can be described with an equation such as this:


    To break down this complicated seeming equation, we start with the three to five monosaccharides or monomers that are the building blocks of HMO (Figure 412-3). Depending on the way these five building blocks are combined together with a number of different structural ways to connect, they form more than 200 HMO isoforms (Thurl et al. 2010).

     


    The disaccharide lactose is a combination of D‑glucose (Glu, blue circle Figures 412-3 and 412-4) with D-galactose (Gal, yellow circle, Figures 412-3 and 412-4) connected via a β1-4 bond (Figure 412-5). As free disaccharide or dimer, lactose is the major carbohydrate in mother's milk and thus called milk sugar. Lactose is a core component of all HMO isoforms: It is located at the terminal end of all HMO and further modified by the addition of galactose, N‑acetyllactosamine, fucose, or sialic acid, elongated and branched in various ways to form the multitude of known HMO isoforms (Figure 412-4) (Bode. 2012⁠, 2006).

    The type of connection – that is the glycosidic bond – plays a crucial role in HMO formation. It can define the 3D structure, thus determine interaction of the HMO to microorganisms (decoy receptor) or access of enzymes and other metabolites, and therefore affect functionality of the HMO isoform that was synthesised.

    As example Figure 412-6 shows the two HMO building blocks lacto‑N-biose and N-acetyllactosamine. Both are dimers from two of the five monomers: D-galactose and N‑acetylglucosamine (yellow circle, blue square; Figures 412-3 and 412-4). The only difference lies in the β1‑3 bond to form lacto‑N‑biose (Gal β1‑3 N‑acetlyglucosamine, Figure 412-6) compared with the β1‑4 bond that forms N‑acetyllactosamine (Gal β1‑4 N‑acetlyglucosamine, Figure 412-6). Fucose (red triangle, Figure 412-4) and sialic acid (purple diamond, Figure 412-4) can be added in α1‑2, α1‑3, α1‑4 and α2‑3, and α2‑6 bonds, to the lactose molecules, lactose-N‑biose or N‑acetyllactosamine, respectively (Bode. 2006).


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  • Structural diversity – Human milk oligosaccharides can be categorised by their residues


    Human milk oligosaccharides structures are described by a basic blueprint (Figure 412-3): Lactose is a core component linked with at least one further residue or unit. Based on the presence of these residues, HMO can be sorted into three different categories:

    1. Fucosylated HMO (Figure 412-7) are linked with at least one L-fucose residue.
    2. Sialylated or acidic HMO (Figure 412-8) are oligosaccharides linked with at least one sialic acid residue.
    3. Non-fucosylated or neutral HMO (Figure 412-9) are linked with at least one galactose, N‑acetyllactosamine, or lacto‑N‑biose unit. They are neither linked with fucose nor sialic acid (Ayechu-Muruzabal et al. 2018⁠; Kunz et al. 2000).

    Non-fucosylated neutral human milk oligosaccharides are the most diverse and extensive category representing between 42 ‑ 55% of the entire human milk oligosaccharide fraction, followed by fucosylated human milk oligosaccharides with 35 ‑ 50%. Sialylated, acidic human milk oligosaccharides are the least extensive category, representing approx. 13% of total human milk oligosaccharides (Donovan and Comstock. 2016).




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  • Human milk oligosaccharides may be prebiotics


    Since 2017, prebiotics are defined by the The International Scientific Association for Probiotics and Prebiotics (ISAPP) as “a substrate that is selectively utilized by host microorganisms conferring a health benefit.” This statement keeps a microbiota-mediated health benefit, but does not restrict a prebiotic component to be a food or carbohydrate nor are the effects limited to the gastro-intestinal tract (Gibson et al. 2017). This definition still requires that a prebiotic substance (1) reaches the microorganisms intact, (2) that selected, not all, microorganisms use the prebiotic candidate as substrate, and (3) that the beneficial effect to the host is mediated via actions of these microorganisms (La Fata et al. 2017).

    HMO meet the first and second set of requirements, whereas the third set is actively under investigation. HMO are resistant to digestive enzymes which makes them predominantly indigestible fibres and are unaffected by intestinal pH (Engfer et al. 2000⁠; Gnoth et al. 2000); only 1-2% of HMO are absorbed. Consequently, many HMO are reaching the colon intact (Obermeier et al. 1999) where individual isoforms are candidate prebiotics by serving as nutrient source for specific colonic microbiota species (Gibson et al. 2017).

    The HMO fraction as total has been associated with the establishment of a favourable intestinal microbiome (Kunz. 2012). When comparing the gut microbiome of breastfed and non-breastfed infants, different bacterial composition was identified (Harmsen et al. 2000). The predominance of Bifidobacteria species in breastfed infants was attributed to HMO presence (Kunz. 2012). When adding the two industrially generated HMO isoforms 2'‑fucosyllactose and lacto-N-neo-tetraose as mixture to infant formula, a shift of the stool microbiota composition was detected towards a similar composition to that of breastfed infants (Steenhout et al. 2016). Similarly, in vitro studies on cell lines are supporting a HMO-mediated growth advantage for beneficial over pathogenic bacteria (Sela and Mills. 2010). Individual HMO types, including 2'‑fucosyllactose, 3‑fucosyllactose, lacto‑difucotetraose, 3'‑sialyllactose, and 6'‑sialyllactose, promote the growth of Bifidobacteria strains (B. infantis, B. bifidus, B. breve, B. longum), Bacteroides genera, and specific Lactobacillus species (Lactobacillus delbrueckii) (Lewis et al. 2015⁠; Yu et al. 2012). This may be due to the specialised ability of B. breve, B. infantis, and most B. longum species of using fucosylated HMO as growth substrate that these pathogens lack (Sakanaka et al. 2019). In contrast, the same HMO isoforms cannot be used as growth substrate by many pathogens, including Escherichia coli, Clostridium perfringens, Streptococcus agaltictiae, Enterobacter, Acinetobacter baumannii (Ackerman et al. 2018⁠; Underwood et al. 2015⁠; Yu et al. 2013) or Streptococcus aureus, the latter being one of the most frequent causes for bacterial infections in infants (Lin et al. 2017).

    Besides directly affecting microbiota growth by serving as substrate of particular species, HMO are indirectly promoting bacterial growth via cross-feeding (Smith et al. 2019). When bacterial strains ferment HMO and other prebiotic substrates in the intestinal lumen the left-overs and bacterial metabolites serve other bacterial strains as growth substrate (Sela and Mills. 2010). This supports the development of a healthy and diverse microbiota ecosystem.

    Demonstrating the third set of requirements for a prebiotic classification of HMO – that is the demonstration of health benefits mediated via colonic microorganisms – has been difficult. This is because – until about 2000 – HMO could only be extracted from mother's milk and tested small-scale in laboratory settings. Since then, technological advancements have been making individual HMO isoforms available for large scale clinical studies or commercial productions (Bode et al. 2016) and data from clinical safety and/or efficacy studies have been slowly accumulating (Reverri et al. 2018).

    Health benefits associated with HMO include

    • anti-inflammatory properties: Pro-inflammatory cytokine concentrations in circulation were lower for infants fed formula with 2'-fucosyllactose in comparison to infants fed formula without (Goehring et al. 2016),
    • bifidogenicity,
    • decreased intestinal pH: Many beneficial bacteria strains are associated with short-chain fatty acid (SCFA) production (Yu et al. 2013). SCFA reduce intestinal pH, which is a mechanism of prebiotics that inhibits pathogen infection by creating unfavourable growth conditions (Ríos-Covián et al. 2016),
    • pathogen deflection and decoy effect.

    More information around prebiotics is available here.

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  • Human milk oligosaccharides deflect pathogens


    Breastfed infants may receive a clinically relevant infection protection that is mediated by human milk oligosaccharides. High HMO concentrations are associated with a reduced risk of diarrhoea (Morrow et al. 2004⁠; Stepans et al. 2006), an effect that seems to be particularly related to fucosylated HMO (Newburg et al. 2004). In addition, the risk for respiratory and bronchial infections seems to be reduced and may be related to 2'‑fucosyllactose and lacto‑N‑neo‑tetraose (Puccio et al. 2017⁠; Stepans et al. 2006).

    HMO are capable of binding to pathogens as decoy receptors and thereby blocking the attachment of pathogens to glycans in the intestine (Bode. 2012⁠; Triantis et al. 2018). Interactions between glycan structures and carbohydrate-binding proteins are a common metabolic process. They mediate selective substance uptake and cellular signal recognition (Taylor and Drickamer. 2014). Pathogens make use of this process because various cells in the intestine and respiratory tract have glycan structures on their surface. These represent binding targets to microbial pathogens. HMO show structural similarities to these surface glycans and some isoforms use the same mechanism of inhibiting pathogen infection: HMO either bind to the pathogen itself or they bind competitively to the cell surface, thereby blocking the interaction sites of pathogens or the receptor docking sites, respectively (Plaza-Diaz et al. 2013⁠; Triantis et al. 2018). This way, human milk oligosaccharides protect mechanically from infection.

    Representatives of each HMO category bind specifically to bacteria or viruses and bacterial toxins. Sialylated HMO (Figure 412-8) prevent adhesion of E. coli (Angeloni et al. 2005⁠; Facinelli et al. 2019) and fucosylated HMO (Figure 412-7) bind to various pathogens, including Campylobacter jejuni (Ruiz-Palacios et al. 2003⁠; Weichert et al. 2013), Helicobacter pylori (Xu et al. 2004), Salmonella enterica, Pseudomonas aeruginosa and enteropathogenic E. coli (EPEC) (Weichert et al. 2013). In addition, fucosylated HMO prevent adhesion of (intestinal) viruses such as Norwalk or Noroviruses by blocking their docking sites (decoy receptor) (Koromyslova et al. 2017⁠; Laucirica et al. 2017⁠; Shang et al. 2013). The efficacy of pathogen inhibition is structurally dependent; e.g. 2'-fucosyllactose has greater inhibition capacity on Campylobacter jejuni than 3'‑fucosyllactose (Weichert et al. 2013).

    HMO not only bind pathogens but also their toxins: Fucosylated HMO bind heat-stable enterotoxin of E. coli in vitro (Newburg et al., 1990) and may mitigate the activity of different bacterial exotoxins such as toxin A and B of Clostridium difficile, Shiga toxin type 1, and type 2 holotoxin (El-Hawiet et al. 2015⁠; Nguyen et al. 2016).

    Many of the protective effects of breast milk may be related to HMO presence, concentrations, and composition of the HMO fraction. However, a direct effect of specific HMO isoforms or the HMO cluster with reduced disease incidence has not been demonstrated yet. Since breast milk is rich in bioactive compounds – many of which are involved in immune protection – not all preventive effects can be dedicated to the HMO cluster or individual isoforms (Ballard and Morrow. 2013). Clinical data are needed to clearly identify the extent and mechanisms behind preventative effects hypothesised for HMO. Nevertheless, HMO deflect various pathogens and are thereby promising prebiotic candidates contributing significantly to microbiota-mediated health benefits (Triantis et al. 2018).

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  • Human milk oligosaccharide composition is genetically regulated


    Human milk can be sorted into four groups dependent on gene activation – that is on the Lewis positive/negative (Le gene) and secretor/non‑secretor (Se gene) status. These milk groups differ mostly in fucosylated HMO (Kumazaki and Yoshida. 1984⁠; Thurl et al. 1997). Sialylated and neutral non-fucosylated HMO (Figures 412-7 and 412-8) are abundant with relatively stable concentrations in all groups (Kunz et al. 2017⁠; Thurl et al. 2017).

    Enzymes define the HMO isoforms. Theoretically a great number of structures are possible. About 200 isoforms are present in human milk because the enzymes for their construction limit the possibilities of what building blocks are added where within the molecule (Figures 412-3, 412-4, and 412-5) (Kobata. 2010⁠; Zivkovic et al. 2010). Generally, 13 core structures are found in human milk (Urashima et al. 2012).

    Fucosylated HMO are generated by two different enzymes (Figure 412‑7): Fucosyltransferase‑2 encoded by the secretor (Se) gene (Kumazaki and Yoshida. 1984) and fucosyltransferase‑3 encoded by the Lewis blood group (Le) gene (Xu et al. 1996). Both genes are known to control blood group antigens (Dotz and Wuhrer. 2016⁠; Shen et al. 1968).

    Dependent on the genetic phenotype, the Le and Se genes can either be active or inactive (Kumazaki and Yoshida. 1984⁠; Shen et al. 1968). Individuals with active Se gene are “secretors” or "Se+" (Kumazaki and Yoshida. 1984) and individuals with active Le gene are “Le‑positive” or "Le+" (Xu et al. 1996).

    Le-positive secretors (Le+/Se+) express high oligosaccharide concentrations and all fucosylated human milk oligosaccharide isoforms from both fucosyltransferase‑2 and ‑3. Le-negative secretors (Le-/Se+) express similar oligosaccharide concentrations but are lacking the human milk oligosaccharides from fucosyltransferase‑3 such as lacto-N-fucopentaose‑II and ‑III. Presence of the HMO isoform 3'-fucosyllactose in this milk group is under debate because recent reports state its absence (Kunz et al. 2017) but older reports stated presence of 3'‑fucosyllactose (Ayechu-Muruzabal et al. 2018⁠; Thurl et al. 2010⁠; Thurl et al. 1997). If fucosyltransferase‑3 is responsible to generate 3'‑fucosyllactose it would be logical to expect its absence from this group.

    Le-positive non-secretors (Le+/Se-) express lower total oligosaccharide concentrations compared to the other groups. Because fucosyltransferase‑2 is absent, this group lacks the 2'-fucosyllactose, the most abundant human milk oligosaccharide isoform in the majority of milk samples (Kunz et al. 2017). Less than 1% of women are Le-negative non‑secretors (Le-/Se-) and compositional data of their milks are scarce. Total HMO concentrations have not been reported to date but are estimated to be comparable to Le-positive non-secretors (Thurl et al. 1997). Fucosylated human milk oligosaccharides are barely traceable and sialylated HMO take higher precedence in the total oligosaccharide fraction compared to the other milk groups.

    Although both enzymes are absent in Le-negative non‑secretors, traces of fucosylated HMO are detectable in these milk samples. This observation indicates that Le and Se-independent fucosyltransferases with very low efficacy exist (Erney et al. 2000⁠; Thurl et al. 1997). Their biological relevance remains to be determined.

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  • Why are human milk oligosaccharides a hot topic in infant nutrition?


    Publications on HMO have almost quadrupled since 2010 (National Library of Medicine https://pubmed.ncbi.nlm.nih.gov/). This is because novel processing techniques allow production of certain HMO isoforms on industrial scale (Faijes et al. 2019⁠; Sprenger et al. 2017). Until the turn of this millennium, human milk oligosaccharides could only be extracted from mother's milk, their function tested small scale and limited to laboratory settings (Bode et al. 2016⁠; Furuike et al. 2003). Cow's or goat's milk are poor sources for milk oligosaccharides because concentrations are low and lack the diversity of those in human milk (Zeuner et al. 2019).

    These generated molecules are structurally identical to those isolated from mother's milk. Four of these – 2'‑fucosyllactose (2'‑FL) – lacto‑N‑neotetraose (LNnT) – the mixture of 2'‑fucosyllactose with difucosyllactose (DiFL) – and as of April 2020, lacto‑N‑tetraose (LNT) are permitted on the European market and in food for infants (EU/2016/375⁠; EU/2016/376⁠; EU/2019/1979⁠; EU/2020/484).

    As part of the novel food application process in Europe, a safety evaluation is made by the European Food Safety Agency (EFSA) on behalf of the European Commission. Novel food applications are currently ongoing for 3'‑ and 6'-sialyllactose (3'‑SL and 6'‑SL, respectively) [https://ec.europa.eu/food/safety/novel_food/authorisations/summary-applications-and-notifications_en]. As a consequence, communication on these components in foods is increasing in parallel to the novel scientific insights on their function and potential health benefits generated at high pace.

    More information around prebiotics is available here.

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  • The most abundant human milk oligosaccharides that have been identified from milk samples around the world


    Table 412- 1 The table represents the most abundant human milk oligosaccharides that have been identified from milk samples around the world. Presence and concentrations of these respective HMO isoforms in an individual sample are affected by ethnicity yet additionally by individual genetic traits and lactation stage but little by maternal intake (Urashima et al. 2012). Structures, symbols and coloration of the respective HMO isoform are shown according to guidelines for glycans (Neelamegham et al. 2019); the images were drawn with the DrawGlycan tool at http://www.virtualglycome.org/DrawGlycan/ (Cheng et al. 2017) defining Gal, galactose as yellow circle, Glc, glucose as blue circle, Fuc, L-fucose as red triangle, Neu5Ac, sialic acid as purple diamond, GlcNAc, N-acetyllactosamine as blue square. The chemical terminology as per International Union of Pure and Applied Chemistry (IUPAC, https://iupac.org/) explains the structures and bonds between monomers. Glycosidic bonds are represented by α and β terminology. The lactose dimer in each HMO is emphasised in bold. Monomers in brackets are bound to the monomer following after the bracket.


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  • Maximum concentrations of isolated human milk oligosaccharides allowed as per European Commission


    Table 412- 2 Maximum concentrations of isolated human milk oligosaccharides allowed as per European Commission.

     

    Products for infants younger than 12 months

    Baby food for infants and young children

     

     

    Infant
    formula1

    Follow-on formula

    Processed cereal-based food

    Milk-based drinks or similar

    Safety evaluation by EFSA

    Age range1

    0-6 months

    6-12 months

    6 - ≤ 36 months

     

    HMO isoform and EU legislation implementing the respective HMO as novel food in Europe

     

     

     

     

    2'‑fucosyllactose

    (EU/2016/375⁠; EU/2017/2470⁠; EU/2019/1979)

    1.2 g/l alone

    or in combination with lacto-N-neotetraose;

    1.6 g/l as specific mix with difucosyllactose

    1.2 g/l alone or in combination with lacto-N-neotetraose;

    1.2 g/l as specific mix with difucosyllactose

    12 g/kg for products other than beverages alone or 10 g/kg as specific mix with difucosyllactose;

    1.2 g/l for liquid food ready to use alone or as specific mix with difucosyllactose

    1.2 g/l alone, in a specific mix with difucosyllactose or at a 2:1 ratio with lacto-N-neotetraose

    (EFSA NDA. 2015a)

    Lacto‑N‑neotetraose

    (EU/2016/375⁠; EU/2017/2470)

    -

    -

    6 g/kg for products other than beverages; 0.6 g/l for liquid food ready to use;

    0.6 g/l

    (EFSA NDA. 2015b⁠, 2015c)

    Mix lacto‑N‑neotetraose + 2'‑fucosyllactose

    (EU/2016/375⁠; EU/2017/2470)

    0.6 g/l in combination with 1.2 g/l of 2'‑fucosyllactose at a ratio of 1:2

    0.6 g/l in combination with 1.2 g/l of 2'‑fucosyllactose at a ratio of 1:2

    6 g/kg for products other than beverages;

    0.6 g/l for liquid foods

    0.6 g/l in combination with 2'FL at a ratio of 1:2 in the final product

    (EFSA NDA. 2015b)

    Difucosyllactose

    (EU/2019/1979)

    -

    -

    -

    -

     

    Mix difucosyllactose + 2'‑fucosyllactose2

    (EU/2019/1979)

    1.6 g/l of the mixture

    1.2 g/l of the mixture

    1.2 g/l (beverages)

    10 g/kg for products other than beverages

    1.2 g/l (beverages)

    10 g/kg for products other than beverages

    (EFSA NDA. 2019a)

    Lacto‑N‑tetraose

    (EU/2020/484)

    0.8 g/l

    0.6 g/l

    0.6 g/l (beverages)

    5 g/kg for products other than beverages

    0.6 g/l (beverages)

    5 g/kg for products other than beverages

    (EFSA NDA et al. 2019b)

    3'‑sialyllactose3,4

     

    0.2 g/l

    0.15 g/l

    0.15 g/l in a ready to feed product ;

    1.25 g/kg for products other than beverages

    0.15 g/l in a ready to feed product;

    1.25 g/kg for products other than beverages

    (EFSA NDA. 2020a)

    6'-sialyllactose2,3

     

    0.4 g/l

    0.3 g/l

    0.3 g/l in a ready to feed product;

    2.5 g/kg for products other than beverages

    0.3 g/l in a ready to feed product;

    2.5 g/kg for products other than beverages

    (EFSA NDA. 2020b)

    3'-galactosyllactose

    -

    -

    -

    -

    -

     

    1Age range and product descriptions as per Regulation EU/2013/609 .

    2Mix contains ≥ 75% 2'‑FL and ≥ 5% DiFL (w/w in % of dry matter) EU/2019/1979

    3Novel food applications for 3'‑SL and 6'‑SL have been submitted to the European Commission beginning 2019 [https://ec.europa.eu/food/safety/novel_food/authorisations/summary-applications-and-notifications_en]

    4Values proposed by EFSA

    The maxima are given for products ready to feed or according to preparation instructions of the manufacturer (EC/2006/125⁠; EU/2016/375). Products should bear a statement that "these products should not be used if breast milk or other foods containing [the added HMO isoform or mixture] are consumed at the same day" (EU/2019/1979⁠; EU/2020/484). Concentrations for Foods for Special Medical Purposes (FSMP) are dependent on the nutrient requirements of the patient population that needs the particular product.

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  • References


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