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Main functions of HMO 2'-FL

Main functions of HMO 2'-FL

The various ingredients in breast milk each help the baby grow and develop. Among the various components of breast milk, human milk oligosaccharide (HMO) is studied to affect human intestinal, immune, and brain development.

Helps gut health

Human milk oligosaccharide is a bifidus growth factor. Especially 2’-FL selectively increases intestinal Bifidobacterium because Bifidobacterium bifidum, B. dentium, B. infantis, only these three types of bifidobacterial, can utilize it. Bifidobacterium which metabolites 2’-FL, secretes strong acidic acetic acid, which results in lower pH circumstance where harmful bacteria can not proliferate well and finally increases relative dominance of Bifidobacteria to make healthy gut system. Go to see related papers1

At birth, the baby passes through the mother's vagina and gets intestinal microorganisms. If baby takes breast milk, B. infantis is dominant by being grown up on human milk oligosaccharide (HMO) given by your mother. It has stronger adherence to intestinal epithelial cell than the microorganisms fed on other carbon source (lactose, etc.), which results in dominance in gut, inhibits the expression of inflammatory genes and acts as an inflammatory control to increase the secretion of substances that suppress inflammation. Go to see related papers2

There are several research reports human milk oligosaccharide helps improve the symptoms of necrotizing colitis (NEC), a fatal inflammatory bowel disease in premature babies. Especially for newborns, they need to intake human milk oligosaccharide (HMO) in order that Bifidobacterium infantis becomes an intestinal dominant microorganism and plays a key role in gut and immune health as an inflammation control factor. Go to see related papers3

Helps immune health

Human milk oligosaccharide (HMO) acts directly on the intestinal epithelium of a person, resulting in increase of immunoglobulin. And human milk oligosaccharide enhances both humoral immunity and cellular immunity by suppressing inflammatory factors, which helps immune system mature by improving a person's innate immune system. It has been also reported this immune-boosting mechanism also affects the reduction of food-borne allergies. * Humoral immunity : An antibody and antigen in human or animal blood react to exclude foreign antigens. * Cellular Immunity: Lymphocytes with specific reactivity to certain antigens may be directly involved in immune responses. (Source: Nurse Abuse Dictionary) Go to see related papers4 Go to see related papers5 Go to see related papers6

Human milk oligosaccharide (HMO) is structurally similar to that of intestinal epithelial glycan receptors and makes pathogenic bacteria bind to human milk milk oligosaccharide by mistaking it as a glycan receptor. Like this, it acts to prevent pathogenic bacteria from attaching to the intestinal epithelium by signaling a change in the shape of the glycan receptor. Go to see related papers7

Through the prevention mechanism of intestinal epithelial attachment of pathogenic bacteria as described above, human milk oligosaccharide 2'-FL reduces infection rate of Campylobacter jejuni, heat-resistant E. coli, rotavirus and Pseudomonas aeruginosa, which helps reduce antibiotic use and respiratory diseases Go to see related papers8

Helps your memory and cognitive health

The human brain is made up of billions of neurons which receive or send information through synapses. The connectivity of these synapses changes over time, called neuroplasticity, and this synaptic plasticity is related to learning and memorizing processes. Repeated events such as something happening frequently or investigating it can reinforce synapses of the brain, called long-term potentialization (LTP), which can be seen as memory formation. HMO 2'-FL affects this Long-term potentialization (LTP) and there are many animal experiments that help improve memory and learning skills. Go to see related papers9

Helps Skin and Tooth health

Aforementioned Inflammation control mechanism of the human milk oligosaccharide (HMO)-FL weakens the inflammation of keratinocytes and the prevention mechanism of harmful bacteria helps prevent cavities by interfering with growth and tooth attachment of cavity bacteria. Go to see related papers10 Go to see related papers11

Effects on gut health

Human milk oligosaccharide (HMO) 2’-FL helps increase the number of bifidobacteria in the intestines by feeding Bifidobacterium selectively.

Humans do not have enzymes that digest human milk oligosaccharide (HMO). Why exists human milk oligosaccharide (HMO) in breast milk when humans can't even digest it?

Since the beginning of time, human milk oligosaccharide (HMO) has not been a source of human energy, but only certain microbes living in the human intestine have enzymes that can digest human milk oligosaccharide.

That means that this particular microorganism is essential to the human intestine, so we can think of the hypothesis that it allows it to grow well while feeding human milk oligosaccharide. So what specific microorganisms can digest human milk oligosaccharide? Bifidobacterium, well known for its health, has enzymes that can digest human milk oligosaccharide (HMO), but not all types of Bifidobacterium can metabolite human milk oligosaccharide (HMO).

There are not many species of Bifidobacterium that can digest human milk oligosaccharide (HMO) as shown in below table. In particular, the enzymes that can break down human milk oligosaccharide (HMO) 2'-FL can be found only in Bifidobacterium bifidum, Bifidobacterium dentium and Bifidobacterium phosphantis, which means that these three types of Bifidobacterium can only metabolite HMO 2'-FL.

HMO-degradable enzymes existing in the bifidobacterium

Bifidobacterium with
sequence confirmed
Fucosidase Sialidase Lacto-N-biose Phosphorylase
Bifidobacterium adolecentis ATCC 15703;L2-32 - - -
Bifidobacterium animalis sp. lactis AD011;HN019 - - -
Bifidobacterium animalis sp. lactis BI-04;DSM 10140 - - -
Bifidobacterium bifidum NCIMB 41171 1 2 4
Bifidobacterium breve 20213 - 1 2
Bifidobacterium catenulatum DSM 16992 - - -
Bifidobacterium dentium ATCC 27678 1 - -
Bifidobacterium dentium Bd1 - - -
Bifidobacterium longgum DJO10A - - 2
Bifidobacterium longgum NCC2705 - - 1
Bifidobacterium infantis ATCC 15697 4 2 1
Bifidobacterium Infantis ATCC 55813a - - 1
Bifidobacterium Infantis CCUG 52486a - - 1
Bifidobacterium sudocatenulatum DSM 20438 - - -

* Source of data : The Influence of Milk Oligosaccharides on Microbiota of Infants: Opportunities for Formulas

Intaking 5g, 10g, and 20g of human milk oligosaccharide (HMO) in adults for two weeks increased intestinal bifidobacteria, especially in the 10g intake group.

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* Source of data : Oral supplementation of healthy adults with 2′-O-fucosyllactose and lacto-N-neotetraose is well tolerated and
shifts the intestinal microbiota British Journal of Nutrition (2016), 116, 1356–1368

Bifidobacterium infantis grown on human milk oligosaccharide (HMO) becomes an intestinal dominant species due to its high adherence and is involved in controlling body immunity and inflammatory substances.

Bifidobacterium infantis and Bifidobacterium bifidum grown on lactose and HMO 2'-FL were checked for adhesion to Caco-2 and HT-29 cell and HMO 2'-FL-grown Bifidobacterium infantis showed significantly higher adhesion in HT-29 cells. This experiment was conducted in vitro, but implies that it can be better attached to intestinal epithelium.

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Bifidobacterium infantis and breve, cultured on HMO 2'-FL, have been shown to inhibit gene expression of inflammatory chemokines.

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* Source of data : Bifidobacteria grown on human milk oligosaccharides downregulate the expression of infla mmation-related genes in Caco-2 cells
BMC Microbiology volume 15, Article number: 172 (2015)

Human milk oligosaccharide helps prevent necrotic colitis (NEC) from getting worse.

Necrotic colitis (NEC) is a necrotic enteritis in small intestine or large intestine of an infant and is one of the most severe neonatal diseases caused by premature birth, high concentrations of milk, hypoxia, too fast nutrition, plethora and infection. It is a scary disease with a mortality rate of 20% with various levels of necrosis of the mucous membrane even if it gets treatment.

* Source of data: Asan Medical Center in Seoul

After causing necrotic colitis (NEC) in rodents, breast milk, infant formula, breast milk+2'-FL, and infant formula+2'-FL have been shown to help with daily weight gain and lower the severity of NEC in HMO 2’-FL supplementary experimental group.

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* Source of data : The human milk oligosaccharide 2′-fucosyllactose attenuates the severity of experimental necrotising enterocolitis by enhancing mesenteric perfusion
in the neonatal intestine (British Journal of Nutrition (2016), 116, 1175–1187)

Human milk oligosaccharide (HMO) 2'-FL and LNnT induce beneficial bifidobacterium increase without gastrointestinal disturbances in irritable bowel syndrome (IBS) subjects.

Irritable Bowel Syndrome (IBS) whose main reason is guessed as genetic factors, stress, psychological factors, gastrointestinal inflammation, overreaction to certain foods and abnormal changes in the composition of resident bacteria in the colon, are complex symptoms of abdominal pain or abdominal discomfort even though its precise cause is not clarified.

* Source of data : Samsung Medical Center

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* Source of data : Human milk oligosaccharide supplementation in irritable bowel syndrome patients: A parallel, randomized, double-blind, placebo-controlled study
Neurogastroenterology & Motility. 2020;00:e13920.

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Human milk oligosaccharide supplementation in irritable bowel syndrome patients: A parallel, randomized, double-blind, placebo-controlled study
Neurogastroenterology & Motility. 2020;00:e13920

Human milk oligosaccharide (HMO) 2'-FL affects the adaptation response to enterectomy.

The supplementation of human milk oligosaccharide (HMO) 2’-FL to the diet of mice with intestinal resection showed that it affected rapid weight gain and fast establishment of various microbial clusters in small intestine compared with the group not fed with HMO.

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* Source of data : The human milk oligosaccharide 2'-fucosyllactose augments the adaptive response to extensive intestinal Am J Physiol Gastrointest Liver Physiol 310: G427–G438, 2016

There was no effect of 2'-FL supplementation between non-surgical groups and the ICR(Ileocecal resection) group, while the weight gain of 2'-FL supplemented group increased faster than that of not supplemented group. Prior to and after intestinal resection surgery in rats, 2'-FL supplementation showed an increase in intestinal bacteria (blue) in the group that supplemented 2'-FL prior to surgery. After surgery, Bifidobacterium and Clostridium increased noticeably and after intestinal resection, microbial colonies showed diversity in groups supplemented with 2'FL. Therefore, human milk oligosaccharide (HMO) 2'-FL has been shown to affect weight gain and various clusters of intestinal microorganisms after intestinal resection.

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* Source of data : The human milk oligosaccharide 2'-fucosyllactose augments the adaptive response to extensive intestinal
Am J Physiol Gastrointest Liver Physiol 310: G427–G438, 2016

Effect on immunity

Human milk oligosaccharide (HMO) 2’-FL affects improving congenital immunity

The administration of human milk oligosaccharide (HMO) 2'-FL in influenza-infected mice confirmed an increase in DTH and immunoglobulin specific to influenza vaccines, indicating that dietary supplementation of human milk oligosaccharide (HMO) 2'-FL could improve both humoral immunity and cellular immunity.

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* Source of data : Human Milk Oligosaccharide 2′-Fucosyllactose Improves Innate and Adaptive Immunity in an Influenza-Specific Murine Vaccination Model Front. Immunol., 09 March 2018

㎍/mL Day 8 Day 16
REF 2'-FL REF 2'-FL
IgM 5.65 ± 0.19 5.74 ± 0.31 19.49 ± 0.75 18.83 ± 1.15
IgG 2123.26 ± 78.15 2454.14 ± 76.43* 3693.28 ± 180.15 5732.33 ± 284.11*
IgG1 112.53 ± 3.00 105.36 ± 7.14 273.60 ± 6.67 296.84 ± 33.20
IgG2a 476.66 ± 24.12 483.95 ± 12.71 722.84 ± 17.44 884.24 ±25.87*
IgG2b 558.21 ± 51.12 834.30 ± 37.10* 1055.80 ± 26.15 2452.3 ± 166.19*
IgG2c 975.86 ± 78.55 1030.52 ± 28.18 1641.03 ± 170.39 2098.97 ± 79.03*
Th1/Th2 2.65 ± 0.18 3.16 ± 0.05* 2.71 ± 0.18 3.85 ± 0.17*
IgA 38.88 ± 3.06 45.37 ± 1.88 63.32 ± 1.49 90.15 ± 3.37*

* Source of data : Immunomodulatory and Prebiotic Effects of 2'-FL in suckling rats, Frontiers in Immunology

* Reference p < 0.05 (by Mann-Whitney U-test) Th1/Th2 = (IgG2b+IgG2c) / (IgG1+IgG2a) REF: Reference, 2'-FL: 2'-O-Pucosilactose

The height and area of the intestinal epithelial villi increased on 8th day of intake in young mice fed with 2'-FL.

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* Source of data : Immunomodulatory and Prebiotic Effects of 2'-FL in suckling rats Frontiers in Immunology REF : 레퍼런스, 2'-FL : 2'-O-푸코실락토오스

Human milk oligosaccharide (HMO) 2'-FL affects food allergy reduction.

Experiments with supplementation of 2'-FL and 6'-SL (HMO) and lactose in mice that caused allergies with OVA (obualbumin) showed that 2'-FL and 6'-SL reduced diarrhea and hypothermia caused by allergies and increased immunoglobulins while decreasing inflammatory cytokines.

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* Source of data : Attenuation of food allergy symptoms following treatment with human milk oligosaccharides in a mouse model. Allergy 2015; 70: 1091–1102.

human milk oligosaccharide (HMO) 2’-FL prevents infection by various pathogens.

The infection of the harmful bacteria begins when they attach to the glycan receptor in the intestinal epithelial cells. Human milk oligosaccharide (HMO) is structurally similar to glycan receptors and pathogenic bacteria mistakes HMO as a glycan receptor and combines to HMO. In other words, it acts as a decoy and prevents harmful acteria and viruses from attaching to intestinal epithelial cells.

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* Source of data : What are human milk oligosaccharides : Basic Science (Nestle Nutrition Institute)

Also, the human milk oligosaccharide (HMO) that reaches intestinal epithelial cells, changes the shape of the intestinal epithelial glycans by making the gene expression different. By doing so, harmful bacteria and pathogens that reach intestinal epithelial cells are prevented from attaching.

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* Source of data : What are human milk oligosaccharides : Basic Science (Nestle Nutrition Institute)

Various studies have been conducted as shown in below table that human milk oligosaccharide (HMO) interferes with the infection of pathogenic bacteria by the mechanism of preventing pathogenic bacteria from attaching to intestinal epithelial cell.

HMOs’ Interference with pathogenic bacteria by preclinical and clinical research

pathogenic bacteria HMO Source of data
Norwalk virus Fucosylated oligosaccharide (Ruvoen-clouet et al. 2006)
Campylobacter jejuny (Morrow et al. 2004, Ruiz-Palacios et al. 2003)
Vibrio cholera (Ruiz-Palacios et al. 2003)
E. coli (Heat resistant enterotoxin) (Newburg et al. 1990, Newburg et al. 2004b)
Streptococcus pneumonia Cialactose (Leach et al. 2005)
Cholera toxin (Idota et al. 1995)
E. coli (Virkola et al. 1993)
Pseudomonas aeruginosa (Devaraj et al. 1994)
Aspergillus fumigatus conidia (Bouchara et al. 1997)
Influenza virus (Gambaryan et al.1997, Matrosovich et al.1993)
poliovirus (Stehle et al. 1994)
Helicobacter pylori (Mysore et al. 1999)
HIV-1 Oligosaccharide (Hong et al. 2009)
Streptococcus pneumoniae (Anderson et al.1986, Idanpaan-Heikkila et al.1997)
Enteropathogenic Escherichia coli (Cravioto et al. 1991)
Haemophilus influenzae (Idanpaan-Heikkila et al. 1997)

Source of data : The Influence of Milk Oligosaccharides on Microbiota of Infants: Opportunities for Formulas Annu. Rev. Food Sci. Technol. 2011. 2:331–351

Studies have shown that HMO 2'-FL protects infection of Campylobacter jejuni (acute gastrointestinal inflammation), E. coli (diarrhea, abdominal pain, vomiting, hemolytic urticaria), rotavirus (vomiting, fever, watery diarrhea, dehydration), and Pseudomonas aeruginosa (sepsis, high fever) by preventing their attachment to intestinal epithelial cell.

Number of diarrhea cases in infants due to the relative amount of fucosylated oligosaccharide in breast milk

The higher the amount of fucosylated oligosaccharide (2'-FL is representative), the lower the number of diarrhea in infants.

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* Pucosylated oligosaccharide (2'-FL is representative)
* Source of data : e Journal Pediatrics, Vol. 145 (3), pages 297–303 Morrow et al.,
Human milk and diarrhea in breast-fed infants

Infant symptoms of heat-resistant E. coli infection according to the ratio of fucosylated oligosaccharide in breast milk

The higher the percentage of fucosylated oligosaccharides in breast milk, the lower the rate of heat-resistant E. coli infection in infants. (The higher the number of infants without symptom or not infected)

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* Source of data : Glycobiology, Vol. 14 (3), Newburg et al. pages 253–263
Innate protection conferred by fucosylated oligosaccharides of
human milk against diarrhea in breast-fed infants

Effect on brain

Human milk oligosacchride (HMO) 2'-FL enhances LTP (Long Term Potentiation) to help strengthen memory and improve learning ability.

Input/Output performance tests on the stimulation of rodents showed that both control and 2'-FL supplemented groups tended to increase steadily with the intensity of the stimulation, and the 2'-FL fed group's field excitatory postsynaptic potential (fEPSP) levels were significantly higher, suggesting that the 2'-FL dietary supplement could help strengthen memory.

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* Source of data : Effects of a human milk oligosaccharide, 2′-fucosyllactose, on hippocampal long-term potentiation and learning capabilities in rodents

After 10 days of experiment with getting feed by pressing the lever when the speaker sounds the start and end, it was found that reaching time to test standard for mice with dietary supplement of 2'-FL was shorter than that for mice without 2'-FL and number of pressing lever in a timely manner was higher, too. This suggests that the intake of 2'-FL can improve learning ability.

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* Source of data : Influence of 2'-fucosyllactose and galacto-oligosaccharides on the growth and adhesion of Streptococcus mutans British Journal of Nutrition (2020), 124, 824–831

Effect on skin

Human milk oligosaccharide (HMO) 2’-FL helps to weaken the inflammation of keratinocytes.

2'-FL has been shown to weaken inflammation through inhibition of hypoxia-causing factors in keratinocytes.

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* Source of data : 2′-Fucosyllactose Attenuates Particulate Matter-Induced Inflammation via Inhibition of Hypoxia-Inducible Factor in Keratinocytes Biol. Pharm. Bull. 42, 1620–1627 (2019)

As a result of this experiment, human milk oligosaccharide 2'-FL inhibited inflammatory mediator induced by PM10 and protected the skin's epidermis from irritation of PM10. This suggests that 2'-FL can be used as a major component of cosmeceuticals to alleviate skin irritation and inflammation caused by urban air pollution.

Effect on oral cavity

Human milk oligosaccharide (HMO) 2’-FL inhibits the growth of cavities and prevents its tooth attachment.

Three types of streptococcus mutans can easily grow on galactose, lactose, glucose and TSB medium while they can not grow well on HMO 2'-FL and xylitol.

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* Source of data : Influence of 2'-fucosyllactose and galacto-oligosaccharides on the growth and adhesion of Streptococcus mutans British Journal of Nutrition (2020), 124, 824–831

Researches significantly show that human milk oligosaccharide 2'-FL and galactooligosaccharide in hydroxyapatite with saliva interfere with the attachment of Streptococcus mutans CI2366, a cavity bacterium to tooth.

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* Source of data : Influence of 2'-fucosyllactose and galacto-oligosaccharides on the growth and adhesion of Streptococcus mutans British Journal of Nutrition (2020), 124, 824–831

Aa a result of examining the attachment of cavity bacteria on the surface of glass, it was found that HMO 2'-FL, galactooligosaccharide and lactose inhibit the attachment of Streptococcus mutans DSM20523.

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* Source of data : Influence of 2'-fucosyllactose and galacto-oligosaccharides on the growth and adhesion of Streptococcus mutans British Journal of Nutrition (2020), 124, 824–831

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