Why are Human Milk Oligosaccharides the "Magic" Prebiotic?

April 02, 2022 6 min read

Why are Human Milk Oligosaccharides the "Magic" Prebiotic? | Layer Origin Nutrition

Consumer goods geared towards the improvement of gut health have become increasingly popular over the past several years. Among them, products containing probiotics have perhaps received the most attention.

What are probiotics?

Probiotics are live bacterial organisms purported to confer health benefits by supporting a healthy microbiome. However, because the colon contains upwards of 100 trillion bacteria and most probiotics contain only billions of organisms, they have been described by some as merely “a drop in the ocean”.

Thus, although specific probiotics may confer health benefits in certain contexts, many individuals may see little benefit through their consumption.

Furthermore, research has revealed that probiotics can actually be counterproductive in certain contexts, such as in the setting of microbiome restoration post-antibiotics. To learn more about this surprising finding read our previous blog post.

What are prebiotics?

The most effective approach to microbiome modulation and optimization is through the targeted use of prebiotics. Prebiotics are molecules that cannot be broken down by our digestive processes and, as such, arrive intact in the colon where they can directly feed resident bacteria.

These molecules can either come from foods and dietary supplements (e.g., resistant starches and polyphenols) or from nutraceuticals. Some of the most important prebiotics becoming increasingly popular in the nutraceutical space are human milk oligosaccharides (HMOs).

The traditional prebiotics such as GOS and FOS, often found in infant formulas, were made to mimic the functions of HMOs.

 What are HMOs?

First characterized in human breast milk, the function of HMOs is to provide a food source for the nascent microbiome in the infant gut. In turn, the microbiome helps to shape the healthy development of the baby’s immune system and protects against infection.

In adults, supplementation with HMOs may help to prevent or ameliorate inflammatory bowel diseases, colorectal cancer, leaky gut, viral and bacterial infection, and food sensitivities and allergies.

These benefits largely result from enhancements in the populations of Bifidobacteria in the gut, which can effectively break down HMOs and release metabolites that feed other beneficial gut microbes.

Types of HMOs

There are upwards of 200 HMOs present in breast milk falling into three primary classifications: fucosylated HMOs, sialylated HMOs, and nonfucosylated neutral HMOs. Fucosylated HMOs constitute 35-50% of breast milk oligosaccharide content, sialylated HMOs constitute 12-14%, and non-fucosylated neutral HMOs constitute 42-55%.

Currently, there are three HMOs available on the market for consumer use:

  • 2’-fucosyllactose (2’FL)
  • lacto-N-neotetraose (LNnT)
  • lacto-N-tetraose (LNT)

However, several others will be emerging onto the market in the next few years. Not only will the availability of these products improve infant nutrition for babies that do not have access to breast milk, but they will also provide adults with more options for gut and immune health optimization and disease prevention.

2’-Fucosyllactose (2’FL)

2’FL is a fucosylated HMO and is the most abundant HMO in breast milk. Interestingly, 20% of women lack the ability to secrete 2’FL into their breast milk due to loss-of-function mutations in the gene FUT2. These so called “non-secretors” also have increased risk for inflammatory bowel diseases and colon cancer. However, supplementation with HMOs can mitigate much of the amplified disease risks faced by these individuals. To learn more about secretor status, its health implications, and how to determine yours, check out our previous blog post on this topic here.

3-Fucosyllactose (3FL)

3FL is another major fucosylated HMO. It is an isomer of 2’FL, meaning that it contains the same atoms at 2’FL but in a slightly different arrangement. Non-secretor mothers are capable of producing 3FL but to a lesser extent than secretors. In general, non-secretors have low capacity for the production of most fucosylated HMOs, so these individuals should prioritize the supplementation of these molecules for themselves and their children for optimal support of gut and immune health and development.

Difucosyllactose (DFL)

DFL, also known as lactodifucotetraose (LDFT), is another primary fucosylated HMO. Like 2’FL, its production is also suppressed in non-secretors. In addition to feeding Bifidobacteria, DFL can also enter into the blood circulation where it suppresses the release of inflammatory factors from blood platelets and also inhibits their adhesion, thereby reducing clotting.

Lacto-N-neotetraose (LNnT) and lacto-N-tetraose (LNT)

LNnT and LNT are the most abundant non-fucosylated neutral HMOs, with levels tracking closely with levels of 2’FL in breast milk. LNnT confers anti-inflammatory and wound healing effects, and consumption of both 2’FL and LNnT increase the relative abundance of Actinobacteria, including Bifidobacteria, in the gut while reducing Firmicutes and Proteobacteria. LNnT and LNT almost exclusively feed key species of Bifidobacteria in the infant gut, and both secretors and non-secretors can produce LNnT and LNT.

Lacto-N-fucopentaose (LNFP)

LNFP is a fucosylated HMO that exists in three distinct forms: LNFP I, LNFP II, and LNFP III. The prevalence of the forms varies based on an individual’s secretor status. For example, while 2’FL and LNFP I are the predominant HMOs in secretor breast milk, LNFP II and lacto-N-difucohexaose (LNDFH) are the predominant HMOs in non-secretor breast milk. This results in lower levels of Lactobacillus, Enterococcus, Streptococcus, and Bifidobacteria and higher levels of Staphylococcaceae in infants breast feeding from non-secretor mothers. Moreover, the general microbial diversity of these infants is also lower than their counterparts breast fed by secretor mothers.

Lacto-N-difucohexaose (LNDFH)

LNDFH exists in two forms: LNDFH I and II. LNDFH I production is dependent upon FUT2. Thus, non-secretors do not produce much of this HMO. Conversely, LNDFH II is enriched in breast milk from non-secretors.

3'-Sialyllactose (3’SL) and 6'-Sialyllactose (6’SL)

Finally, among the sialylated HMOs, are 3’SL and 6’SL. Interestingly, 3’SL is associated with improved cognition and language learning in young children. Moreover, it has been shown to exert anti-inflammatory, anti-arthritic, and immunomodulatory effects. With regards to its anti-arthritic benefits, research indicates that 3’SL can halt the progression of rheumatoid arthritis by stimulating cartilage regeneration, preventing cartilage breakdown, and downregulating the production of inflammatory factors by immune cells in the joints. In addition, both 3’SL and 6’SL suppress the production of inflammatory mediators in the gut and facilitate the maintenance of intestinal barrier function.

The Takeaway 

Overall, the emergence of newly characterized HMOs onto the consumer market will provide individuals with exciting new strategies by which to improve the health and well-being of both themselves and their children. In the future, healthcare practitioners may have the ability to recommend supplementation with specific combinations ofHMOs to prevent at-risk individuals from developing certain diseases or to treat patients with pre-existing pathology.

The development of these simple and financially non-prohibitive interventions will make health optimization and disease prevention something that is achievable regardless of one’s socioeconomic status.

Written by: Dr. Alexis Cowan, a Princeton-trained PhD specializing in the metabolic physiology of nutritional and exercise interventions.

Follow Dr. Cowan on Instagram: @dralexisjazmyn 

 

References

Hegar B, Wibowo Y, Basrowi RW, Ranuh RG, Sudarmo SM, Munasir Z, Atthiyah AF, Widodo AD, Supriatmo, Kadim M, Suryawan A, Diana NR, Manoppo C, Vandenplas Y. The Role of Two Human Milk Oligosaccharides, 2'-Fucosyllactose and Lacto-N-Neotetraose, in Infant Nutrition. Pediatr Gastroenterol Hepatol Nutr. 2019 Jul;22(4):330-340. doi: 10.5223/pghn.2019.22.4.330. Epub 2019 Jun 25. PMID: 31338308; PMCID: PMC6629589.

Newburg DS, Tanritanir AC, Chakrabarti S. Lactodifucotetraose, a human milk oligosaccharide, attenuates platelet function and inflammatory cytokine release. J Thromb Thrombolysis. 2016 Jul;42(1):46-55. doi: 10.1007/s11239-015-1331-2. PMID: 26743063.

Cabrera-Rubio R, Kunz C, Rudloff S, García-Mantrana I, Crehuá-Gaudiza E, Martínez-Costa C, Collado MC. Association of Maternal Secretor Status and Human Milk Oligosaccharides With Milk Microbiota: An Observational Pilot Study. J Pediatr Gastroenterol Nutr. 2019 Feb;68(2):256-263. doi: 10.1097/MPG.0000000000002216. PMID: 30540710.

Wang M, Zhao Z, Zhao A, Zhang J, Wu W, Ren Z, Wang P, Zhang Y. Neutral Human Milk Oligosaccharides Are Associated with Multiple Fixed and Modifiable Maternal and Infant Characteristics. Nutrients. 2020 Mar 20;12(3):826. doi: 10.3390/nu12030826. PMID: 32244912; PMCID: PMC7146356.

Wang M, Zhao Z, Zhao A, Zhang J, Wu W, Ren Z, Wang P, Zhang Y. Neutral Human Milk Oligosaccharides Are Associated with Multiple Fixed and Modifiable Maternal and Infant Characteristics. Nutrients. 2020 Mar 20;12(3):826. doi: 10.3390/nu12030826. PMID: 32244912; PMCID: PMC7146356.

Cho S, Zhu Z, Li T, Baluyot K, Howell BR, Hazlett HC, Elison JT, Hauser J, Sprenger N, Wu D, Lin W. Human milk 3'-Sialyllactose is positively associated with language development during infancy. Am J Clin Nutr. 2021 Aug 2;114(2):588-597. doi: 10.1093/ajcn/nqab103. PMID: 34020453; PMCID: PMC8326052.

Kang, LJ., Oh, E., Cho, C. et al. 3′-Sialyllactose prebiotics prevents skin inflammation via regulatory T cell differentiation in atopic dermatitis mouse models. Sci Rep 10, 5603 (2020). https://doi.org/10.1038/s41598-020-62527-5

 


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