Human Milk Oligosaccharides: 2’-FL a treatment option for Adults

Written by Swisse Nutra+, Lilly Ashworth BHSc (Nutrition)

Human milk oligosaccharides (HMOs) are the third most abundant component of human breast milk, after lactose and lipids,[1] and have gained a considerable amount of attention recently due to their biological roles and benefits.[2] These HMO structures are complex oligosaccharides made up of unconjugated glycans that essentially act as a prebiotic within the gastrointestinal tract, and have diverse functions and health benefits. Whilst there are over 150 different HMOs discovered to date, 2’-FL (HMO) is the most abundant in human milk and therefore one of the most researched of the HMOs.[3]

Being a prebiotic structure, the majority of HMOs, including 2’-FL (HMO), reach the large intestine mostly undigested where they impart positive physiological benefits on the host. These benefits have been well researched in infants, showing immune, gastrointestinal, and even cognitive benefits,[4] however there is emerging research demonstrating that they may offer health benefits for adults, especially in gut health.

Whilst formula-fed infants, weaned children, and adults are generally not exposed to dietary sources of 2’-FL, technology now exists that allows 2’-FL to be enzymatically synthesised through a fermentation process, creating structurally identical 2’-FL to the one found in human breast milk[5]. This means HMOs can now be created and added to toddler milk drinks, dietary supplements, and medical foods for the benefit of those cohorts who would otherwise miss out.

Although HMOs have been studied for over 100 years[6] and have been used for treatment and supplementation for some time in the US, Europe and China, the TGA and FSANZ in Australia have only recently approved HMOs for use in supplements and formula, finally giving Australians access to this incredibly beneficial ingredient.

2’-FL mechanism of action

Structurally, 2’-FL is one of the most simple of the HMOs, consisting of a lactose plus a fucose group. These structures are predominantly resistant to digestion by human enzymes, making the 2’-FL available as a prebiotic fuel source for the gut microbiota in the colon.

2’-FLs’ mechanisms of action include its selective prebiotic effect, its ability to increase short-chain fatty acid production, and its antimicrobial effects. Through these actions, 2’-FL encourages the growth of beneficial commensal bacteria, whilst hindering harmful pathogens and supporting gastrointestinal wall health, resulting in an overall improvement in gut health and therefore systemic health[7].

Benefits of 2’-FL for adults

2’-FL supplementation for adults is a fairly novel concept, with new studies and research published regularly. As such, we are still learning the full benefits and potential health treatments of this ingredient. However, current substantiated areas of benefit include:

Microbial balance improvement

• Resistant to human enzymatic activity, 2’-FL acts as a prebiotic to normalise colonic function.[8]
• Unlike other prebiotics, such as GOS or FOS, 2’-FL exclusively favours the growth of beneficial bacteria within the gastrointestinal tract.⁴
• Bacteria species belonging to the genus Bifidobacterium are uniquely suited to metabolising 2’-FL as a growth substrate,[9]^,[10] this selective growth of Bifidobacterium species means 2’-FL can be described as “bifidogenic”.[11]
• Supplementation of adults with 2’-FL has demonstrated both bifidogenic and butyrogenic effects with an increase in short chain fatty acid (SCFA) production, resulting in the management of symptoms in those with irritable bowel syndrome (IBS) and ulcerative colitis.[12]^,[13] These benefits are achieved without significant side effects in healthy adults or those with IBS.¹¹
• Research has demonstrated a correlation between a low abundance of Bifidobacterium species in the gastrointestinal tract with a large range of conditions, including inflammatory bowel disease, IBS, celiac disease, atopic disease, allergies, and cystic fibrosis.[14] 2’-FL has been shown to increase Bifidobacterium species in healthy adults when taken for two weeks.[15]

Gastrointestinal integrity

• 2’-FL exhibits anti-inflammatory activity within the large intestine to support the strengthening of the gut wall and intestinal barrier.¹
• Pre-clinical studies demonstrate HMOs, including 2’-FL, protect and strengthen the intestinal barrier and decrease permeability by modulating mRNA transcription and protein expression of mucin.¹
• 2’-FL increases SCFA production after three weeks, particularly butyrate,[16] which has been shown to support tight junction formation of the intestinal barrier.[17]
• HMOs also directly interact with gut epithelial cells and modulate their glycan expression on intestinal cell surface.[18]

Immune function

• Research has shown that HMOs exhibit immunomodulatory and anti-inflammatory activity within the large intestine, and 2’-FL is associated with anti-infective capacity of human milk.[xix]
• 2’-FL can help to inhibit pathogenic adhesion to intestinal epithelial cells by acting as a decoy receptor, helping to prevent viral and bacterial infections.¹
• Pre-clinical trials have demonstrated 2’-FL’s immunomodulatory effects, showing that supplementation resulted in twice as many natural killer cells, five times as many basophils, and with increased expression of IFN-γ and IL-10.²
• Additionally, 2’-FL can support immune balance by reducing pro-inflammatory cytokine secretion.²
• Dietary 2’-FL can reduce infection susceptibility through the direct stimulation of immune cells, alteration of intestinal bacterial populations, modulation of intestinal barrier function, and the alteration of viral pathogenicity.[xx]
• Through improvements in the bifidogenic environment and through direct interaction with the gastrointestinal immune system, 2’-FL can act both on the innate and adaptive immune response.²

2’-FL looks to be an exciting new ingredient in the space of gut health, that can potentially offer a holistic approach to gastrointestinal homeostasis, immunity, function, and overall health. We look forward to continuing to highlight exciting new evidence and research on this novel ingredient as it is published.

[1] Rousseaux A, Brosseau C, Le Gall S, Piloquet H, Barbarot S, Bodinier M. Human Milk Oligosaccharides: Their Effects on the Host and Their Potential as Therapeutic Agents. Front Immunol. 2021;12:680911. Published 2021 May 24. doi:10.3389/fimmu.2021.680911

[2] Plaza-Díaz, J., et al. (2018). Nutrients, 10(8), 1038. https://doi.org/10.3390/nu10081038

[3] Castanys-Muñoz E, Martin MJ, Prieto PA. 2'-fucosyllactose: an abundant, genetically determined soluble glycan present in human milk. Nutr Rev. 2013;71(12):773-789. doi:10.1111/nure.12079

[4] Berger PK, Plows JF, Jones RB, Alderete TL, Yonemitsu C, Poulsen M, et al. (2020) Human milk oligosaccharide 2’-fucosyllactose links feedings at 1 month to cognitive development at 24 months in infants of normal and overweight mothers. PLoS ONE 15(2): e0228323. https://doi.org/10.1371/journal.pone.0228323

[5] Bych K, Mikš MH, Johanson T, Hederos MJ, Vigsnæs LK, Becker P. Production of hmos using microbial hosts — from cell engineering to large scale production. Current Opinion in Biotechnology. 2019;56:130-137. doi:10.1016/j.copbio.2018.11.003

[6] Sprenger N, Tytgat HLP, Binia A, Austin S, Singhal A. Biology of human milk oligosaccharides: From basic science to clinical evidence. J Hum Nutr Diet. 2022;35(2):280-299. doi:10.1111/jhn.12990

[7] Walsh C, Lane JA, van Sinderen D, Hickey RM. Human milk oligosaccharides: Shaping the infant gut microbiota and supporting health. Journal of Functional Foods. 2020;72:104074. doi:10.1016/j.jff.2020.104074

[8] Salli K, Hirvonen J, Siitonen J, Ahonen I, Anglenius H, Maukonen J. Selective Utilization of the Human Milk Oligosaccharides 2'-Fucosyllactose, 3-Fucosyllactose, and Difucosyllactose by Various Probiotic and Pathogenic Bacteria. J Agric Food Chem. 2021;69(1):170-182. doi:10.1021/acs.jafc.0c06041

[9] Garrido D, Barile D, Mills DA. A molecular basis for bifidobacterial enrichment in the infant gastrointestinal tract. Adv Nutr. 2012;3(3):415S-21S. Published 2012 May 1. doi:10.3945/an.111.001586

[10] Sela DA, Chapman J, Adeuya A, et al. The genome sequence of Bifidobacterium longum subsp. infantis reveals adaptations for milk utilization within the infant microbiome. Proc Natl Acad Sci U S A. 2008;105(48):18964-18969. doi:10.1073/pnas.0809584105

[11] Musilova S, Rada V, Vlkova E, Bunesova V. Beneficial effects of human milk oligosaccharides on gut microbiota. Beneficial Microbes. 2014;5(3):273-283. doi:10.3920/bm2013.0080

[12] Ryan JJ, Monteagudo-Mera A, Contractor N, Gibson GR. Impact of 2'-Fucosyllactose on Gut Microbiota Composition in Adults with Chronic Gastrointestinal Conditions: Batch Culture Fermentation Model and Pilot Clinical Trial Findings. Nutrients. 2021;13(3):938. Published 2021 Mar 14. doi:10.3390/nu13030938

[13] Palsson OS, Peery A, Seitzberg D, Amundsen ID, McConnell B, Simrén M. Human milk oligosaccharides support normal bowel function and improve symptoms of irritable bowel syndrome: A Multicenter, open-label trial. Clinical and Translational Gastroenterology. 2020;11(12). doi:10.14309/ctg.0000000000000276.

[14]Tojo R, Suárez A, Clemente MG, et al. Intestinal microbiota in health and disease: role of bifidobacteria in gut homeostasis. World J Gastroenterol. 2014;20(41):15163-15176. doi:10.3748/wjg.v20.i41.15163

[15] Elison E, Vigsnaes LK, Rindom Krogsgaard L, et al. Oral supplementation of healthy adults with 2'-O-fucosyllactose and lacto-N-neotetraose is well tolerated and shifts the intestinal microbiota. Br J Nutr. 2016;116(8):1356-1368. doi:10.1017/S0007114516003354

[16] Šuligoj T, Vigsnæs LK, Abbeele PVD, et al. Effects of Human Milk Oligosaccharides on the Adult Gut Microbiota and Barrier Function. Nutrients. 2020;12(9):2808. Published 2020 Sep 13. doi:10.3390/nu12092808

[17] Peng L, Li ZR, Green RS, Holzman IR, Lin J. Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. J Nutr. 2009;139(9):1619-1625. doi:10.3945/jn.109.104638

[18] Sprenger N, Tytgat HLP, Binia A, Austin S, Singhal A. Biology of human milk oligosaccharides: From basic science to clinical evidence. J Hum Nutr Diet. 2022;35(2):280-299. doi:10.1111/jhn.12990

[xix] Quitadamo PA, Comegna L, Cristalli P. Anti-Infective, Anti-Inflammatory, and Immunomodulatory Properties of Breast Milk Factors for the Protection of Infants in the Pandemic From COVID-19. Front Public Health. 2021;8:589736. Published 2021 Mar 2. doi:10.3389/fpubh.2020.589736

[xx] Comstock SS, Li M, Wang M, et al. Dietary Human Milk Oligosaccharides but Not Prebiotic Oligosaccharides Increase Circulating Natural Killer Cell and Mesenteric Lymph Node Memory T Cell Populations in Noninfected and Rotavirus-Infected Neonatal Piglets. J Nutr. 2017;147(6):1041-1047. doi:10.3945/jn.116.243774