What are 3’-Sialyllactose (3’SL) and 6’-Sialyllactose (6’SL)?

October 12, 2023 8 min read

What are the 2 human milk oligosaccharides: 3’-Sialyllactose (3’SL) and 6’-Sialyllactose (6’SL)?

The aging process, it’s a funny thing. As children, we take our flexible, robust bodies for granted, and wish to be older. On the flip side, when we are old, although most of us are happy to be older, we also reminisce about the times when our bodies were younger and free from aches and pains.

Unfortunately, aches and pains appear to be on the cards for most of us as we age. Even if we’re lucky enough to make it to old age with minimal health issues, most will experience painful wear and tear, like achy, creaky joints, stiffness, and a slowing of our physical abilities. There’s also a good chance that many of us will encounter cognitive issues, even if only mild.

All is not lost though, there may be a ray of hope in the form of HMOs. Specifically, 3’sialyllactose (3’SL), and 6’siallylactose (6’SL), are two powerhouses that could have a positive impact on our physical and cognitive health. Let’s find out more.

What are 3’-SL and 6’-SL?

Being a glycan found in human milk, the HMO, 3’-SL is a source of energy or a type of prebiotic (food) for your gut bacteria. It also initiates multiple chemical reactions or interactions within the body that help to establish our first fortress against invading pathogens during infancy.

6’-SL is another example of a glycan energy powerhouse. It’s also a prebiotic food source for your gut bacteria and possesses qualities that may aid your overall health, cognition, and immunity.

Structure of 3’-SL and 6’-SL

3’-SL is known as a trisaccharide because it is composed of three monosaccharide molecules, galactose, glucose, and N-acetylneuraminic acid (Neu5Ac). If you are already familiar with Layer Origin’s products or are an avid reader of our blog, you may be aware that different HMOs have different structural properties. For example, 2’-fucosyllactose (2’-FL) is an example of a fucosylated HMO because it has fucose sugars added to it during a process called fucosylation. 3’SL and 6’SL on the other hand, are referred to as sialylated[i].

That’s because, during a process called sialylation, sialic acid is added to the end of the carbohydrate chain. Interestingly, sialylated HMOs have strong immune benefits in the newborn and infant colon because they are able to exert local biological effects and attach to sialic acid-dependent pathogens, preventing them from making the infant sick[ii]. In human milk, 3’-SL levels are maintained throughout lactation, whereas 6’-SL levels will gradually drop over time[iii].

As research progresses, scientists are unlocking the potential benefits of these HMOs in adults too.

3’-SL and 6’-SL are very similar. In fact, 3’-SL is what’s known as a regioisomer of 6’-SL. In other words, they are both comprised of the same components (galactose, glucose, and Neu5Ac) they’re just attached at different positions[iv].  

chemical structure of 3'-SL and 6'-SL

Figure 1. Structure of 3’-SL and 6’-SL. N-acetyl-d-neuraminic acid and d-galactose are attached at 2-6 rather than 2-3 in 6’-SL. The structures are very similar, but the binding sites are what set these HMOs apart from one another. Source: Pandey et al., 2018.[v]

Benefits of 3’-SL and 6’-SL

HMOs in general help to support the normal function of our gut microbiota through their prebiotic effects. In turn, this helps to increase the production of short-chain fatty acids (SCFAs) which is associated with a more robust gut barrier, and a lower prevalence of leaky gut syndrome.

HMOs, by nourishing our gut microbes, promote their growth and ensure a more diverse bacterial community. Bifidobacteria are particularly fond of HMOs. A reduced abundance of this genus of bacteria has been identified in a variety of people with specific conditions, like irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and type 2 diabetes.

For example, both 3’-SL and 6’-SL are thought to have numerous important benefits for our health. Because of their close structural resemblance, they are often seen together in research studies. Some studies have shown that these HMOs may reduce the severity of symptoms relating to different diseases such as necrotizing enterocolitis (NEC), a major prevalent gut disease amongst premature babies[vi]. 3’-SL has also been shown to interact with the Caco-2 cells that line the colon. Here, this interaction sees 3’-SL influence the Caco-2 cells in a way that alters the profile of their glycan surface, making potential receptor sites for pathogens problematic to attach to. Without the ability to attach, pathogens will become less likely to cause disease[vii]

The research and insights around the role of HMOs supporting the gut are extensive, but what about their other effects? 3’-SL and 6’-SL, for example, also support the development of the infant brain with the supply of sialic acid, essential for brain development.

3’-SL, 6’-SL and cognition

In animal studies, both 3’-SL and 6’-SL boost and enhance cognitive performance. This is due to their ability to increase gangliosides in the brain and the nervous system through the provision of sialic acid. Gangliosides are fatty compounds that are important for cell signalling and communication.

The sialic acid acts as signalling molecules to the gangliosides[viii]. These are microdomains of cell membranes that actively modulate the crucially important ion channels and proteins, integral to our whole signalling network[ix][x][xi].

We are talking here of the signal network that operates from the brain to the rest of the body, literally sending every command to all the extremities and back, it could even encompass our memory[xii]. Some people who do not have normal ganglioside function can show symptoms associated with neurodegenerative conditions, like Alzheimer’s, further highlighting the importance of these HMOs in supporting our cognitive health.

Imagine the complexity of a rail network, the sialic acid is like the controller, supplying information to the ganglioside (lights), that keep the trains and cargo running safely and able to reach the correct destination, but on a much grander scale. Absolute genius.

The enhanced production of SCFAs by probiotic bacteria from the prebiotic nourishment given by 3’-SL and 6’-SL could also contribute to brain health. Several studies have alluded to the potential benefits of SCFAs on cognitive functioning. A recent 2023 study found that butyrate may alleviate neurodegeneration[xiii] and protect against cognitive impairment[xiv]. But the effects of increased SCFAs extend beyond just cognition. These postbiotics protect against many chronic diseases and are often in low numbers in various chronic disease states. Adding a supplement containing 3’-SL and 6’-SL, like SuperHMO® Prebiotic Mix could do wonders to maintain, support, and maybe even improve our health.

3’-SL and cartilage regeneration

Although we cannot reverse aging, there may be things we can do to help support its gradual development. Many of these things, we’re already aware of, such as eating a healthy, balanced diet and getting plenty of exercise, but others like supplementing with 3’-SL may be less well known.

In some research, 3’-SL  has been shown to facilitate the maintenance (homeostasis) of cartilage – the strong but flexible tissue that protects your bones and joints. Both in vitroand ex vivo studies have demonstrated 3’-SL  interacting with or initiating the expression of Sox9, a protein that is an important transcription factor in the synthesis of Col2a1. In short, the synthesis of Col2a1 is key for cartilage regeneration. As such, studies researching rheumatoid arthritis (RA), have stated 3’-SL could be used as a therapeutic agent in the treatment of RA[xv][xvi].

Excitement is already building around the potential of 3’-SL protecting against the cartilage destruction synonymous with osteoarthritis. In mice studies, mice receiving 3’-SL for 10 weeks had less cartilage destruction than those who received a placebo[xvii]. Watch this space but if you’re interested in how you could support your own aging and reduce inflammation, check out our MitiAging Anti-Aging Support.         


The research to date highlights there is a need for more research to be urgently conducted into the benefits of HMOs, particularly the less common examples.

It also shows the potential for infant milk formula to be fortified with HMOs, particularly sialylated HMOs like 3’-SL and 6’-SL, because of their role in gut, brain, and bone development and growth[xviii]. But it also demonstrates how fundamental these HMOs could be to adult health, particularly as we age and experience cognitive differences, increased inflammation and a growing prevalence of inflammatory conditions such as arthritis.

Written byLeanne Edermaniger, M.Sc. Leanne is a professional science writer who specializes in human health and enjoys writing about all things related to the gut microbiome. 


[i] PubChem [Internet]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; 2004-. PubChem Compound Summary for CID 123914, 3'-Sialyllactose; [cited 2023 Oct. 10]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/3_-Sialyllactose

[ii] Lis-Kuberka J, Orczyk-Pawiłowicz M. Sialylated Oligosaccharides and Glycoconjugates of Human Milk. The Impact on Infant and Newborn Protection, Development and Well-Being. Nutrients. 2019 Feb 1;11(2):306. doi: 10.3390/nu11020306. PMID: 30717166; PMCID: PMC6413137.

[iii] Eom HY, Jang SI, Lee JH. Development and Validation of a Bioanalytical Method for 3'- and 6'-Sialyllactose in Minipig Liver and Kidney Using Liquid Chromatography-Tandem Mass Spectrometry and Its Application to Analysis of Tissue Distribution. Molecules. 2020 Dec 3;25(23):5721. doi: 10.3390/molecules25235721. PMID: 33287423; PMCID: PMC7731434.

[iv] Safety of frozen and freeze‐dried formulations of the lesser ... - EFSA [Internet]. [cited 2023 Oct 11]. Available from: https://efsa.onlinelibrary.wiley.com/doi/full/10.2903/j.efsa.2022.7325

[v] Pandey RP, Kim DH, Woo J, Song J, Jang SH, Kim JB, et al. Broad-spectrum neutralization of avian influenza viruses by sialylated human milk oligosaccharides: In vivo assessment of 3′-SIALYLLACTOSE against H9N2 in chickens. Scientific Reports. 2018;8(1). doi:10.1038/s41598-018-20955-4

[vi] Human milk oligosaccharides 3′-sialyllactose and 6′-sialyllactose protect intestine against necrotizing enterocolitis damage induced by hypoxia

[vii] Wiciński M, Sawicka E, Gębalski J, Kubiak K, Malinowski B. Human Milk Oligosaccharides: Health Benefits, Potential Applications in Infant Formulas, and Pharmacology. Nutrients. 2020 Jan 20;12(1):266. doi: 10.3390/nu12010266. PMID: 31968617; PMCID: PMC7019891.

[viii] Schauer R. Sialic acids as regulators of molecular and cellular interactions. Curr Opin Struct Biol. 2009 Oct;19(5):507-14. doi: 10.1016/j.sbi.2009.06.003. Epub 2009 Aug 19. PMID: 19699080; PMCID: PMC7127376.

[ix] Wang Y, Ze X, Rui B, Li X, Zeng N, Yuan J, Li W, Yan J, Li M. Studies and Application of Sialylated Milk Components on Regulating Neonatal Gut Microbiota and Health. Front Nutr. 2021 Nov 10;8:766606. doi: 10.3389/fnut.2021.766606. PMID: 34859034; PMCID: PMC8631720.

[x] Zhu, Y., Zhang, J., Zhang, W., & Mu, W. (2023). Recent progress on health effects and biosynthesis of two key sialylated human milk oligosaccharides, 3'-sialyllactose and 6'-sialyllactose. Biotechnology advances62, 108058. https://doi.org/10.1016/j.biotechadv.2022.108058

[xi] Hu H, Ataka K, Menny A, Fourati Z, Sauguet L, Corringer PJ, Koehl P, Heberle J, Delarue M. Electrostatics, proton sensor, and networks governing the gating transition in GLIC, a proton-gated pentameric ion channel. Proc Natl Acad Sci U S A. 2018 Dec 26;115(52):E12172-E12181. doi: 10.1073/pnas.1813378116. Epub 2018 Dec 12. PMID: 30541892; PMCID: PMC6310827.

[xii] Ito T, Hearne L, Mill R, Cocuzza C, Cole MW. Discovering the Computational Relevance of Brain Network Organization. Trends Cogn Sci. 2020 Jan;24(1):25-38. doi: 10.1016/j.tics.2019.10.005. Epub 2019 Nov 11. PMID: 31727507; PMCID: PMC6943194.

[xiii] Ge X, Zheng M, Hu M, Fang X, Geng D, Liu S, Wang L, Zhang J, Guan L, Zheng P, Xie Y, Pan W, Zhou M, Zhou L, Tang R, Zheng K, Yu Y, Huang XF. Butyrate ameliorates quinolinic acid-induced cognitive decline in obesity models. J Clin Invest. 2023 Feb 15;133(4):e154612. doi: 10.1172/JCI154612. PMID: 36787221; PMCID: PMC9927952.

[xiv] Meyer K, Lulla A, Debroy K, Shikany JM, Yaffe K, Meirelles O, et al. Association of the gut microbiota with Cognitive Function in midlife. JAMA Network Open. 2022;5(2). doi:10.1001/jamanetworkopen.2021.43941

[xv] Kang LJ, Kwon ES, Lee KM, Cho C, Lee JI, Ryu YB, Youm TH, Jeon J, Cho MR, Jeong SY, Lee SR, Kim W, Yang S. 3'-Sialyllactose as an inhibitor of p65 phosphorylation ameliorates the progression of experimental rheumatoid arthritis. Br J Pharmacol. 2018 Dec;175(23):4295-4309. doi: 10.1111/bph.14486. Epub 2018 Oct 17. PMID: 30152858; PMCID: PMC6240131.

[xvi] Jeon J, Kang LJ, Lee KM, Cho C, Song EK, Kim W, Park TJ, Yang S. 3'-Sialyllactose protects against osteoarthritic development by facilitating cartilage homeostasis. J Cell Mol Med. 2018 Jan;22(1):57-66. doi: 10.1111/jcmm.13292. Epub 2017 Aug 7. PMID: 28782172; PMCID: PMC5742729.

[xvii] Jeon J, Kang LJ, Lee KM, Cho C, Song EK, Kim W, Park TJ, Yang S. 3'-Sialyllactose protects against osteoarthritic development by facilitating cartilage homeostasis. J Cell Mol Med. 2018 Jan;22(1):57-66. doi: 10.1111/jcmm.13292. Epub 2017 Aug 7. PMID: 28782172; PMCID: PMC5742729.

[xviii] Hobbs, M.; Jahan, M.; Ghorashi, S.A.; Wang, B. Current Perspective of Sialylated Milk Oligosaccharides in Mammalian Milk: Implications for Brain and Gut Health of Newborns. Foods 202110, 473. https://doi.org/10.3390/foods10020473

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