How 3’-Sialyllactose could hold the key to gut barrier integrity

There is an increasing recognition of the fundamental role that gut health plays in overall wellbeing.

A robust body of evidence now links gut function to a wide range of physiological and pathological conditions, including immune response, metabolic regulation, and even neurological health.¹⁻² Central to this is the role of the gut mucosal barrier, and the developing view that strengthening this can yield significant health benefits.

Human milk oligosaccharides (HMOs) are gaining a growing reputation as a means to influence gut microbial populations. These complex carbohydrates, naturally present in human breast milk, have demonstrated potential in shaping gut microbiota composition and promoting health.

Of particular interest are sialylated HMOs, which include two main types – 3’-Sialyllactose (3’-SL) and 6’-Sialyllactose (6’-SL). Unlike most neutral HMOs, sialylated HMOs, such as 3′-SL and 6′-SL, are acidic as they are composed of sialic acid and lactose – their functional benefits are primarily attributed to the presence of sialic acid.

Attention is now also turning to 3’-SL for its role in supporting gut function. This adds to previous research showing the benefits it is able to deliver in supporting joint and bone health.³ Ongoing scientific advances are uncovering the mechanisms by which 3’-SL contributes to gut health, prompting deeper investigation into its therapeutic potential. The ability of 3’-SL to strengthen the gut barrier is particularly important, as research begins to suggest that gut barrier integrity could be more important than gut microbiota to overall health.⁴

A targeted approach to gut barrier support

3’-SL is a sialylated HMO, naturally found in high concentrations in human breast milk. Structurally, 3′-SL is a small carbohydrate made of three sugar units, where a sialic acid is attached to lactose in a specific way that helps it reach the gut intact and feed beneficial bacteria. The HMO, among others, plays key roles in early life immune system and gut development.

3’-SL is not digested by human enzymes but instead reaches the colon intact, where it functions as a selective substrate for certain beneficial gut bacteria. This action supports the growth of microbial populations associated with improved gut function, while simultaneously contributing to a more resilient intestinal environment. Additionally, 3’-SL has been shown to interact with epithelial cells and immune signaling pathways, influencing gut barrier integrity and inflammation.

These characteristics suggest that 3’-SL could play a beneficial role in supporting gut health across a range of physiological processes:

Gut mucosal defense function Gut barrier integrity is essential for overall health, functioning as a selective filter that permits nutrient absorption while blocking harmful microbes, toxins, and antigens from entering the bloodstream. This protective function relies heavily on tight junction proteins, such as ZO-1 and Occludin, which form the seals between intestinal cells. Disruption of these proteins can lead to inflammation, immune dysregulation, and chronic diseases. Emerging evidence shows that 3’-SL supports the expression and maintenance of these tight junction proteins, thereby helping to maintain mucosal defense and reinforce the gut barrier.⁵

Gut epithelial cells growth Recent studies show that 3’-SL promotes the growth and renewal of gut epithelial cells. In a study on piglets fed with HMO supplements, increased levels of Ki67-positive cells – a marker of cell proliferation – were observed, alongside wider intestinal crypts and reduced signs of diarrhea.⁶ These results indicate that 3’-SL can strengthen the gut lining structure by supporting cellular regeneration and growth.

SCFAs production In vitro research demonstrates that supplementation with 3’-SL can shift the gut microbiota toward a more beneficial profile. Specifically, it increases the abundance of short-chain fatty acids (SCFAs)-producing bacteria such as Phascolarctobacterium and members of the Lachnospiraceae family.⁷ SCFAs, in turn, are crucial for intestinal health, serving as energy sources for epithelial cells and supporting mucosal integrity.

Digestive function improvement 3’-SL also contributes to improved digestive efficiency. One study found that supplementation increased the height of intestinal villi – the small finger-like projections in the gut that increase surface area for nutrient absorption.⁸ Taller villi are associated with more active digestive enzymes like sucrase and maltase, which enhance the breakdown and absorption of nutrients, supporting overall digestive health.

Gut inflammation reduction Another important role of 3’-SL is its ability to reduce gut inflammation. Studies have shown that it can suppress the production of pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6.⁹ This anti-inflammatory effect may reduce the risk of inflammatory bowel diseases (IBD), which are often associated with microbial imbalances and immune system overactivation.

Infection prevention Research indicates that 3’-SL inhibits the adhesion of harmful pathogens to the gut lining, thereby preventing infection. It has been shown to reduce the binding of Helicobacter pylori to gastrointestinal epithelial cells and similarly block the adhesion of Escherichia coli to Caco-2 cells.¹⁰ These findings highlight 3’-SL’s potential role in lowering susceptibility to gastrointestinal infections by reinforcing the gut’s microbial defenses.

Proven safety

3’-SL has a well-established safety profile, supported by its extensive use in infant formulas where it plays a key role in promoting infant gut health and development. Building on this proven track record, GeneChem is leveraging emerging research on 3’-SL’s potential to enhance gut health – a critical focus given that an estimated 70-80% of the body’s immune cells reside in the gut, underscoring the importance of a healthy gut environment for overall immune function.¹¹ These efforts aim to support long-term gut integrity, immune balance, and overall wellness.

Using its broader position as an innovator in sialyllactose research and production, GeneChem has become a leading player in the development of high-purity sialyllactose ingredients and supplements. This has culminated with the company advancing its 6’-SL-based Siallac® brand – designed to translate cutting-edge insights into practical health solutions, such as enhancing muscle mass, improving workout recovery, and reducing fatigue.

In addition, 3′-SL will be available through the Siallac® brand. For additional details or queries, please email: info_siallac@genechem.co.kr

References

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2. Patrice, D.; et al. Metabolic Endotoxemia Initiates Obesity and Insulin Resistance. Diabetes; 2007; 56 (7): 1761–1772.
3. Baek, A.; et al. 3′-Sialyllactose alleviates bone loss by regulating bone homeostasis. Commun Biol; 2024, 7, 110.
4. NutraIngredients. The gut microbiota is not the key to health—it’s the gut barrier,’ says microbiologist.
5. Duan, Q.; et al. Effect of sialyllactose on growth performance and intestinal epithelium functions in weaned pigs challenged by enterotoxigenic Escherichia Coli. J Animal Sci Biotechnol; 2022, 13, 30.
6. Yang, C.; et al. Molecular Mechanisms Underlying How Sialyllactose Intervention Promotes Intestinal Maturity by Upregulating GDNF Through a CREB-Dependent Pathway in Neonatal Piglets. Mol Neurobiol; 2019 Dec;56(12):7994-8007.
7. Sato, Y.; et al. Sialyllactose Enhances the Short-Chain Fatty Acid Production and Barrier Function of Gut Epithelial Cells via Nonbifidogenic Modification of the Fecal Microbiome in Human Adults. Microorganisms; 2024, 12(2), 252.
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9. Kang, L-J.; et al. 3′-Sialyllactose prebiotics prevents skin inflammation via regulatory T cell differentiation in atopic dermatitis mouse models. Scientific Reports; 2022, 10: 5603.
10. Simon, P. M.; et al. Inhibition of Helicobacter pylori binding to gastrointestinal epithelial cells by sialic acid-containing oligosaccharides. ASM Journals. Infection and Immunity; 1997, 65(2).
11. Wiertsema, S.P.; et al. The Interplay between the Gut Microbiome and the Immune System in the Context of Infectious Diseases throughout Life and the Role of Nutrition in Optimizing Treatment Strategies. Nutrients. 2021;13(3):886.