Sage Journals: Discover world-class research

Abstract

Inflammatory bowel diseases (IBD) are chronic and recurrent conditions of the gastrointestinal tract. IBD is often challenging to manage due to the complex etiology and involvement of multiple dysregulated immune pathways. Current treatments, including biologics and immunosuppressants, are associated with significant risks and side effects, highlighting the need for safer alternatives. Human milk oligosaccharides (HMOs), a group of bioactive carbohydrates found in human breast milk, play a crucial role in shaping the infant gut microbiome, modulating microbial metabolism and immune responses, and reducing inflammation. Notably, HMOs have no nutritional value for the infant and travel undigested through the upper gastrointestinal tract, serving as selective substrates for beneficial gut bacteria and supporting intestinal epithelial health. Among these, 2′-fucosyllactose (2′-FL) is the most abundant and well-studied HMO, functioning as a trisaccharide prebiotic. Emerging evidence suggests that the benefits of HMOs extend beyond infancy, with potential therapeutic applications in modulating immune responses, promoting epithelial health, and reducing inflammation in IBD. This review summarizes current research on the role of 2′-FL in inflammation and colitis, exploring its potential role in treating IBD.

Plain language summary

A natural sugar from breast milk may help treat inflammatory bowel disease

Inflammatory bowel diseases (IBD) like Crohn’s disease and ulcerative colitis cause chronic gut inflammation and can be difficult to treat. Current medicines don’t work for everyone and may have side effects, so researchers are looking for safer ways to improve gut health. One option is to target the gut microbiome; the community of microbes that support digestion, immunity, and gut lining integrity. In IBD, this microbiome is often out of balance. 2′-fucosyllactose (2′-FL), a natural sugar found in breast milk, feeds beneficial bacteria such as Bifidobacterium. In infants, it helps protect the gut lining and regulate immune function. Studies in animals and laboratory models show that 2′-FL can boost helpful bacteria, reduce harmful species, lower inflammation, and strengthen the gut barrier. Early research in ulcerative colitis suggests that 2′-FL may improve microbiome balance, gut health, and quality of life. Ongoing clinical trials are exploring its use in IBD, alone or combined with other treatments like faecal microbiota transplantation. If proven effective, 2′-FL could offer a safe, natural addition to standard therapies, helping more people with IBD achieve better symptom control.

Keywords

2′-Fucosyllactose (2′-FL)dietary fibers dysbiosis gut microbiota gut permeability inflammatory bowel diseases (IBD)prebiotics

Introduction

Inflammatory bowel diseases (IBD) are chronic inflammatory conditions of the gastrointestinal tract, encompassing two main subtypes: ulcerative colitis (UC) and Crohn’s disease (CD). The pathogenesis of IBD is complex and multifactorial, involving immune dysregulation, genetic predisposition, dysbiosis, and environmental triggers.¹ These interconnected factors drive chronic inflammation and tissue damage, leading to debilitating symptoms such as abdominal pain, diarrhea, weight loss, and fatigue, all of which significantly impair quality of life. To improve efficacy, current therapies, including biologics and the newer immunosuppressants such as JAK inhibitors, are more specific than corticosteroids and typically target singular disease pathways, but come with limitations in achieving long-term corticosteroid-free remission, mucosal healing, and prevention of disease progression. Furthermore, the long-term safety of current treatment remains a concern. Thus, there is a significant unmet medical need to develop safer and more effective drugs for IBD, particularly those that target multiple pathways involved in intestinal inflammation.

Human milk oligosaccharides (HMOs) are a family of unconjugated glycans present in high concentrations in human breast milk. Following fats and lactose, HMOs comprise the third most abundant solid component of human breast milk. Approximately 200 structurally distinct bioactive HMOs have been identified.² HMOs are highly conserved over the course of mammalian evolution, underscoring their biological importance. They have no direct nutritional value for the newborn, instead serving as an essential substrate to support the development of a healthy gut microbiome, microbial metabolism, mucosal health, and modulate both local and systemic immune responses.³

2′-Fucosyllactose (2′-FL) is the most abundant HMO and has unique therapeutic potential in IBD. Unlike traditional advanced therapies, which primarily modulate specific immune pathways, 2′-FL exerts its effects through multiple mechanisms. It fosters the growth of beneficial gut bacteria, such as Bifidobacterium species, which possess anti-inflammatory, barrier-enhancing, mucus-producing, and immunomodulatory properties.⁴ Simultaneously, it inhibits pathogenic bacteria such as Proteobacteria and Enterobacteriaceae, which are elevated in IBD and contribute to gut inflammation.^5,6 Beyond its microbiome effects, 2′-FL strengthens the epithelial barrier by enhancing tight junction integrity, modulating the immune system, and reducing gut permeability.⁴ These multifaceted mechanisms distinguish 2′-FL from existing therapies and highlight its potential as a novel treatment modality.

In this review, we aim to summarize the evidence supporting 2′-FL as a treatment option for IBD, including data from multiple animal models of colitis and supporting human data. Finally, the potential of 2′-FL as an adjuvant therapy in conjunction with fecal microbiota transplantation (FMT) is discussed as part of a combined therapeutic approach.

Pathogenesis of IBDs

IBD pathogenesis is postulated to be influenced by genetics, environment, diet, and the gut microbiome. A gut microbiome composition that is more predisposing to intestinal health is associated with improved immune regulation and maintenance of epithelial barrier integrity. Beneficial microbes produce metabolites such as short-chain fatty acids (SCFAs), including butyrate and propionate, which promote anti-inflammatory cytokines (IL-10, TGF-β), T and B cell development, and strengthening of the epithelial integrity.^7,8

In IBD, disruptions in microbial composition may impair SCFA production and promote inflammation.^8,9 This microbial imbalance elevates pro-inflammatory cytokines (IL-12, IL-23, and TNF-α), triggering Th17 immune activation and promoting the growth of pathogenic bacteria such as Enterobacteriaceae, Ruminococcus, and Escherichia coli.¹⁰ As inflammation escalates, the intestinal barrier weakens, increasing permeability and allowing immune-microbiome interactions that exacerbate gut damage.¹¹ Enterococcus faecalis, for instance, produces metalloproteinases and gelatinases that degrade gut lining.¹² In addition, reduced bacterial diversity and SCFA production impair gut healing, leaving patients more vulnerable to relapsing inflammation.⁸ Alterations in the gut microbiota composition further compromise tight junction proteins, such as occludin, claudins, and ZO-1, thereby increasing intestinal permeability.¹³ Pro-inflammatory cytokines suppress goblet cell function, reducing the secretion of mucins (such as MUC2). This thinning of the mucus layer exposes the epithelium to microbial contact, thereby amplifying immune activation and perpetuating inflammation.¹³

While current therapies primarily focus on immune modulation, they often fail to address the potential relevance of the underlying microbial dysbiosis that drives and perpetuates epithelial dysfunction and inflammation. This gap in treatment highlights the need for novel approaches that target dysbiosis and its downstream effects on epithelial integrity. These limitations have spurred interest in emerging therapies, particularly probiotics and prebiotics, as potential strategies to rebalance the microbiome and improve disease outcomes.

IBDs and current treatment options

The prevalence of IBD has historically been highest in developed countries, but the incidence has risen substantially in developing nations.¹⁴ Compounding prevalence has resulted in escalating age-specific prevalence in the elderly, a group that is most sensitive to infectious and malignant risks associated with immunosuppressive therapies.¹⁵ As such, new treatments that are least likely to result in systemic immunosuppression are required. Microbial manipulation may be one strategy that might effectively treat IBD without inducing immunosuppression.^16,17 Immune modulatory treatments, aside from potential side effects, may have a delayed onset of efficacy and often fail to induce long-term remission, contributing to increased healthcare burden.^18,19

Microbial-based therapy for IBD

Developing microbiome-based therapies for IBD is a promising yet complex field that faces several challenges. FMT has emerged as an approach for restoring gut microbiota balance in patients with IBD.^16,20 A recent systematic review highlighted its potential to achieve clinical and endoscopic remission in individuals with active UC.²¹ The success of FMT depends on several factors, including the diversity and composition of the donor microbiome, the genetic profile of the recipient, and the protocols followed during the procedure.²² Selecting suitable stool donors is critical, with ideal donors being healthy individuals who are free from risk factors for infectious or chronic diseases. The concept of “super-donors,” individuals whose microbiota consistently yield superior outcomes, has emerged as a promising strategy to optimize FMT efficacy.²³ In addition, matching donors and recipients based on specific microbial imbalances may further enhance therapeutic success.²⁴

One of the primary obstacles to FMT success is the complexity and variability of the human gut microbiome.²⁵ Each individual’s microbiome is unique, influenced by age, genetics, diet, environment, stress, sleep patterns, and lifestyle, making it difficult to create a one-size-fits-all treatment. In addition, the precise mechanisms through which the microbiome influences IBD are not fully understood, making the development of targeted therapies more complex.²⁶ For instance, while FMT has shown promise in some cases, its efficacy is variable.²⁷ The consortia-based approach has also been challenging due to the high cost of manufacturing, the difficulty in identifying the optimal bacterial combination for administration, and the challenges in ensuring engraftment.²⁸ Moreover, the variability in response to microbiome-based therapies underscores the importance of stratifying patients based on microbiome profiles, disease phenotypes, and other biomarkers to improve treatment outcomes.²⁸ Diet and physical activity are also well-recognized modulators of gut microbiota composition.^29–31 Variations in these factors across study populations may confound microbiota-targeted trials, further contributing to the heterogeneity observed in clinical outcomes.³² Understanding the specific characteristics of each individual’s microbiome is crucial for identifying which treatments are most likely to be effective, pointing to the need for personalized and targeted approaches. These considerations align with the challenges faced by therapies such as SER-287, an oral bacterial formulation of Firmicutes spores derived from healthy individuals, which failed to meet its primary endpoint in a phase IIb study for UC,³³ highlighting the need for a deeper understanding of the microbiome’s role in IBD. At present, due to limited and variable evidence, FMT is not recommended for routine clinical use in IBD outside clinical trials. Notably, variations in donor selection, stool processing methods, administration protocols, and patient microbiota profiles hinder the design of standardized trials, contributing to outcome heterogeneity. This variability is reflected in clinical outcomes: among four major randomized controlled trials of FMT in UC, clinical remission rates have ranged from approximately 24% to 44%, highlighting both the therapeutic potential and inconsistency of response.^16,34–36 These findings underscore the need for more rigorously designed and stratified studies to better define the role of FMT in IBD.

Probiotics are live, non-pathogenic microbes that promote host health by improving or restoring the gut microbiota, inhibiting the growth of harmful bacteria, and enhancing intestinal barrier function and immunity.^37,38 They have been investigated as a treatment for IBD with variable success.³⁹

Despite mixed findings, probiotics may offer benefits for IBD.³⁸ Meta-analyses have reported that probiotics, particularly high-dose or multi-strain formulations, may aid in inducing remission and preventing relapse in UC and pouchitis; however, study heterogeneity limits definitive conclusions.^40–42 Maintenance therapy for pouchitis has the most robust evidence, with multi-strain formulations such as VSL#3, shown to help maintain remission and restore microbial diversity.⁴³ Current guidelines do not recommend the use of probiotics for IBD, except in cases of pouchitis, reflecting the need for more consistent data in UC and CD.⁴⁴

Beyond these clinical outcomes, specific mechanisms of probiotics have been studied, demonstrating their potential to modulate the gut microbiota and reduce inflammation. For example, supplementation with Bifidobacterium longum BB536 in patients with colorectal cancer undergoing surgical resection altered fecal bacteria composition and reduced inflammatory markers (e.g., IL-6 and CRP) within 7–14 days.⁴⁵ Similarly, a combination of Lactobacillus and Bifidobacteria species in patients with UC significantly increased beneficial gut microbiome levels, such as proteobacteria and reduced the abundance of Gram-negative bacteria.⁴⁶

However, several studies and products have faced setbacks in this area. For example, the use of probiotics as a treatment for IBD has yielded mixed results; some clinical trials have shown no significant benefit, and in some cases, probiotics have even exacerbated symptoms.^28,47 There is also considerable variation in terms of bacterial strain effects.⁴⁸ Issues such as quality control persist, as probiotic products are often standardized for potency or purity,⁴⁹ but variations in formulation, storage conditions, and manufacturing processes can still impact their effectiveness. In a recent study reported by Hazan and Papousis,⁵⁰ 26 commercially available probiotics were analyzed; of these, only 5 probiotics that claimed to contain Bifidobacteria actually contained the bacteria. Finally, there is limited evidence of successful engraftment of probiotics in an inflamed human gut, and their survival during transit through the GI tract can be compromised by stomach acid and bile concentrations, reducing their effectiveness.^47,51

Prebiotics

Prebiotics are compounds, such as polysaccharides, oligosaccharides, and certain microalgae, that are indigestible and unabsorbable by the human body but serve as a food source for beneficial gut microorganisms, selectively promoting their growth and activity.⁵² Among these, oligosaccharides are the most commonly recognized prebiotics, with fructooligosaccharides (FOS) and galactooligosaccharides (GOS) being extensively studied examples.⁵³ Natural sources of prebiotics include fruits, vegetables, and fibers, such as wheat, soybeans, bananas, mushrooms, berries, curcumin, honey, tomatoes, black and green tea, and both human and cow’s milk.^53,54

A systematic review highlighted the potential of prebiotics in IBD, with FOS showing efficacy in inducing remission in UC and germinated barley foodstuff demonstrating promise for maintaining remission in UC. While the certainty of evidence remains low, these findings support further exploration of prebiotics as adjunct therapies for IBD.⁵⁵ Kennedy et al.⁵⁶ further reviewed trials demonstrating that FOS, GOS, and the HMO 2′-FL can improve clinical outcomes, microbiota composition, and SCFA levels in UC. This aligns with findings from individual studies that have demonstrated how prebiotics can enhance resistance to pathogens, regulate the immune system, improve mineral absorption, and promote the production of SCFAs.⁵⁷ One study demonstrated that a polysaccharide derived from Scutellaria baicalensis Georgi acts as a prebiotic by modulating the immune system and ameliorating colonic damage in mice with dextran sulfate sodium (DSS)-induced colitis.⁵⁸ Similarly, in an acetic acid-induced colitis mouse model, the consumption of FOS over 2 weeks reduced harmful bacteria, increased SCFAs and beneficial bacteria, improved gut motility, and decreased disease activity index.⁵⁹ Additionally, FOS-enriched inulin supplementation in CD patients significantly increased SCFA levels and enhanced populations of Lactobacillus and Bifidobacterium.⁶⁰

Unlike probiotics, prebiotics do not require cold storage, making them easier to transport while preserving their benefits. Furthermore, prebiotics are considered safer for conditions involving increased intestinal permeability or bleeding, as they do not contain live microorganisms. Notably, the human genome does not encode enzymes capable of digesting prebiotics, ensuring their selective utilization by the gut microbiota.

Human milk oligosaccharides

HMOs are naturally occurring prebiotics found in human milk and have critical roles in infant development, immune system modulation, and anti-inflammatory effects.⁶¹ HMOs are the third most abundant solid component in human milk after lactose and lipids.⁶¹ They are indigestible in the small intestine and serve as a selective substrate for the growth of beneficial gut bacteria, particularly Bifidobacteria, while also preventing harmful pathogens from binding to the intestinal epithelial cells.^61,62

There are over 200 structurally diverse bioactive HMOs, each with various biological functions.² They typically contain a lactose-reducing end elongated with fucosylated and/or sialylated N-acetyllactosamine units (Figure 1).⁶³ The concentration of HMOs can reach up to 20 g/L in colostrum and generally ranges between 5 and 23 g/L in mature human milk.⁶³ Human milk contains three major types of HMOs, categorized based on their monosaccharide building blocks: Neutral Fucosylated HMOs (35%–50% of total HMOs), such as 2′-FL and 3′-FL; Neutral Nonfucosylated N-containing HMOs (42%–55%), including Lacto-N-tetraose (LNT) and Lacto-N-neotetraose (LNnT); and Acidic Sialylated HMOs (12%–14%), represented by 2′-sialyllactose (2′-SL) and 6′-sialyllactose (6′-SL; Figure 1).⁶³ The composition of HMOs varies among mothers due to genetic polymorphisms in the FUT2 and FUT3, with inactive FUT2 polymorphisms preventing the synthesis of α1-2 fucosylated HMOs (e.g., 2′-FL), and inactive FUT3 polymorphisms causing the absence of α1-3/4 fucosylated HMOs.⁶⁴

Figure 1.

Classification of HMOs into three main types: neutral fucosylated HMOs, neutral nonfucosylated HMOs, and acidic sialylated HMOs. Examples of each category include 2′-FL and 3′-FL, LNT and LNnT, and 3′-SL and 6′-SL, respectively. This categorization highlights the structural diversity of HMOs and their key components.

2′-FL is the most abundant HMO and a key trisaccharide prebiotic in human milk. It plays a central role in supporting a healthy gut microbiome and the healthy development of the infant. However, there is increasing interest in evaluating its potential therapeutic effects beyond infancy, including applications in IBD.⁶¹

Animal models of colitis

2′-FL has shown therapeutic potential in preclinical colitis models. Immune dysfunction plays a critical role in the pathogenesis of IBD, and 2′-FL has been shown to enhance systemic immunity by increasing IgG and IgA plasma levels and promoting the maturation of T cell subsets in mesenteric lymph nodes.⁶⁵ These findings suggest that 2′-FL supports immune homeostasis, positioning it as a promising therapeutic agent in colitis.⁶⁵

In chemically induced models of colitis, 2′-FL has demonstrated robust anti-inflammatory effects by targeting key pathways involved in intestinal inflammation. In lipopolysaccharide (LPS)-induced inflammation, 2′-FL restored colon length, improved histological integrity, and regulated intestinal gene expression.^66,67 Similarly, in DSS-induced colitis, 2′-FL improved intestinal barrier function, modulated gut microbiota composition, suppressed pro-inflammatory cytokines, and promoted anti-inflammatory cytokines.⁶⁸ 2′-FL also alleviated immune checkpoint blockade-associated colitis by reshaping gut microbiota and activating the aryl hydrocarbon receptor ligand pathway, further highlighting its dual immunomodulatory and anti-inflammatory effects.⁶⁹ 2′-FL was also shown to regulate 26 dysregulated metabolic pathways identified in the fecal microbiota of UC patients, restoring microbial metabolism and promoting gut homeostasis in colitis-affected mice.⁷⁰

2′-FL suppresses pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), reduces neutrophil and macrophage infiltration, and promotes anti-inflammatory mediators such as IL-10 by modulating inflammatory pathways such as TLR4/MyD88/NF-κB and RAR-related orphan receptor gamma-t (RORγt) signaling, crucial in IBD pathogenesis.^71,72 This reduces inflammatory cell infiltration in colonic tissue.^73,74 Furthermore, 2′-FL reduces oxidative stress via the AMPK/SIRT1/FOXO1 pathway, enhancing superoxide dismutase and glutathione peroxidase, which protect intestinal cells from oxidative damage.⁷⁵

2′-FL strengthens the intestinal barrier by enhancing goblet cell function, upregulating the MUC2 gene, and elevating tight junction proteins such as ZO-1 and occludin.^73,76 These actions reduce intestinal permeability, a hallmark of “leaky gut” in IBD, and improve overall epithelial integrity⁷³ (Figure 2). Moreover, 2′-FL reduces epithelial cell apoptosis and protects epithelial cells from inflammatory and oxidative stress, further stabilizing the gut lining.⁷⁷ Collectively, these mechanisms suggest that 2′-FL interferes with bacterial adhesion and invasion processes, crucial for pathogen-induced colitis development.

Figure 2.

Pathophysiological alterations in IBD: dysbiosis of the gut microbiota, disruption of the gut barrier, and inflammation, can be improved by 2′-FL through different pathways.

2′-FL has proven efficacy in models of pathogen-induced inflammation, where it plays a dual role in protecting intestinal integrity and mitigating inflammation. In Campylobacter jejuni-infected mouse intestinal mucosa, 2′-FL reduced cytokine production, restored epithelial barrier integrity, and alleviated inflammation.⁷⁸ Similarly, 2′-FL showed protective effects in mouse models of infection with type 1 pili enterotoxigenic E. coli and adherent-invasive E. coli, where it reduced LPS-induced IL-8 expression, inhibited CD14 transcription and translation, and protected against epithelial damage caused by the pathogens.⁷⁹ In addition, 2′-FL reduced E. coli O157 colonization by over 90% and inhibited its adhesion to intestinal epithelial cells.⁸⁰ It has also been shown to reduce biofilm formation by Group B Streptococcus.⁸¹ These mechanisms, which are critical in countering pathogen-induced damage, are also highly relevant to the inflammatory and barrier-disrupting processes observed in colitis models.

While 2′-FL is the most extensively studied HMO in IBD, other HMOs such as 3′-SL and 6′-SL, also show therapeutic potential. 3′-SL has been shown to modulate immune responses by reducing neutrophil activity, while both 3′-SL and 6′-SL enhance intestinal barrier function and promote beneficial gut bacteria, similar to 2′-FL. These findings highlight the broader relevance of HMOs in managing intestinal inflammation and support further exploration of their roles in IBD.^82,83

Human experience

Consistent with findings from preclinical models, human studies support the therapeutic potential of 2′-FL, demonstrating its microbiome-modulating effects and clinical benefits.⁸⁴ In an in vitro fermentation study using stool from patients with UC, 2′-FL modulated the gut microbiome by enriching Bifidobacterium and Faecalibacterium prausnitzii, increasing SCFA production, and reducing pathogenic bacteria such as Desulfovibrio spp.⁸⁵ A pilot clinical trial involving patients with UC found that 2′-FL supplementation improved IBD-specific quality of life, as measured by Inflammatory Bowel Disease Questionnaire scores. Microbiome and SCFA changes were also observed across the broader cohort.⁸⁶

In pediatric CD populations, 2′-FL has been linked to favorable shifts in microbiota composition, supporting its bifidogenic and butyrogenic effects that may enhance epithelial barrier integrity and modulate inflammation.⁸⁷

Beyond IBD, 2′-FL has shown promise in diverse clinical contexts. The EFFICAD trial in adults with mild-to-moderate anxiety and depression demonstrated that 2′-FL, alone or combined with oligofructose, altered gut microbial composition and improved mood state parameters.⁸⁸ A randomized controlled trial in infants demonstrated that 2′-FL supplementation reduced plasma inflammatory cytokine levels, highlighting its systemic anti-inflammatory properties.⁸⁹ Studies in non-breastfed infants supplemented with 2′-FL demonstrated enrichment of Bifidobacterium species and delayed adult-like microbiome transitions, underscoring its early role in shaping gut health.^90,91 Similarly, a randomized trial in healthy adults showed that 2′-FL supplementation increased Actinobacteria species and Bifidobacterium levels, suggesting its broad microbiota-modulating properties.⁶ In addition, a prospective pilot study of 25 children and young adults undergoing hematopoietic stem cell transplantation demonstrated that oral 2′-FL supplementation increased SCFA production, preserved microbiome diversity, and reduced markers of dysbiosis, while showing improvements in quality-of-life scores and digestive symptoms.⁹² There were numerically fewer cases of acute GI graft-versus-host disease (0 vs 3) in the 2′-FL treated cohort. While not specific to IBD, these findings highlight 2′-FL’s capacity to influence microbial diversity and gut function, which are central to IBD pathophysiology.

Ongoing clinical research continues to focus on integrating 2′-FL into therapeutic strategies for IBD (ClinicalTrials.gov identifiers: NCT03847467, NCT06050811). These include the PRIME trial, which is evaluating 2′-FL as an adjunct to anti-TNF therapy in pediatric and young adult patients, and the PRInCE-UC trial, a phase IIa study assessing the safety, tolerability, and microbiota outcomes of different doses of 2′-FL in adults with UC (ClinicalTrials.gov identifiers: NCT03847467, NCT06050811). Collectively, these studies highlight growing interest in integrating 2′-FL into therapeutic strategies for IBD, with evidence from large-scale trials anticipated to further clarify its clinical utility.

Future directions

The therapeutic potential of 2′-FL in IBD opens new avenues for effective microbiome-based clinical interventions. Building on its prebiotic properties, 2′-FL could enhance the efficacy of FMT by selectively optimizing gut microbial composition, improving FMT engraftment and treatment outcomes.⁶ Future research should refine integration strategies, including the timing of 2′-FL supplementation, donor microbiome conditioning, and individualized treatment protocols. This aligns with broader advancements in microbiome-directed therapies, which emphasize dietary and microbial modulation as key strategies for improving IBD outcomes.⁹³ Beyond bacterial modulation, future investigations should also explore other components of the gut microbiome, including fungi, viruses, archaea, and protists, as these have been increasingly implicated in IBD pathogenesis and may offer novel therapeutic avenues.^94,95

In addition to its role in enhancing FMT, 2′-FL holds promise as a complementary therapy alongside existing treatments for IBD, such as biologics and small-molecule inhibitors. Its ability to fortify the epithelial barrier, regulate immune responses, and alleviate inflammation could address critical aspects of disease pathophysiology that current therapies may not fully resolve. Furthermore, tailoring 2′-FL interventions to individual microbiome profiles and disease phenotypes could optimize outcomes, offering a personalized approach for patients who do not respond adequately to conventional treatments.

Although no studies have directly examined 2′-FL for preventing IBD or protecting infants born to mothers with IBD, its established effects on early microbiota composition, epithelial barrier integrity, and immune development support further investigation into its potential role in the preclinical stage of IBD, particularly in high-risk populations.

While the potential of 2′-FL as a therapeutic agent is promising, clinical evidence remains limited, and its long-term effects require further investigation. Future research should focus on addressing these gaps, particularly through large-scale trials to evaluate safety and clinical efficacy across diverse populations. Combining microbiota-directed approaches, such as 2′-FL supplementation or FMT, with established immunomodulatory therapies represents a promising strategy that may help overcome the current therapeutic ceiling in IBD management and warrants further investigation in future studies.

Conclusion

IBD is a complex condition requiring innovative therapies that address both symptoms and underlying molecular pathophysiology. Among emerging interventions, 2′-FL has demonstrated significant potential as a prebiotic therapy by reducing inflammation, enhancing mucosal healing, and modulating the gut microbiome. Its multifaceted mechanisms and consistent efficacy across diverse models position 2′-FL as a promising adjunct to existing treatments. Preliminary evidence suggests that 2′-FL may complement FMT, offering a novel approach to addressing dysbiosis that drives IBD pathogenesis.

While promising, further clinical trials are essential to validate the safety and efficacy of 2′-FL in diverse patient populations. Standardized protocols for integration with FMT and other therapies will be key to maximizing its therapeutic impact. As a novel addition to the IBD treatment landscape, 2′-FL holds the potential to improve patient outcomes, sustain remission, and significantly enhance quality of life.

Footnotes

Acknowledgements

All images were created using Biorender.com.

Declarations

ORCID iDs

Nicholas Fanous

Nicholas J. Talley

Thanaboon Chaemsupaphan

Binod Rayamajhee

Rupert W. Leong

References

Guan

A comprehensive review and update on the pathogenesis of inflammatory bowel disease. J Immunol Res 2019; 2019: 7247238.

Thurl

Munzert

Boehm

, et al. Systematic review of the concentrations of oligosaccharides in human milk. Nutr Rev 2017; 75(11): 920–933.

Zhang

Xie

, et al. Gold standard for nutrition: a review of human milk oligosaccharide and its effects on infant gut microbiota. Microb Cell Fact 2021; 20(1): 108.

Suligoj

Vigsnaes

Abbeele

PVD

, et al. Effects of human milk oligosaccharides on the adult gut microbiota and barrier function. Nutrients 2020; 12(9): 2808.

Khorsand

Asadzadeh Aghdaei

Nazemalhosseini-Mojarad

, et al. Overrepresentation of Enterobacteriaceae and Escherichia coli is the major gut microbiome signature in Crohn’s disease and ulcerative colitis; a comprehensive metagenomic analysis of IBDMDB datasets. Front Cell Infect Microbiol 2022; 12: 1015890.

Elison

Vigsnaes

Rindom Krogsgaard

, 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.

Santana

Rosas

SLB

Ribeiro

, et al. Dysbiosis in inflammatory bowel disease: pathogenic role and potential therapeutic targets. Int J Mol Sci 2022; 23(7): 3464.

Parada Venegas

De la Fuente

Landskron

, et al. Short chain fatty acids (SCFAs)-mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases. Front Immunol 2019; 10: 277.

Machiels

Joossens

Sabino

, et al. A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut 2014; 63(8): 1275–1283.

10.

Qiu

Ishimoto

, et al. The gut microbiota in inflammatory bowel disease. Front Cell Infect Microbiol 2022; 12: 733992.

11.

Di Vincenzo

Del Gaudio

Petito

, et al. Gut microbiota, intestinal permeability, and systemic inflammation: a narrative review. Intern Emerg Med 2024; 19(2): 275–293.

12.

Maharshak

Huh

Paiboonrungruang

, et al. Enterococcus faecalis gelatinase mediates intestinal permeability via protease-activated receptor 2. Infect Immun 2015; 83(7): 2762–2770.

13.

Tonetti

Eguileor

Llorente

Goblet cells: guardians of gut immunity and their role in gastrointestinal diseases. eGastroenterology 2024; 2(3): e100098.

14.

Muzammil

Fariha

Patel

, et al. Advancements in inflammatory bowel disease: a narrative review of diagnostics, management, epidemiology, prevalence, patient outcomes, quality of life, and clinical presentation. Cureus 2023; 15(6): e41120.

15.

Pudipeddi

Liu

Kariyawasam

, et al. High prevalence of Crohn disease and ulcerative colitis among older people in Sydney. Med J Aust 2021; 214(8): 365–370.

16.

Haifer

Paramsothy

Kaakoush

, et al. Lyophilised oral faecal microbiota transplantation for ulcerative colitis (LOTUS): a randomised, double-blind, placebo-controlled trial. Lancet Gastroenterol Hepatol 2022; 7(2): 141–151.

17.

Haifer

Luu

LDW

Paramsothy

, et al. Microbial determinants of effective donors in faecal microbiota transplantation for UC. Gut. Epub ahead of print July 2022. DOI: 10.1136/gutjnl-2022-327742.

18.

Liu

LL.

Recent advances in the treatment of IBD: targets, mechanisms and related therapies. Cytokine Growth Factor Rev 2023; 71–72: 1–12.

19.

Bhat

Click

Regueiro

Safety and monitoring of inflammatory bowel disease advanced therapies. Inflamm Bowel Dis 2024; 30(5): 829–843.

20.

Haifer

Kelly

Paramsothy

, et al. Australian consensus statements for the regulation, production and use of faecal microbiota transplantation in clinical practice. Gut 2020; 69(5): 801–810.

21.

Imdad

Pandit

Zaman

, et al. Fecal transplantation for treatment of inflammatory bowel disease. Cochrane Database Syst Rev 2023; 4(4): CD012774.

22.

Porcari

Benech

Valles-Colomer

, et al. Key determinants of success in fecal microbiota transplantation: from microbiome to clinic. Cell Host Microbe 2023; 31(5): 712–733.

23.

Wilson

Vatanen

Cutfield

, et al. The super-donor phenomenon in fecal microbiota transplantation. Front Cell Infect Microbiol 2019; 9: 2.

24.

Bibbo

Settanni

Porcari

, et al. Fecal microbiota transplantation: screening and selection to choose the optimal donor. J Clin Med 2020; 9(6): 1757.

25.

Allaband

McDonald

Vazquez-Baeza

, et al. Microbiome 101: studying, analyzing, and interpreting gut microbiome data for clinicians. Clin Gastroenterol Hepatol 2019; 17(2): 218–230.

26.

Haneishi

Furuya

Hasegawa

, et al. Inflammatory bowel diseases and gut microbiota. Int J Mol Sci 2023; 24(4): 3817.

27.

Colman

Rubin

DT.

Fecal microbiota transplantation as therapy for inflammatory bowel disease: a systematic review and meta-analysis. J Crohns Colitis 2014; 8(12): 1569–1581.

28.

Paudel

Nair

DVT

Joseph

, et al. Gastrointestinal microbiota-directed nutritional and therapeutic interventions for inflammatory bowel disease: opportunities and challenges. Gastroenterol Rep (Oxf) 2024; 12: goae033.

29.

David

Maurice

Carmody

, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 2014; 505(7484): 559–563.

30.

Clarke

Murphy

O’Sullivan

, et al. Exercise and associated dietary extremes impact on gut microbial diversity. Gut 2014; 63(12): 1913–1920.

31.

Ghosh

Shanahan

O’Toole

PW.

The gut microbiome as a modulator of healthy ageing. Nat Rev Gastroenterol Hepatol 2022; 19(9): 565–584.

32.

Cullen

JMA

Shahzad

Dhillon

A systematic review on the effects of exercise on gut microbial diversity, taxonomic composition, and microbial metabolites: identifying research gaps and future directions. Front Physiol 2023; 14: 1292673.

33.

Henn

O’Brien

Diao

, et al. A phase 1b safety study of SER-287, a spore-based microbiome therapeutic, for active mild to moderate ulcerative colitis. Gastroenterology 2021; 160(1): 115–127.e30.

34.

Moayyedi

Surette

Kim

, et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology 2015; 149(1): 102–109.e6.

35.

Paramsothy

Rubin

, et al. Faecal microbiota transplantation for inflammatory bowel disease: a systematic review and meta-analysis. J Crohns Colitis 2017; 11(10): 1180–1199.

36.

Costello

Hughes

Waters

, et al. Effect of fecal microbiota transplantation on 8-week remission in patients with ulcerative colitis: a randomized clinical trial. JAMA 2019; 321(2): 156–164.

37.

Wang

Zhang

Probiotics regulate gut microbiota: an effective method to improve immunity. Molecules 2021; 26(19): 6076.

38.

Chandrasekaran

Weiskirchen

Effects of probiotics on gut microbiota: an overview. Int J Mol Sci 2024; 25(11): 6022.

39.

Huang

Hao

Wang

, et al. Probiotics for the treatment of ulcerative colitis: a review of experimental research from 2018 to 2022. Front Microbiol 2023; 14: 1211271.

40.

Estevinho

Yuan

Rodriguez-Lago

, et al. Efficacy and safety of probiotics in IBD: an overview of systematic reviews and updated meta-analysis of randomized controlled trials. United European Gastroenterol J 2024; 12(7): 960–981.

41.

Shen

Zuo

Mao

AP.

Effect of probiotics on inducing remission and maintaining therapy in ulcerative colitis, Crohn’s disease, and pouchitis: meta-analysis of randomized controlled trials. Inflamm Bowel Dis 2014; 20(1): 21–35.

42.

Zheng

Yang

, et al. Efficacy and safety probiotics as adjuvant treatment for Crohn’s disease: a meta-analysis of randomized controlled trials. Curr Res Food Sci 2025; 10: 101061.

43.

Puca

Del Gaudio

Becherucci

, et al. Diet and microbiota modulation for chronic pouchitis: evidence, challenges, and opportunities. Nutrients 2024; 16(24): 4337.

44.

Barnes

Agrawal

Syal

, et al. AGA clinical practice guideline on the management of pouchitis and inflammatory pouch disorders. Gastroenterology 2024; 166(1): 59–85.

45.

Mizuta

Endo

Yamamoto

, et al. Perioperative supplementation with bifidobacteria improves postoperative nutritional recovery, inflammatory response, and fecal microbiota in patients undergoing colorectal surgery: a prospective, randomized clinical trial. Biosci Microbiota Food Health 2016; 35(2): 77–87.

46.

Pilarczyk-Zurek

Zwolinska-Wcislo

Mach

, et al. Influence of Lactobacillus and Bifidobacterium combination on the gut microbiota, clinical course, and local gut inflammation in patients with ulcerative colitis: a preliminary, single-center, open-label study. J Probiotics Health 2017; 5(1): 1–6.

47.

Jauregui-Amezaga

Smet

The microbiome in inflammatory bowel disease. J Clin Med 2024; 13(16): 4622.

48.

Derwa

Gracie

Hamlin

, et al. Systematic review with meta-analysis: the efficacy of probiotics in inflammatory bowel disease. Aliment Pharmacol Ther 2017; 46(4): 389–400.

49.

Ahire

Rohilla

Kumar

, et al. Quality management of probiotics: ensuring safety and maximizing health benefits. Curr Microbiol 2023; 81(1): 1.

50.

Hazan

Papousis

S240 Probiotics Counterfeit! Study finds most labels mislead customers. Am J Gastroenterol 2023; 118(10S): S179–S180.

51.

Ferreiro

Dantas

Ciorba

MA.

Insights into how probiotics colonize the healthy human gut. Gastroenterology 2019; 156(3): 820–822.

52.

You

Yan

, et al. The promotion mechanism of prebiotics for probiotics: a review. Front Nutr 2022; 9: 1000517.

53.

Selvamani

Mehta

Ali

Enshasy

, et al. Efficacy of probiotics-based interventions as therapy for inflammatory bowel disease: a recent update. Saudi J Biol Sci 2022; 29(5): 3546–3567.

54.

Sendani

Farmani

Kazemifard

, et al. Molecular mechanisms and therapeutic effects of natural products in inflammatory bowel disease. Clin Nutr Open Sci 2024; 58: 21–42.

55.

Limketkai

Godoy-Brewer

Shah

, et al. Prebiotics for induction and maintenance of remission in inflammatory bowel disease: systematic review and meta-analysis. Inflamm Bowel Dis 2025; 31(5): 1220–1230.

56.

Kennedy

De Silva

Walton

, et al. A review on the use of prebiotics in ulcerative colitis. Trends Microbiol 2024; 32(5): 507–515.

57.

Peredo-Lovillo

Romero-Luna

Jimenez-Fernandez

Health promoting microbial metabolites produced by gut microbiota after prebiotics metabolism. Food Res Int 2020; 136: 109473.

58.

Cui

Guan

Ding

, et al. Scutellaria baicalensis Georgi polysaccharide ameliorates DSS-induced ulcerative colitis by improving intestinal barrier function and modulating gut microbiota. Int J Biol Macromol 2021; 166: 1035–1045.

59.

Capitan-Canadas

Ocon

Aranda

, et al. Fructooligosaccharides exert intestinal anti-inflammatory activity in the CD4+ CD62L+ T cell transfer model of colitis in C57BL/6J mice. Eur J Nutr 2016; 55(4): 1445–1454.

60.

Le Bastard

Chapelet

Javaudin

, et al. The effects of inulin on gut microbial composition: a systematic review of evidence from human studies. Eur J Clin Microbiol Infect Dis 2020; 39(3): 403–413.

61.

Plaza-Diaz

Fontana

Gil

Human milk oligosaccharides and immune system development. Nutrients 2018; 10(8): 1038.

62.

Fernandez

Langa

Martin

, et al. The human milk microbiota: origin and potential roles in health and disease. Pharmacol Res 2013; 69(1): 1–10.

63.

Chen

Human milk oligosaccharides (HMOS): structure, function, and enzyme-catalyzed synthesis. Adv Carbohydr Chem Biochem 2015; 72: 113–190.

64.

Lefebvre

Shevlyakova

Charpagne

, et al. Time of lactation and maternal fucosyltransferase genetic polymorphisms determine the variability in human milk oligosaccharides. Front Nutr 2020; 7: 574459.

65.

Azagra-Boronat

Massot-Cladera

Mayneris-Perxachs

, et al. Immunomodulatory and prebiotic effects of 2′-fucosyllactose in suckling rats. Front Immunol 2019; 10: 1773.

66.

Grabinger

Glaus Garzon

Hausmann

, et al. Alleviation of intestinal inflammation by oral supplementation with 2-fucosyllactose in mice. Front Microbiol 2019; 10: 1385.

67.

Kim

Lee

Kim

, et al. Ameliorating effect of 2′-fucosyllactose and 6′-sialyllactose on lipopolysaccharide-induced intestinal inflammation. J Dairy Sci 2024; 107(7): 4147–4160.

68.

Chen

Yang

, et al. Human milk oligosaccharide 2′-fucosyllactose alleviates DSS-induced ulcerative colitis via improving intestinal barrier function and regulating gut microbiota. Food Biosci 2024; 59: 104162.

69.

Yan

Tian

, et al. 2′-Fucosyllactose alleviate immune checkpoint blockade-associated colitis by reshaping gut microbiota and activating AHR pathway. Food Sci Hum Wellness 2024; 13(5): 2543–2561.

70.

Schalich

Buendia

Kaur

, et al. A human milk oligosaccharide prevents intestinal inflammation in adulthood via modulating gut microbial metabolism. mBio 2024; 15(4): e0029824.

71.

Yao

Gao

, et al. The milk active ingredient, 2′-fucosyllactose, inhibits inflammation and promotes MUC2 secretion in LS174T goblet cells in vitro. Foods 2023; 12(1): 186.

72.

Sodhi

Wipf

Yamaguchi

, et al. The human milk oligosaccharides 2′-fucosyllactose and 6′-sialyllactose protect against the development of necrotizing enterocolitis by inhibiting toll-like receptor 4 signaling. Pediatr Res 2021; 89(1): 91–101.

73.

Yao

Fan

Zheng

, et al. 2′-Fucosyllactose ameliorates inflammatory bowel disease by modulating gut microbiota and promoting MUC2 expression. Front Nutr 2022; 9: 822020.

74.

Lei

Wang

Lin

, et al. 2′-Fucosyllactose inhibits imiquimod-induced psoriasis in mice by regulating Th17 cell response via the STAT3 signaling pathway. Int Immunopharmacol 2020; 85: 106659.

75.

Wang

Song

, et al. 2′-Fucosyllactose ameliorates oxidative stress damage in d-galactose-induced aging mice by regulating gut microbiota and AMPK/SIRT1/FOXO1 pathway. Foods 2022; 11(2): 151.

76.

Cheng

Kong

Walvoort

MTC

, et al. Human milk oligosaccharides differently modulate goblet cells under homeostatic, proinflammatory conditions and ER stress. Mol Nutr Food Res 2020; 64(5): e1900976.

77.

Zhao

Williams

Washington

, et al. 2′-Fucosyllactose ameliorates chemotherapy-induced intestinal mucositis by protecting intestinal epithelial cells against apoptosis. Cell Mol Gastroenterol Hepatol 2022; 13(2): 441–457.

78.

Nanthakumar

Newburg

DS.

The human milk oligosaccharide 2′-Fucosyllactose quenches Campylobacter jejuni-induced inflammation in human epithelial cells HEp-2 and HT-29 and in mouse intestinal mucosa. J Nutr 2016; 146(10): 1980–1990.

79.

Liu

Kling

, et al. The human milk oligosaccharide 2′-fucosyllactose modulates CD14 expression in human enterocytes, thereby attenuating LPS-induced inflammation. Gut 2016; 65(1): 33–46.

80.

Wang

Zou

Wang

, et al. The protective effects of 2′-fucosyllactose against E. Coli O157 infection are mediated by the regulation of gut microbiota and the inhibition of pathogen adhesion. Nutrients 2020; 12(5): 1284.

81.

Craft

Townsend

SD.

1-Amino-2′-fucosyllactose inhibits biofilm formation by

Streptococcus agalactiae. J Antibiot (Tokyo) 2019; 72(6): 507–512.

82.

Brazil

Azcutia

Kelm

, et al. CD11B/CD18 Sialylation regulates neutrophil trafficking and inflammatory function in the intestine. Inflamm Bowel Dis 2024; 30(1): S65.

83.

Sato

Kanayama

Nakajima

, 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.

84.

Chen

Gasaly

Tang

, et al. The effect of nerve cells on the intestinal barrier function and the influence of human milk oligosaccharides (hMOs) on the intestinal neuro-epithelial crosstalk. Curr Res Food Sci 2024; 9: 100851.

85.

Kennedy

De Silva

Walton

, et al. Comparison of prebiotic candidates in ulcerative colitis using an in vitro fermentation model. J Appl Microbiol 2024; 135(2): lxae034.

86.

Ryan

Monteagudo-Mera

Contractor

, et al. 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.

87.

Otaru

Bajic

Van den Abbeele

, et al. Bifidogenic effect of human milk oligosaccharides on pediatric IBD fecal microbiota. Microorganisms 2024; 12(10): 1977.

88.

Jackson

Wijeyesekera

Williams

, et al. Inulin-type fructans and 2′-fucosyllactose alter both microbial composition and appear to alleviate stress-induced mood state in a working population compared to placebo (maltodextrin): the EFFICAD trial, a randomized, controlled trial. Am J Clin Nutr 2023; 118(5): 938–955.

89.

Goehring

Marriage

Oliver

, et al. Similar to those who are breastfed, infants fed a formula containing 2′-fucosyllactose have lower inflammatory cytokines in a randomized controlled trial. J Nutr 2016; 146(12): 2559–2566.

90.

Berger

Porta

Foata

, et al. Linking human milk oligosaccharides, infant fecal community types, and later risk to require antibiotics. mBio 2020; 11(2): e03196-19.

91.

Boulange

Pedersen

Martin

, et al. An extensively hydrolyzed formula supplemented with two human milk oligosaccharides modifies the fecal microbiome and metabolome in infants with cow’s milk protein allergy. Int J Mol Sci 2023; 24(14): 11422.

92.

Ramos

Lake

Hoerth

, et al. Administration of human milk oligosaccharide (2′-fucosyllactose) reduces dysbiosis and increases short chain fatty acids in children and young adults following HSCT: a prospective, single-center study. Transplant Cell Ther 2024; 30(2, Suppl.): S16.

93.

Ananthakrishnan

Whelan

Allegretti

, et al. Diet and microbiome-directed therapy 2.0 for IBD. Clin Gastroenterol Hepatol 2025; 23(3): 406–418.

94.

Catalan-Serra

Thorsvik

Beisvag

, et al. Fungal microbiota composition in inflammatory bowel disease patients: characterization in different phenotypes and correlation with clinical activity and disease course. Inflamm Bowel Dis 2024; 30(7): 1164–1177.

95.

Cheng

Lin

, et al. Gut virome and its implications in the pathogenesis and therapeutics of inflammatory bowel disease. BMC Med 2025; 23(1): 183.

Microbiota-targeted strategies in IBD: therapeutic promise of 2′-fucosyllactose and beyond

Abstract

Plain language summary

Keywords

Introduction

Pathogenesis of IBDs

IBDs and current treatment options

Microbial-based therapy for IBD

Prebiotics

Human milk oligosaccharides

Animal models of colitis

Human experience

Future directions

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iDs

References