A sweet delicacy for adult gut health

By Cristina Iribarren, PhD.

Div. of Immunology and Allergy, Dept. of Medicine Solna, and Center for Molecular Medicine, Karolinska Institutet, Karolinska Institutet Hospital, Stockholm, Sweden.

During the first months of a newborn’s life, every drop of human milk counts. Human breast milk ensures the groundwork for adequate growth in early life and for the development of functional biological systems that are crucial later in adulthood. Being so important for infants, can you imagine its potential to prevent, manage, or alleviate a condition later in life? As part of my PhD adventure at the University of Gothenburg (Sweden), I dived into the study of the effects of very special breast milk sugars in irritable bowel syndrome (IBS). 

What makes human milk so special?

Human breast milk’s composition is exclusive, like ‘liquid gold’. Although to a large extent being composed of water (~87%) it also contains a variety of nutrients and bioactive components essential in infant nutrition. After lactose and lipids, human milk oligosaccharides (HMOs) are the third most abundant macronutrient in breast milk. HMOs englobe a galaxy of at least 150 soluble sugar-based structures - known as glycans - that originate from the combination of glucose (Glc), galactose (Gal), fucose, N-acetylglucosamine, and/or sialic acid, always including a lactose (Gal-Glc) core at the reducing end (Figure 1). They are found in concentrations that differ for each individual glycan and fluctuate throughout the lactation period.

Figure 1 Sugar building blocks of HMOs and schematic representation of a few examples: 2’-O-fucosyllactose (2’FL), 3’-O-fucosyllactose (3’FL), lacto-N-neotetraose (LNnT), and 6’-sialyllactose (6’SL). Original figure.

A sweet delicacy with postulated health benefits

As other prebiotics, HMOs reach the colon undigested and serve as a nutrient source for specific health-related bacteria, such as bifidobacteria, and influence gut microbiota composition and function, directly or through cross-feeding interactions (Figure 2). Still, HMO properties seem to go beyond this bifidogenic effect.

Over the years, observational and pre-clinical studies have associated HMOs and their metabolic end products, such as short-chain fatty acids (SCFAs), with a broad range of benefits in infant health, from influencing the neurodevelopment to conferring protection against gastrointestinal diseases and infections and regulating components of the host immune system. Even so, strong evidence from human-controlled studies supporting health benefits is still lacking and HMOs cannot yet be included under the formal umbrella of prebiotics.

Figure 2 Human milk oligosaccharides, gut bacteria, and other luminal factors in a healthy gut. Illustration by J. Kesti

Biosynthetic HMOs: opening new horizons in HMO research

For many years, the uniqueness of these sugars has been the major challenge in HMO research. Today, after two decades of technological advances, it is possible to isolate, synthesize or microbially engineer certain HMOs at large-scale and at a reasonable price. As HMOs gradually become more easily accessible and the understanding of their functional effects for infant health slowly piece together, it does not sound so far-fetched that some scientists envision potential benefits of HMOs also for children and adult health.

Among the currently manufactured HMOs, 2’FL and LNnT are widely and well-studied glycans. In healthy individuals, these glycans show promise as dietary supplements, being a safe food ingredient able to exert a bifidogenic effect in the gut. While ‘fixing a healthy gut’ may sound contradictory, this first step was indispensable to address safety and tolerance before proving the ability of HMOs to restore a disturbed gut microbiota with low bifidobacteria abundance like in IBS.

Chronic abdominal pain and altered bowel movements are key symptoms in IBS, sometimes associated with an altered gut microbiota. During my doctoral studies, I played a part in the first placebo-controlled study exploring the effects of HMOs in adult patients with IBS. Our study demonstrated that a daily dose (10 g) of a 4:1 blend of 2’FL:LNnT was not only well tolerated but had the potential to modulate gut microbiota composition, including increasing Bifidobacterium adolescentis and Bifidobacterium longum proportions after 4 weeks. Besides microbiota composition, 2’FL:LNnT intake had an impact on the fecal and plasma metabolite profiles, possibly reflecting some changes in what microbes do (microbiota function). Our study however could not detect changes in the immune response at intestinal mucosa level. In parallel, another study conducted in the US showed that daily intake of 5 g of the same blend (2’FL:LNnT) could stabilize bowel habits, and improve symptom severity and life quality already after one month of a 12-week intervention. Whether the clinical benefit comes along with the shift of the intestinal microenvironment is not clear and awaits further investigations in a larger cohort including a placebo control group.

Cristina Iribarren nailing her doctoral thesis. University of Gothenburg, May 18th 2022.

Just the tip of the iceberg

Other potential effects of HMO consumption in adults have been tackled by other groups. For instance, a small group of patients with various gastrointestinal diseases, including IBS, showed improvement in gastrointestinal and extraintestinal symptoms after consumption of a nutritional formula containing 2’FL. In a healthy elderly population, bifidobacteria bloomed only in those individuals receiving 2’FL (vs placebo). However, inflammation related to aging remained stable despite changes in specific metabolite and circulating inflammatory proteins. In combination with Bifidobacterium infantis, an HMO blend (prepared from breast milk) improved gut engraftment of the probiotic in a reversible manner, suggesting its potential use as synbiotic for healthy adults.

All these studies open new horizons to further explore the effects of different glycans in adult populations, alone, as a blend, or in combination with other supplements. Among the current portfolio of microbiota-targeted strategies, HMOs seem promising. Whether patients – either with gastrointestinal disease or other diseases – will benefit from these special sugars in the future as supplement to other therapies, is still being explored. Until then, remember that HMOs are essential for the upbringing of new healthy generations while holding promise for the older ones to come.


References

  • Bode L: Human milk oligosaccharides: Every baby needs a sugar mama. Glycobiology 2012, 22(9):1147-1162.

  • Bode L, Contractor N, Barile D, Pohl N, Prudden AR, Boons G-J, Jin Y-S, Jennewein S: Overcoming the limited availability of human milk oligosaccharides: challenges and opportunities for research and application. Nut Rev 2016, 74(10):635-644.

  • Button JE, Autran CA, Reens AL, Cosetta CM, Smriga S, Ericson M, Pierce JV, Cook DN, Lee ML, Sun AK et al: Dosing a synbiotic of human milk oligosaccharides and B. infantis leads to reversible engraftment in healthy adult microbiomes without antibiotics. Cell Host & Microbe 2022, 30(5):712-725.e717.

  • Carter MM, Demis D, Perelman D, Onge MS, Petlura C, Cunanan K, Mathi K, Maecker HT, Chow JM, Robinson JL et al: A human milk oligosaccharide alters the microbiome, circulating hormones, cytokines and metabolites in a randomized controlled trial of older individuals. medRxiv 2023:2023.2008.2018.23294085 (preprint accessed in April 2024).

  • Elison E, Vigsnaes LK, Rindom Krogsgaard L, Rasmussen J, Sørensen N, McConnell B, Hennet T, Sommer MO, Bytzer P: 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.

  • Gibson GR, Hutkins R, Sanders ME, Prescott SL, Reimer RA, Salminen SJ, Scott K, Stanton C, Swanson KS, Cani PD et al: Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat Rev Gastroenterol Hepatol 2017, 14(8):491-502.

  • Iribarren C, Törnblom H, Aziz I, Magnusson MK, Sundin J, Vigsnæs LK, Amundsen ID, McConnell B, Seitzberg D, Öhman L et al: Human milk oligosaccharide supplementation in irritable bowel syndrome patients: a parallel, randomized, double-blind, placebo-controlled study. Neurogastroenterol Motil 2020, 32(10):e13920.

  • Iribarren C, Magnusson MK, Vigsnæs LK, Aziz I, Amundsen ID, Šuligoj T, Juge N, Patel P, Sapnara M, Johnsen L et al: The effects of human milk oligosaccharides on gut microbiota, metabolite profiles and host mucosal response in patients with irritable bowel syndrome. Nutrients 2021, 13(11):3836.

  • 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. Clin Transl Gastroenterol 2020, 11(12):e00276.

  • Roager HM, Stanton C, Hall LJ: Microbial metabolites as modulators of the infant gut microbiome and host-microbial interactions in early life. Gut Microbes 2023, 15(1):2192151.

  • 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.

  • 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.

  • Schönknecht YB, Moreno Tovar MV, Jensen SR, Parschat K: Clinical studies on the supplementation of manufactured human milk oligosaccharides: a systematic review. Nutrients 2023, 15(16):3622.

  • Soyyılmaz B, Mikš MH, Röhrig CH, Matwiejuk M, Meszaros-Matwiejuk A, Vigsnæs LK: The mean of milk: a review of human milk oligosaccharide concentrations throughout lactation. Nutrients 2021, 13(8):2737.

ISAPP_SFA