Human milk oligosaccharides improve ‘leaky’ guts
Human milk oligosaccharides (HMOs) in breast milk shape the healthy gut microbiota of infants. However, the potential for manufactured HMOs to improve digestive health of adults, and the likely mechanisms involved, are not yet fully understood. A research collaboration between Prof. Nathalie Juge’s team at Quadram Institute Bioscience (QIB), and three industry partners[i]; ProDigest, Glycom, (part of DSM since April 2020); and Emulate Inc., has demonstrated that, in addition to encouraging beneficial Bifidobacterium species, two manufactured HMOs, 2′-fucosyllactose (2’FL) and lacto-N neotetraose (LNnT), also modulated adult immune function by making the gut barrier less ‘leaky’. This confirms the potential for HMOs to provide health benefits in adults as well as infants.
Glycom is a biotechnology company developing HMOs as key ingredients in food supplements and infant formula. They supplied the two manufactured HMOs studied (2’FL and LNnT). To investigate the action of the two HMOs on adult gut microbiota, the research team used an in vitro gastrointestinal fermentation model, ‘Simulator of the Human Intestinal Microbial Ecosystem (SHIME®)’ at ProDigest; the model simulates digestion in the gut enabling the effect of HMOs on the abundance of beneficial Bifidobacterium species to be established. Using Caco2 cells grown as a single layer (an effective model of the gut epithelial lining), it was possible to establish the relationship between HMOs and gut barrier function (i.e. permeability) at QIB. This was further elaborated using advanced gut-on-chip models at the Quadram Institute with organoids derived from colonic biopsies (colon intestinal gut organoid-on-chips; biopsy material from healthy endoscopy patient volunteers at the Norfolk and Norwich University Hospital (NNUH), donated via the Norwich Research Park Biorepository); cultured under conditions that recreated the gut epithelial structure and function, following Emulate’s technology. Using these models, the research team demonstrated that the two manufactured HMOs provided by Glycom supported growth of beneficial gut bacteria in the adult microbiota, modulated immune function, and improved gut barrier function.
HMOs are a family of over two hundred different, highly complex, undigestible sugars found naturally in breast milk. Recent breakthroughs in commercial production techniques have meant that they can now be manufactured through industrial fermentation processes. In numerous studies they have been shown to improve the health of infants by acting as a prebiotic[ii],[iii] and the European Food Safety Authority (EFSA) consider these commercially-produced HMOs as safe, novel food ingredients (Commission Implemented Regulation EU 2017/2470). In infants, the majority of ingested HMOs reach the large intestine where they provide selective substrates for beneficial gut bacteria such as Bifidobacterium species[iv], strengthen the immune system, reduce the risk of allergic reactions, support neuronal development and deter colonisation by intestinal pathogens[v]. Manufactured HMOs are currently used in infant milk formula preparations[vi], supplements and foods with health benefits. The Quadram research team have expanded the potential impact reach of commercially-produced HMOs by defining the mechanisms that provide the beneficial health properties and by proving that HMOs have the capacity to modulate immune function and the gut barrier in adults as well as infants.
“HMOs are being used to improve health in infants, as supplements in formula milk, but this work shows the potential application for adults, particularly for those with disorders linked to a ‘leaky’ gut – such as IBS. More research is now needed, particularly in people with the conditions we want to treat, but this study also highlights the potential of the gut-on-chip platform as a physiological model, based on human biopsies, to gain mechanistic insights into gut barrier function.” Prof. Nathalie Juge, QIB Group leader
New therapies for gastrointestinal (GI) diseases are urgently required and could have significant social and economic impact. Globally more than 40% of people, of all ages, suffer with acute and chronic GI disorders that affect their quality of life and health care use. Low levels of Bifidobacterium species have been linked to the most common GI disorders including: Irritable Bowel Syndrome (IBS), which afflicts ~11% of the world population; antibiotic-associated diarrhoea; Inflammatory Bowel Disease (IBD); and disorders associated with obesity and allergies[vii]. Impaired (‘leaky’) gut barrier function is a critical factor in predisposition to coeliac disease and Crohn’s disease. Together, these diseases account for frequent hospital visits globally, cause significant discomfort to individuals, and represent a sizeable sector of the pharmaceutical / beneficial foods market. As an example, treating patients with GI disorders had a reported economic cost approaching £250 million to the NHS in 2018-19[viii] (Category FD and FE on the NHS national schedule only). The GI therapeutics market was estimated at £37 billion in 2016[ix] and is expected to see a compound annual growth rate of nearly 6.5% between 2018 and 2026[x].
Glycom commercial products already target IBS and digestive health and these new data will inform and support the continued development of their products. Glycom released two products with HMOs for adult supplementation in 2018: Holigos® IBS Restore, a medical food product for IBS sufferers, and Holigos® Maintain, a dietary supplement for general digestive health.
“The continued development of our IBS and digestive health products will be informed by the QIB study. Their research helped us understand the mechanisms behind HMO health benefits, not only in infants, but also in adults.” James Young, VP Innovation and Business Development of DSM.
A collaborative manuscript detailing the research findings[xi] is having good academic impact; the full text has been viewed by almost 1,500 people as of January 2021. It is performing well on ResearchGate with 43 reads, three recommendations and a research score of 2.2. There have also been news articles published in ‘Nutrition insight’, on the Quadram news feed, and social media platforms such as Facebook and Twitter, which have generated comments and discussion from members of the public.
This collaboration will enable the manufacturers to further develop and refine HMO products that support a healthy human gut microbiome. It has improved our understanding of the mechanisms by which HMOs function as prebiotics and has supported the translation of infant-based products to adult ones.
To date, only a limited number of studies have investigated the effects of HMOs on intestinal barrier function. There is still a lot that we don’t understand and the next steps in this research will most likely involve more extensive, long term studies such as human trials.
At QIB, this research was done in the Juge Group as part of the BBSRC Institute Strategic Programme (ISP) Grant ‘Gut Microbes and Health’ BB/R012490/1, and its constituent project BBS/E/F/000PR10356 (Theme 3), Modulation of the gut microbes to promote health throughout life. George Savva was supported by the BBSRC Core Capability Grant BB/CCG1860/1. Tanja Šuligoj was supported by Glycom A/S and BBSRC BB/R012490/1.
Update March 2022
Prof. Juge’s team have recently been part of a research collaboration which has expanded the possible impact reach and significance of this work through investigating the potential of HMOs to improve living conditions for adults suffering from Irritable Bowel Syndrome (IBS). Biological samples were collected from 58 IBS patients before and after a four-week course of commercially available HMO supplements. They found that the addition of fermented HMOs shaped the gut microbiota in IBS patients, and specifically increased faecal and mucosal B. adolescentis and mucosal B. longum. The study provides additional support for the potential use of HMOs as a strategy to support gut barrier function in adults, although further studies are needed to decipher the underpinning mechanisms and evaluate possible beneficial effects on IBS symptoms. The new manuscript ‘The Effects of Human Milk Oligosaccharides on Gut Microbiota, Metabolite Profiles and Host Mucosal Response in Patients with Irritable Bowel Syndrome’ which details the research findings can be seen here https://doi.org/10.3390/nu13113836.
[i] ProDigest, a spin-out company from the University of Ghent in Belgium; Glycom, a Danish biotechnology company (part of DSM since April 2020); and Emulate Inc., an organ-on-chip biotechnology developer based in Boston, USA.
[ii] Bode L. (2012). Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology, 22(9), 1147–1162. https://doi.org/10.1093/glycob/cws074.
[iii] Bering S. B. (2018). Human milk oligosaccharides to prevent gut dysfunction and necrotizing enterocolitis in preterm neonates. Nutrients 10: 1461. https://doi.org/10.3390/nu10101461
[iv] Thomson P., Medina D.A., Garrido D. (2018) Human milk oligosaccharides and infant gut bifidobacteria: Molecular strategies for their utilization. Food Microbiol. 75: 37–46. https://doi.org/10.1016/j.fm.2017.09.001.
[v] Morozov, V., Hansman, G., Hanisch, F. G., Schroten, H., & Kunz, C. (2018). Human milk oligosaccharides as promising antivirals. Mol. Nut. & Food Res. 62: e1700679. https://doi.org/10.1002/mnfr.201700679
[vi] Vandenplas, Y., Berger, B., Carnielli, V. P., Ksiazyk, J., Lagström, H., Sanchez Luna, M., Migacheva, N., Mosselmans, J. M., Picaud, J. C., Possner, M., Singhal, A., & Wabitsch, M. (2018). Human milk oligosaccharides: 2′-fucosyllactose (2′-FL) and lacto-N-neotetraose (LNnT) in infant formula. Nutrients 10: 1161. https://doi.org/10.3390/nu10091161.
[vii] Rodiño-Janeiro, B. K., Vicario, M., Alonso-Cotoner, C., Pascua-García, R., & Santos, J. (2018). A review of microbiota and Irritable Bowel Syndrome: Future in therapies. Adv. Ther. 35: 289–310. https://doi.org/10.1007/s12325-018-0673-5.
[viii] NHS national cost collection. https://www.england.nhs.uk/national-cost-collection/#ncc1819
[ix] Gastrointestinal market analysis by type. https://www.grandviewresearch.com/industry-analysis/gastrointestinal-therapeutics-market#:~:text=The%20global%20gastrointestinal%20therapeutics%20market%20size%20was%20estimated%20at%20USD,USD%2035.6%20billion%20in%202020.&text=The%20global%20gastrointestinal%20therapeutics%20market%20is%20expected%20to%20grow%20at,USD%2047.2%20billion%20by%202027.
[x] Gastrointestinal Therapeutics | Growth, Trends, and Forecasts (2020 – 2025) (mordorintelligence.com)
[xi] Šuligoj, T., Vigsnæs, L. K., Abbeele, P., Apostolou, A., Karalis, K., Savva, G. M., McConnell, B., & Juge, N. (2020). Effects of human milk oligosaccharides on the adult gut microbiota and barrier function. Nutrients 12: 2808. https://doi.org/10.3390/nu12092808