The influence of glycans on the human gut microbiota is a central topic in contemporary glycoscience. These type of carbohydrates in this environment are not only essential for microbial colonization but also serve important regulatory functions that contribute to immune protection. In this article, we will explore the fundamental roles of glycans, present intriguing case studies, and highlight two practical applications.
Our discussion is informed by the outstanding work of the research team behind a comprehensive study published in May of this year. This study involves scientists from the University of Birmingham and the University of Porto and offers a broad perspective on the current state of the field, addressing key aspects of glycobiology and referencing a wide array of relevant research that has shaped our understanding of the microbiota-glycan connection.
The Glycan Landscape within the Human Microbiota
The collection of lipids and proteins decorated with diverse glycans on the surface of the gut mucosa is called glycocalyx and serves as a major interface between the intestinal lining and microorganisms, as well as with the host’s immune system. Below, we highlight the key structures within the glycocalyx to illustrate how these carbphydrates shape the gut environment, drive microbial interactions, and influence immune system regulation.
Illustration of a healthy colonic human glycocalyx, from The role of glycans in health and disease: Regulators of the interaction between gut microbiota and host immune system. In Seminars in Immunology (Vol. 73, p. 101891). Academic Press.
- Glycoproteins and Glycolipids: The epithelial cell membrane expresses highly diverse glycoproteins and glycolipids, which are decorated with N-linked and O-linked glycans. These carbohydrates, when recognized by immune cells, can dictate the nature of the immune response—either pro-inflammatory or anti-inflammatory.
- Glycan-Binding Proteins (GBPs): Immune cells produce GBPs, such as galectins, siglecs, and C-type lectins, which «read» the glycan code expressed by both host cells and microbes.
- Glycosaminoglycans (GAGs): Chondroitin sulfate, heparan sulfate, and hyaluronan are also important glycans of the glycocalyx. They serve as nutrient sources for gut microbes, such as Bacteroides thetaiotaomicron, highlighting their role in microbial metabolism and colonic health.
- Mucins (MUC1–22): Mucins form the protective mucus layer overlaying the glycocalyx. As an example, it has been shown that MUC1 functions as a decoy to distract and confuse Helicobacter pylori during infection.
- Carbohydrate-Active Enzymes (CAZymes): Gut microbes produce CAZymes like glycoside hydrolases (enzymes depicted as «scissors») to degrade complex glycans into short-chain fatty acids (SCFAs). SCFAs act as essential nutrients for colonocytes and help maintain gut homeostasis.
The Influence of Glycans: Intriguing Case Studies
Several studies have identified the significant role of certain glycans within our microbiota in regulating immune system responses and determining which microbes colonize our gut, ultimately influencing our health and susceptibility to various diseases.
A noteworthy example of this interaction can be seen in research on infants who are either breastfed or formula-fed. Studies reveal that human milk oligosaccharides (HMOs) play a crucial role in fostering the growth of Bifidobacterium longum subsp. infantis, a beneficial bacterium that thrives predominantly in the gut of breastfed infants.
In a more surprising twist, some pathogens have evolved a strategy known as glycan mimicry, where they display glycans on their surface that immune cells fail to recognize as harmful, allowing them to evade detection. A striking example is Neisseria gonorrhoeae, the bacteria responsible for gonorrhea, which incorporates sialic acid from the host onto its lipooligosaccharides, effectively camouflaging itself from the immune system.
Targeting the Glyco-Microenvironment: Two Practical Applications
Several approaches are being explored to target the intestinal glyco-microenvironment, including the enhancement of the mucosal glycome through glycan supplementation or by modifying the activity of CAZymes. Two recent studies have made significant strides in translating these concepts into practical applications.
One study, published in Nature, involves researchers from Washington University School of Medicine and the International Centre for Diarrhoeal Disease Research in Dhaka, Bangladesh. The team identified key bioactive glycan structures, contributing to the development of their MDCF-2 project. This therapeutic food is designed to help restore the gut microbiota of malnourished children, offering hope for improving their gastrointestinal health.
Another study, published in the Proceedings of the National Academy of Sciences, focuses on how gut microbes process plant-derived N-glycans. By identifying specific enzymes that can modify and analyze these N-glycan structures, the research aims to apply these findings to medical and industrial fields. One of the possible applications is to reduce the risk of allergic reactions to foods and medications by leveraging this knowledge.
Conclusions
The intricate interactions between glycans and gut microbes are crucial for understanding and maintaining gut health, as well as for treating immune diseases and gastrointestinal disorders. At Asparia Glycomics, we specialize in supporting cutting-edge research in this field. Whether you’re developing HMOs for synthetic milk or unraveling the composition and structure of bioactive oligosaccharides and polysaccharides, our expertise in glycan synthesis and analysis is here to guide you. We have a proven track record of assisting projects in gut microbiota research and development.
As advances in glycomics continue to unfold, they are unlocking transformative medical applications, from restoring microbiomes in malnourished children to mitigating allergic reactions through glycan engineering. These special carbohydrates undoubtedly hold the key to groundbreaking solutions in human health, and we at Asparia Glycomics are ready to partner with you on this exciting journey. Reach out to explore how we can support your innovation.
References
- Crouch, L. I., Rodrigues, C. S., Bakshani, C. R., Tavares-Gomes, L., Gaifem, J., & Pinho, S. S. (2024, May). The role of glycans in health and disease: Regulators of the interaction between gut microbiota and host immune system. In Seminars in immunology(Vol. 73, p. 101891). Academic Press.
- Crouch, L. I., Urbanowicz, P. A., Baslé, A., Cai, Z. P., Liu, L., Voglmeir, J., … & Bolam, D. N. (2022). Plant N-glycan breakdown by human gut Bacteroides. Proceedings of the National Academy of Sciences, 119(39), e2208168119.
- Hibberd, M. C., Webber, D. M., Rodionov, D. A., Henrissat, S., Chen, R. Y., Zhou, C., … & Gordon, J. I. (2024). Bioactive glycans in a microbiome-directed food for children with malnutrition. Nature, 625(7993), 157-165.
- Wang, Y., Ze, X., Rui, B., Li, X., Zeng, N., Yuan, J., … & Li, M. (2021). Studies and application of sialylated milk components on regulating neonatal gut microbiota and health. Frontiers in Nutrition, 8, 766606.