In the previous article, we looked at the simplest forms of monosaccharides that cannot be further hydrolyzed and their stereoisomers, and then we looked in detail at three representative disaccharides, which are formed by two units of various monosaccharides bound together by glycosidic bonds. Anything two or more can be considered a polysaccharide, but polysaccharides can also be formed by linking tens to thousands of monosaccharides, or as many as 10,000. Therefore, polysaccharides formed by gathering approximately 3 to 10 monosaccharides somewhere between disaccharides and polysaccharides are called oligosaccharides or oligosaccharides. ‘Oligo’ is said to mean ‘few’ or ‘little’. Disaccharides are also included in oligosaccharides, but since we have already covered disaccharides separately, let us look at other oligosaccharides in this article.
Oligosaccharides can be broadly classified into two types: oligosaccharides that occur in nature and are consumed by the human body, and oligosaccharides that are synthesized naturally within the human body.
1. Dietary oligosaccharides
Oligosaccharides primarily found in plants and dairy products are consumed through a variety of foods. Among them, fructo-oligosaccharides (FOS), which are composed mainly of fructose units, are abundant in vegetables like onions, garlic, and bananas. Meanwhile, galacto-oligosaccharides (GOS), primarily composed of galactose, are found in breast milk and dairy products. Malto-oligosaccharides (MOS), made up of glucose units, are generated during the breakdown of starch and are essentially longer versions of maltose, which is itself made of two glucose units. Inulin, which is a longer-chain version of FOS with more fructose units, is found in plants such as chicory and asparagus.
The primary function of fructooligosaccharides (FOS), galactooligosaccharides (GOS), inulin, and maltooligosaccharides (MOS) is to act as food for gut microbiota—so-called prebiotics—through a process known as fermentation. To understand this better, we must first examine fermentation as it occurs in the colon.
The human body breaks down carbohydrates via glycolysis to produce usable energy. Once sugars are broken down, the resulting metabolites enter the mitochondrial electron transport chain to generate ATP, a process that requires oxygen. This is because oxygen serves as the final electron acceptor in ATP production. However, in environments where oxygen is absent, other organic compounds, such as pyruvic acid, must act as electron acceptors in place of oxygen. The colon is such an anaerobic environment, and over 90% of the microorganisms living there are anaerobic microbes, meaning they thrive only in the absence of oxygen. These microbes obtain energy by breaking down dietary fibers and oligosaccharides that escape digestion and absorption in the small intestine and reach the colon. Through this process, they produce short-chain fatty acids (SCFAs), alcohols, and gases (such as H₂, CO₂, and CH₄) as metabolic by-products.
This biochemical process of energy production in the anaerobic colon is what we call fermentation. In this sense, acids, alcohols, and gases are the by-products of fermentation. Alcohol is produced only in trace amounts, while the gases may lead to flatulence, burping, or abdominal bloating. However, what we should really pay attention to are the short-chain fatty acids (SCFAs) created during fermentation by these microbes.
When fermentation by gut microbiota increases levels of SCFAs such as acetate, propionate, and butyrate, the pH of the colon is maintained in a slightly acidic range (pH 5–6). Within the gut microbiome, beneficial and harmful bacteria coexist, and the balance between them is directly linked to human health. An acidic environment suppresses the growth of harmful bacteria like E. coli, while promoting the proliferation of beneficial bacteria like Bifidobacteria and Lactobacilli, which thrive under such conditions. This microbial "turf war" for limited space ends up favoring the beneficial bacteria, thereby shifting the overall microbial balance in a positive direction.
Butyrate serves as a major energy source for colonic epithelial cells and promotes the secretion of mucus proteins like mucin, which help protect and regenerate the gut lining and strengthen the intestinal barrier—a critical defense against conditions such as leaky gut syndrome. Propionate, on the other hand, is a key metabolic intermediate involved in gluconeogenesis (the generation of glucose in the liver). It helps to regulate blood sugar levels and enhance insulin sensitivity, playing an important role in preventing diabetes. SCFAs also help boost immune function.
The encounter between short-chain fatty acids and T cells (Treg)
To better understand how SCFAs enhance immune function, let’s first look at T cells, which play a crucial role in our immune system.
T cells are highly specialized immune cells that undergo a rigorous selection process in the thymus, and only a small number of these "elite" cells survive. However, even after passing this tough training, they are not yet fully functional fighters. Since they have not yet encountered any antigens, they are still functionally immature, existing in a resting state as CD4⁺ or CD8⁺ T cells in secondary lymphoid organs such as lymph nodes and the spleen. These immature cells are referred to as naïve T cells.
These cells remain in the lymph nodes in a resting state until they encounter an antigen, which is captured and presented by antigen-presenting cells (APCs) such as macrophages and dendritic cells. Upon recognizing the antigen, they become activated and respond to various cytokines in the surrounding environment. Depending on the signals from these cytokines, they differentiate into various subsets of T cells, including Th1, Th2, Th17, and Treg. Each of these differentiated T cells secretes characteristic cytokines and carries out specialized immune responses.
Among them, Treg cells serve as the “brakes” of the immune system, playing a critical role in suppressing excessive immune responses and maintaining immune balance. They are essential for controlling autoimmune diseases and inflammatory conditions.
What’s fascinating is that It has been discovered that beneficial gut microbes play a role in promoting the differentiation of regulatory T cells (Tregs). A transcription factor called FOXP3 (Forkhead box P3) is a key regulator of Treg development and function. Butyrate acts as a histone deacetylase (HDAC) inhibitor for this gene, directly increasing the expression of FOXP3 and thereby promoting Treg differentiation.
In addition, short-chain fatty acids (SCFAs) produced by gut microbes stimulate intestinal epithelial cells and antigen-presenting cells to increase the secretion of the cytokine TGF-β (transforming growth factor β). The elevated TGF-β, in turn, enhances the expression of the FOXP3 gene in immature CD4⁺ T cells, inducing their differentiation into Tregs.
Ultimately, SCFAs play a dual role—directly upregulating FOXP3 expression and indirectly increasing it through the induction of TGF-β. The Tregs generated through this process produce the potent anti-inflammatory cytokine IL-10, suppress excessive immune responses, and help maintain immune homeostasis.
An increase in Treg cells can positively influence various immune-related diseases. They can help prevent inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis, alleviate hypersensitive immune responses like allergies and asthma, and reduce the risk of autoimmune diseases such as Type 1 diabetes and rheumatoid arthritis. Although research on the relationship between gut microbiota and the immune system is still ongoing, I strongly believe that maintaining a healthy gut environment is clearly essential for preserving immune balance. As someone who has long been a passionate enthusiast of the gut microbiome, I plan to dive deeper into this topic in a future, more structured article.
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2. Oligosaccharides synthesized in the human body
While oligosaccharides found in nature are primarily discovered in plants, those synthesized in the human body exist not independently but rather bound to other biomolecules such as proteins or lipids. If oligosaccharides are defined as molecules in which roughly 2 to 10 monosaccharides are linked via glycosidic bonds, then it would be helpful to also understand the concept of a glycan. In glycobiology, “glycan” is a broad term used to refer to chains of multiple sugars, including oligosaccharides and polysaccharides, and even carbohydrates in general, often interchangeably. Since both oligosaccharides and glycans refer to sugar chains connected by glycosidic bonds, their definitions tend to overlap. For convenience and clarity, we can draw a conceptual boundary by considering oligosaccharides and polysaccharides as subcategories under the broader term glycan.
When glycans are attached to proteins or lipids, they form what are known as glycoconjugates. Among glycoconjugates, glycoproteins and glycolipids are those in which glycans are bound to proteins and lipids, respectively. When glycans make up a significantly larger portion of a glycoprotein’s structure, it is referred to specifically as a proteoglycan.
The process by which sugar chains made of various monosaccharides are enzymatically attached to specific amino acid residues of proteins as they pass through the rough endoplasmic reticulum (ER) and Golgi apparatus after synthesis is known as glycosylation. The short sugar chains added during this step are generally referred to as oligosaccharides or glycans. With that terminology clarified, let us now explore the significance and meaning of attaching oligosaccharides during the protein synthesis process within cells.
First, I’d like to point out that the number of genes that serve as the blueprint for protein synthesis is surprisingly small. Every human cell, with the exception of reproductive cells, contains a complete genome—a full set of genetic information—within its nucleus. As revealed by the Human Genome Project in the early 2000s, the number of genes in the human body capable of encoding proteins is estimated to be only about 20,000 to 25,000. This number was shockingly small and caught everyone by surprise. To make matters even more surprising, the fruit fly has about 15,000 genes of its own.
Fortunately, despite this limited number of genes, the human body has several mechanisms that allow it to generate a vastly greater and more diverse range of proteins. One such mechanism is alternative splicing, through which a single gene can be spliced in different ways to produce multiple distinct proteins. Additionally, post-translational modifications (PTMs) allow proteins to undergo various chemical changes after translation, altering their function and increasing diversity. Proteins can also combine to form protein complexes, giving rise to new functional units with unique roles.
Thanks to these sophisticated strategies, the human body is capable of producing more than a million different proteins—far exceeding the number of genes—allowing it to support the intricate processes of life. Among these strategies, protein glycosylation stands out as one of the most representative and complex forms of post-translational modification.
Alternative gene splicing (alternative RNA splicing)
Protein synthesis process and oligosaccharides
When a cell receives an external signal or has an internal need to synthesize a protein, the process begins with transcribing the information of a specific gene from DNA into messenger RNA (mRNA) within the nucleus. The mRNA then exits the nucleus and enters the cytoplasm, where it is translated by ribosomes, which interpret the genetic code and synthesize proteins accordingly.
Ribosomes are the cell’s protein factories. They either float freely in the cytoplasm or attach themselves to the surface of the endoplasmic reticulum (ER). The ER covered in ribosomes is called the rough endoplasmic reticulum (rough ER), due to its dotted appearance. In contrast, the smooth ER lacks ribosomes on its surface.
A single cell can have thousands to millions of ribosomes, and cells with high metabolic activity tend to have even more. Inside the ribosome, transfer RNA (tRNA) brings amino acids—the building blocks of proteins—and links them together to form a polypeptide chain, which is the basic structure of a protein.
As the newly synthesized polypeptide passes through the ER, it undergoes folding and initial processing to become functionally stable. During this step, N-glycosylation occurs—a process in which oligosaccharides are added to the protein. This modification helps stabilize the protein, regulate its function, and acts as a sort of molecular tag indicating the protein’s final destination.
After this, the protein is transported to the Golgi apparatus, where it may undergo further processing and refinement. Finally, the mature protein is directed to its designated location. It may be integrated into the cell membrane as a membrane protein (such as a channel or transporter), secreted outside the cell as a hormone, neurotransmitter, or antibody, or function within cellular organelles like lysosomes..
Some glycoproteins are attached to the cell membrane, while others are secreted outside the cell or into the extracellular matrix. To name a few familiar examples: cell membrane receptors, which serve as gateways for receiving signals, and antigen proteins that determine blood types, are membrane-bound. On the other hand, glycoproteins like antibodies and hormones are secreted and exist in the bloodstream or extracellular matrix.
Glycosylation of proteins
Let’s take a closer look at how oligosaccharides (or glycans) are attached to proteins. There are two major types of glycosylation: N-linked glycosylation and O-linked glycosylation. The terms “N” and “O” simply refer to the atom at the attachment site—nitrogen (N) or oxygen (O). Among amino acids, only three are capable of forming bonds with sugars: asparagine (Asn), serine (Ser), and threonine (Thr). When a sugar is attached to the nitrogen atom of asparagine, it is called N-linked glycosylation. When a sugar is attached to the oxygen atom of the hydroxyl group in serine or threonine, it is referred to as O-linked glycosylation.
It’s also helpful to remember that oligosaccharides attached via N-linked glycosylation are called N-glycans, and those attached via O-linked glycosylation are called O-glycans. With this in mind, it naturally raises the question: whether we call them oligosaccharides or glycans, what kinds of sugar chains are involved in the extension and modification of proteins and lipids?
Modified or modified sugars
Before attaching oligosaccharides to proteins in the ER or Golgi apparatus, the oligosaccharides to be attached are first combined. In this process, in addition to the numerous monosaccharides we have dealt with so far, new types of monosaccharides appear. In fact, I think it is very surprising that so many monosaccharides, disaccharides, and some oligosaccharides are composed of only three elements: carbon, hydrogen, and oxygen. Now, more elements are added to it. Sugars created by modifying and transforming simple monosaccharides such as glucose or fructose, which we all know well, through a slight chemical process are called modified sugars or derivative sugars. Types of these modified sugars include amino sugars with one internal OH group replaced by an amino group (NH2), sugar alcohols with an OH group attached instead of an aldehyde group or ketone group, and deoxy sugars with the oxygen removed from the OH group. There are acid sugars with a carboxyl group (COOH) and sulfate sugars with a sulfate group (-SO₃⁻).
These modified sugars not only appear in the formation of oligosaccharides, but also participate in the formation of polysaccharides, making cell walls and exoskeletons, and performing important functions in immune regulation and signal transmission. In fact, I confess that when I decided to properly learn about carbohydrates, one of the biggest topics of the 21st century, and came across these modified sugars, my brain slowly lost its focus, my eyes began to lose focus, I began to wander, and I often lost interest. The name was so long and complicated that it was, in short, the perfect point to lose one's mind. However, since modified sugars always appear from the first starting point in the formation of glycoconjugates, it is essential to understand them, so I would like to take this time to organize them properly. I always felt this way, but the longer the name, the more explanations there are, so I decided to let go of my preconceived notions.
In fact, modified sugars are quite familiar to us. Glucosamine, which is said to be effective in treating arthritis by regenerating cartilage; ‘hyaluronic acid,’ which is often featured in cosmetics advertisements because it is excellent at retaining moisture and moisturizing the skin; and alternative sweeteners such as erythritol, which is often used in diets because it has no calories. All of these contain modified sugars. Beyond the sweet taste associated with the name ‘sugar,’ it can be said that its identity as ‘sugar’ is abandoned and transformed in order to perform much more complex and diverse biological functions in the living body. It is these modified sugars that determine our blood type. Modified sugars are also directly related to the point where the virus invades human host cells.
In the following article, we will deal with modified sugars created by modifying monosaccharides in detail, focusing mainly on some representative monosaccharides, including glucose.
[Reference]
doi: 10.1038/nchembio.2576
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