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Human milk oligosaccharides are a type of prebiotic, a substrate that can be used by a bacterium as a source of food for growth. They were first observed in human milk in breast fed babies. HMOs are a group of carbohydrates or complex sugars that are a valuable energy commodity.
Since they were first discovered, more evidence is emerging to show their importance in the establishment of important probiotics (good bacteria) within the human gastrointestinal tract. Alongside this, further evidence is mounting to demonstrate they have an important role in deterring pathogens and aiding immune cell responses. From infancy, HMOs provide sialic acid, thought to be necessary for the development of the brain and cognition[i].
In this article we are going to look at the association between HMOs and Akkermansia muciniphila.The article will focus on the findings from a research study by Kostopoulos et al, (2020) to understand how this well-studied anaerobic bacterium interacts with human milk oligosaccharides (HMO’s).
Belonging to the phylum Verrucomicrobia, A. muciniphila is a gram-negative anaerobe and is the only member of this phylum that’s found in human faecal samples. Its colonies are found in the mucus layer of the human gastrointestinal (GI) tract where it plays a part in the intestinal strength. A. muciniphila accounts for approximately 4% of your total microbiota[ii].
Akkermansia muciniphila has been linked to a healthy mucosal layer, with a higher abundance detected in leaner people. Individuals with chronic metabolic conditions, such as type 2 diabetes and obesity have a lower abundance of A. muciniphila. Interestingly, the same has been found in people with appendicitis and inflammatory bowel disease[iii].
As well as its presence in the adult human gut, Akkermansia has been detected in the infant gut from as early as one month old - this abundance increases with age. It has been found in the breast tissue of lactating mothers as well as human milk, but some studies like Azad et al(2013) & Bergstrom et al (2014) have suggested there is a greater abundance found in infants that have been formula fed[iv][v]. However, a later study by Bäckhed et al (2015) found an increase in A. muciniphila in the infant gut from 4 months to a year old, regardless of the way they were delivered or the method of feeding[vi].
Akkermansia muciniphila is very good at using mucin (a glycoprotein) as an energy, nitrogen and carbon source, and converting it into the short chain fatty acids (SCFAs)[vii], acetate and propionate, both of which are associated with milk to fat synthesis and performance.
The lining of your intestines is made up of epithelial cells that are covered in a layer of mucus – mucus also lines your lungs and is found in bodily fluids like saliva and snot. The mucus helps to strengthen the gut lining whose main function is to allow useful substances to pass into the body but prevent toxins, pathogens, and undigested food particles entering and potentially making you unwell[viii].
The mucus itself is comprised of proteins called mucins which help to form the gel-like substance. Bacteria like Akkermansia muciniphila use the mucins in the gut lining for energy, hence its name – Akkermansia from the microbial ecologist Anton DL Akkermans, and muciniphila from the Latin for to love mucin[ix].
During the first few months of life, a mother’s breast milk is the only source of nutrients and dietary glycans. Dietary glycans are food ingredients which change the growth and activity of your gut microbes (like fibrous solid foods as you get older). Some of them have health benefits and are not digested by you but are utilised by your gut bacteria. The glycans in human milk are called human milk oligosaccharides (HMOs) and have been proven to play a key role in the composition of the infant gut microbiota.
The structure of some HMOs is similar to mucin glycans which may help to explain why some mucin-loving bacteria are capable of using both HMOs and mucins to grow, survive, and thrive.
In the gut, A. muciniphila has a wide selection of specific enzymes it can draw upon to break down the mucins in the gut lining, including sulfatases and glycoside hydrolases (GH). Kostopoulos et al (2020) theorised that the presence of A muciniphila in the human gut from an early age is because the bacterium is able to breakdown the HMOs found in human breast milk using the same tools it uses to digest mucin glycans.
The results of the study by Kostopoulos et al (2020) can be split into four key findings which were, A. muciniphila:
The study found that Akkermansia can grow on human milk and that it does so by using the HMOs that are naturally present. When growing on the human milk, the bacterium used many HMO structures, including:
These two are of particular interest because they alone can promote the growth of A. muciniphila and the production of lactose which is then further broken down into glucose and galactose. The bacteria were able to use the sugars to produce the SCFAs, acetate, propionate, and succinate.
The next part of the study was to identify the enzymes that may be responsible for breaking down human milk and its constituents by Akkermansia. The results showed that this bacterium alone possesses 58 proteins that encode for glycoside hydrolases (GHs).
GHs are important enzymes because they are responsible for separating the glycosidic bonds in carbohydrates, leading to the formation of sugar. In the study, it was shown that Akkermansia uses these enzymes to degrade HMOs and metabolise some of the sugars that are released during this process.
Understanding the character or nature of the A. muciniphila enzymes, or how they work, was determined via five of its glycan degrading enzymes, identified by their proteomics, (proteins).
These enzymes work as they hydrolyse (cause a chemical reaction with water) the HMOs outer layers freeing up sugars which are then imported into the cell. This process also sets free other simpler metabolites and structures that will benefit other good bacteria.
The study also compared the difference in the degradation of HMOs and mucin. This was to see how A. muciniphila adapted to different environmental conditions.
Overall, this study shows that Akkermansia muciniphila can grow on human milk and can use its glycan-degrading enzymes to break down its constituent HMOs into two types of sugars, monosaccharides and disaccharides. A. muciniphila was shown to degrade fucosylated and sialylated HMOs. The study showed that Akkermansia used the fucose found in human milk and the HMO, 2’-FL, as energy sources, resulting in the production of 1,2-propanediol.
The synthesis of 1,2-propanediol is important because it can help to feed other microbes, a process called cross-feeding. A study conducted by Amin et al (2013) demonstrated that Lactobacillus reuteri can metabolise 1,2-propanediol, a feat which may be beneficial for the production of industrial chemicals[x].
Another study by Engels et al (2016) also demonstrated that another important gut microbe, Eubacterium hallii can use 1,2-propanediol to produce propionate[xi]. An important bi-product of bacterial fermentation, propionate is an example of a short-chain fatty acid that is associated with many health benefits within the gut and beyond[xii]
Through its cross-feeding capabilities, A. muciniphila may contribute to the growth and abundance of the infant gut as well as the development of the mucosal layer in the gut lining. This activity is also seen in in A. muciniphila’s sialidase activity, where specific enzymes can split the HMO, 3’-sialyllactose (3’-SL) into lactose and neuraminic acid. Sialic acid was also produced when 3’-SL was broken down, which Akkermansia could not use because it lacks the ability to utilise it. However, because both human milk and mucin are packed with sialyl groups, A. muciniphila’s enzymatic activity means sialic acid is released as it tries to reach other sugars it can use. The sialic acid isn’t wasted because other microorganisms can use it for growth. The sialic acid also plays an important role in neurodevelopment and cognitive functions.
Bifidobacterium breve an important probiotic bacterium, for example, uses sialic acid to grow, contributing to a diverse infant gut microbiome. A study conducted in 2014 found that B. breve cross feeds on sialic acid when 3’-SL is metabolised by another health-promoting gut bacteria called Bifidobacterium bifidum PRL2010[xiii].
As well as showing how A. muciniphila can help to diversify the gut microbiome through it’s cross-feeding mechanisms, it also shows that the bacterium can use HMOs that are present in either breast milk or fortified formula milk to survive in the infant gut microbiome before they reach their intended ‘home’, the intestinal mucosal layer. As such, A muciniphila, may be key to the early development of a healthy, diverse microbiota and the development of the immune system.
Having first being thought of as a source of food for bacterium, HMOs interaction with A. muciniphila are now being shown to be a major component in the development and continued protection of the infant through to adulthood.
The harmony that takes place between what is essentially nourishment for both humans and A. muciniphila, transcends from being just a form of nourishment to a safeguard for your immune system. A gift, almost a guarantee, that if you continue to thrive so will they.
Their interaction also sets off numerous other processes and reactions that aid in keeping us protected and healthy. Evidence continues to mount that the human gastrointestinal tract is central to the maintenance of health, mostly thanks to the ‘good bacteria’ that resides within it.
Written by: Leanne Edermaniger, M.Sc. Leanne is a professional science writer who specializes in human health and enjoys writing about all things related to the gut microbiome.
References:
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[vi] Bäckhed, F. et al. Dynamics and stabilization of the human gut microbiome during the first year of life. Cell Host Microbe 17, 690–703. https://doi.org/10.1016/j.chom.2015.04.004 (2015)
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