A new study shows human milk oligosaccharides can inhibit and kill Streptococcus pneumoniae at physiological concentrations, highlighting their potential role in protecting infant health.
Content outline
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Key finding #1: HMOs inhibit pneumococcal growth in a dose-dependent manner
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Key finding #2: HMOs kill pneumococcal bacteria at physiologically relevant concentrations
Introduction
Respiratory and invasive bacterial infections are a significant cause of illness and death in infants across the world. One of the most concerning pathogens is Streptococcus pneumoniae, an opportunistic bacterium responsible for conditions such as community-acquired pneumonia, meningitis, and blood infections. Many people are carriers of S. pneumoniae; around 40 to 50% of healthy children and 20 to 30% of healthy adults carry the bacteria [1].
Yet, S. pneumoniae is the leading cause of severe infections in children under the age of 2 [2]. According to the World Health Organization, S pneumoniae is the most common cause of bacterial pneumonia in children, and the most significant cause of infection-related death in children globally [3]. Despite advances in vaccination, pneumococcal disease remains a public health challenge, as the bacteria can diversify and adapt.
Human milk oligosaccharides (HMOs), however, are increasingly recognised for their role in bolstering infant immunity. Although they are best known for supporting the growth and activity of beneficial gut microbes, growing research has also demonstrated that they have direct antimicrobial effects against a range of pathogens[4], including Clostridioides difficile.
Here, we explore the results of a new study published in the International Journal of Molecular Science, which suggests that HMOs can inhibit the growth and kill multiple S. pneumoniae strains in a concentration-dependent manner. Therefore, suggesting that HMOs could prevent pneumococcal infections in vulnerable groups, including infants.
Why new approaches to pneumococcal infection are needed
Pneumococcal conjugate vaccines (PCVs) have reduced rates of severe pneumococcal disease, particularly amongst children. One study in China found that PCVS had reduced community-acquired pneumonia by almost 70% [5]. However, there are more than 100 pneumococcal serotypes – distinct types of microbe – and vaccines do not offer universal protection against all of them. Equally, nonencapsulated S. pneumoniae has become an overlooked risk factor for pneumococcal infections, which are not yet targeted by polysaccharide-based vaccines [6].
As well as prevention, treatment for pneumococcal infection is also under scrutiny. Of course, antibiotics are an essential part of treating these infections, but their widespread use also brings drawbacks and limitations. Antibiotic exposure can disrupt the developing gut microbiome, with consequences for immunity and for antimicrobial resistance.
For these reasons, researchers are interested in complementary strategies which may support host defences without relying on pathogen-specific targeting or broad-spectrum antibiotics. HMOs are part of this interest because they occur naturally in human breast milk and have evolved alongside the infant's immune system.
The latest research
Makerewicz and colleagues investigated whether HMOs can directly affect the growth and survival of S. pneumoniae across different serotypes. Rather than focusing on one type, the researchers examined four common pneumococcal isolates, including encapsulated and nonencapsulated variants.
In earlier research, HMOs have been shown to prevent pathogens from binding to their receptors and thereby prevent their growth and infection by binding to pathogens via carbohydrate-carbohydrate interactions [7]. Because HMOs have been shown to inhibit the growth of pathogens, such as Staphylococcus aureus [8] and group B Streptococcus [9], Makerewicz et al aimed to investigate the antipneumococcal activity of HMOs and the potential impact this could have on infant populations. The most common HMOs used in this study were 2′-FL, 3′-FL, LDFT, LNT, LNnT, LNFP I–III, and LNDFH I/II, followed by 3′-SL and 6′-SL.
Key finding #1: HMOs inhibit pneumococcal growth in a dose-dependent manner
Across the four tested serotypes, HMOs inhibited pneumococcal growth in a clear dose-dependent manner. The results are shown in the table below:
|
Serotype |
Isolate |
Growth inhibition concentration |
|
Encapsulated |
STB6 |
1 mg/mL - 2 mg/mL |
|
ST3 |
Above 2 mg/mL |
|
|
ST14 |
Above 2.5 mg/mL |
|
|
ST19A |
2 mg/mL and above 2.5 mg/mL |
|
|
Nonencapsulated |
4 isolates |
1 mg/mL |
|
3 isolates |
2 mg/mL |
These results indicate that HMOs could inhibit pneumococcal growth at relatively low concentrations. Nonencapsulated strains were particularly sensitive, showing growth inhibition at concentrations as low as 1 mg/mL in 4 isolates. This is interesting because the pneumococcal capsule is a major virulence factor that helps the bacteria evade detection by the immune system [10]. Because HMOs inhibited both encapsulated and nonencapsulated strains, the findings suggest a broad antimicrobial effect that does not rely on targeting a single surface structure.
Key finding #2: HMOs kill pneumococcal bacteria at physiologically relevant concentrations
As well as stopping growth, the study also demonstrated that HMOs can kill S pneumoniae strains. In tests measuring colony-forming units (CFU), that is, the number of viable cells in a sample, bactericidal effects of HMOs were detectable at concentrations ranging from 1.25 to 5 mg/mL after a 6-hour growth period (Fig.1). Importantly, these findings show that the effectiveness of HMOs against these pathogenic strains occurred at concentrations similar to those naturally found in breast milk.
Figure 1. CFU/mL quantification after HMO treatment. HMO concentration resulted in bactericidal effects at 1.25 to 5 mg/mL.
How might HMOs exert anti-pneumococcal effects?
The authors of the study suggest several mechanisms by which HMOs may exert their anti-pneumococcal effects, backed up by previous research. Interestingly, their findings showed that HMOs can have potent antimicrobial properties at concentrations similar to those in human breast milk, highlighting that HMOs could be natural defences against pneumococcal infection in infants. They also found that these benefits occurred in serotypes that are less responsive to vaccines, like nonencapsulated serotypes and serotype 3.
The researchers suggest that one of the ways that HMOs may inhibit the growth of pneumococcal pathogens is by interfering with bacterial adhesion. HMOs are already known to act as soluble decoy receptors, binding to pathogens and stopping them from attaching to host tissues. Much earlier research found that LNnT and its sialylated derivative could inhibit the growth of S. pneumoniae in rabbit lung models [11].
Because they can kill pneumococcal pathogens, HMOs may disrupt metabolic or nutrient uptake pathways in the bacteria, affecting their growth and survival. That’s because HMOs are rich in sialylated and galactosylated motifs that structurally resemble host glycans that can act as nutrient sources and adhesion sites for S. pneumoniae. This means that HMOs may initiate similar processes to these glycans. Still, because the bacteria cannot break them down, this leads to metabolic stress and autolysis, which, in effect, means the pathogenic bacteria self-digest and die.
In other studies, HMOs have also demonstrated anti-biofilm properties against different pathogens, although this was not tested in this study. However, the HMOs likely use a combination of each of these mechanisms to create multiple barriers to bacterial survival.
What does this mean for the future?
It has been well established that infants who are exclusively breastfed for 4 months are less likely to experience severe respiratory tract illnesses than non-breastfed infants [12]. The results of this study further highlight the potential of HMOs as a natural therapy to support a healthy gut microbiome in infancy and to prevent pneumococcal infection, a significant risk factor for babies. However, these infections are also prevalent in other high-risk populations, such as the elderly, and HMOs could be a helpful therapeutic agent in groups like these.
More research is needed, however, especially as this research was carried out in vitro. So, these effects need to be assessed in living organisms. Nevertheless, these results support a strong case for continued investigation into the antimicrobial properties of HMOs.
Summary
The results from this study are promising. HMOs can inhibit the growth and even kill pathogenic S. pneumoniae, a bacterial species that is responsible for causing pneumonia, at concentrations found naturally in human breast milk.
As research continues to grow into the biological roles of HMOs, these findings contribute to a growing appreciation of their potential in shaping future therapeutic options for many illnesses and diseases, particularly in vulnerable populations.
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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.
