The researchers, from the Wellcome Sanger Institute, the University of Helsinki, the University of Oslo, and collaborators, analysed the gut bacteria of more than 300 newborn babies from the UK Baby Biome study. They found that the make-up of their gut bacteria, or microbiomes, did not contain multi-drug resistant strains of common hospital pathogens, such as Enterococcus faecalis and Klebsiella pneumoniae.
The new study, recently published in Nature Communications (1 December 2022), also uncovered multiple synergistic relationships between different bacteria that compete against more harmful species such as Escherichia coli (E. coli). This suggests that in the future, it might be possible to enhance these relationships to outcompete resistant or more harmful bacterial strains, instead of relying on the development of new drugs to combat the spread of antibiotic resistance and other drug-resistant bacteria.
As well as creating a map of these bacterial relationships, this is the first time that it has been possible to derive a population-based estimate of how virulent a particular strain of E. coli is, allowing researchers to focus on understanding and preventing the most immediate threats.
The human gut contains thousands of bacterial species and other microorganisms, known as the microbiome. Each person will have a slightly different ecosystem of bacteria, depending on factors such as their environment and diet.
While the majority of bacteria are beneficial, some harbour the considerable potential to cause either mild or severe infections when they get into the bloodstream. One of the most well-known examples of this is E. coli, which is a common cause of bloodstream infections worldwide that seem to have increased over the last decade1.
As an added challenge for healthcare providers, multi-drug resistance (MDR) has become a frequent feature of these bacterial infections. MDR is also seen in other bacterial species, such as Klebsiella pneumoniae1, and Enterococcus faecalis, which can cause a range of mild to life-threatening infections, including urinary tract infections, septicaemia, endocarditis and meningitis2.
Newborn babies are colonised by bacteria very quickly. Analysing their microbiomes through faecal samples allows researchers to see how the microbiome develops, including the interactions between different bacteria.
The team, from the Wellcome Sanger Institute and collaborators, used new high-resolution metagenomics to map the interactions of bacteria that can cause infections, known as pathogenic bacteria, in the microbiomes of more than 300 newborn babies. They found multiple, surprising interactions where pathogenic bacteria existed in harmony with each other, along with other instances where they could colonise alongside each other. For example, strains of E. coli rarely coexist with Klebsiella species.
Multi-drug resistant strains of common pathogenic bacteria, such as Klebsiella lineages that contain the genes for drug resistance, were not found in healthy newborn babies, despite some of them staying at the hospital for multiple days, implying that these strains are more efficient at colonising people under antibiotic treatment or who are immuno-compromised.
This observation was the same for all babies delivered by vaginal birth or caesarean section. This indicates that the C-section did not lead to colonisation by these particularly problematic microbes, despite the fact that C-sections were associated with babies having significantly stunted development of their microbiome, as shown in the original UK Baby Biome study3.
The research was also the first time that it has been possible to estimate the relative virulence, or pathogenic potential, of different strains of E. coli bacteria. This advance was enabled by combining the high-resolution colonisation profiles with data from previous work, such as the Baby Biome study and the BSAC4 and NORM5 bloodstream infection cohort studies, which produced a huge amount of genomic reference data.
Strains of bacteria that can cause high levels of disease and spread from person to person effectively are a public health risk, such as E. coli ST131, a multi-drug resistant lineage which has risen in the UK population and globally in the last decade4,5. Being able to quantify which strains are the most virulent allows researchers and public health officials to focus on tracking these and investigating ways to prevent the spread. In addition to this, research can focus on understanding the genetic code to possibly develop new treatments, and stop other strains from developing similar traits.
Combining virulence information with the map of bacterial relationships in the microbiome could uncover which bacteria would outcompete virulent strains of E. coli, and highlight those that prevent the more dangerous strains from settling in the gut. While further research is needed, finding ways to encourage less virulent and non-drug resistant strains of E. coli in the microbiome could lessen the need for antibiotics and give a new treatment approach to MDR infections.
Dr Trevor Lawley, an author from the Wellcome Sanger Institute, said: “The gut microbiome is a potential therapeutic resource that could interact with and possibly help with things such as drug delivery, bowel conditions, and multidrug-resistant infections. Our finding that babies leave the hospital mostly without multi-drug resistant bacteria shows that these strains cannot colonise our guts at all stages of life. Understanding what protects healthy babies against this could lead to a new way of treating infections, which enhances the microbiome to protect against, or push out, these virulent strains from the gut as a way of reducing the risk of infection and spread of drug resistant pathogens.”
Dr Yan Shao, an author from the Wellcome Sanger Institute, said: “Having a large amount of reference data from healthy babies as part of the Baby Biome study was crucial for this work, and allowed us to uncover new insights about the dynamic relationships between “good” beneficial and "bad“ pathogenic bacteria in the human gut. Continuing to add to and investigate the Baby Biome study data could provide more knowledge about the microbiome in early life. Our research shows the importance of having large-scale, high-quality genomic data and the power of strain-level precision metagenomic analyses, hopefully encouraging more studies to follow suit.”
Professor Jukka Corander, senior author from the Wellcome Sanger Institute, the University of Oslo and the University of Helsinki, said: “Our study is the first time that it has been possible to map the relationships between pathogenic bacteria and accurately estimate virulence at the strain level. All of this would not have been possible without the new methods, technologies and data that have been published over the last few years. This research signposts the most present threats so that we can concentrate on tracking and stopping the spread of antimicrobial resistance. It also gives insight into the development of virulence; for example, the most virulent E. coli strain only appeared around 50 years ago, and understanding how it evolved genetically could help us stop this from happening in the future.”
Image: Janko Ferlic, unsplash
