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Identifying the gut bacteria that threaten neonatal babies

26 May 2023

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Quadram Institute-led study uses genome sequencing to identify why certain strains of gut bacteria can lead to the devastating condition necrotising enterocolitis in pre-term babies.

Genome sequencing has identified what makes some strains of Clostridium perfringens life-threatening in pre-term babies. The findings from the Quadram Institute and University of East Anglia will help identify and track dangerous strains and protect vulnerable neonatal babies.

Neonatal babies with extremely low birth weight are incredibly vulnerable. One major threat is necrotising enterocolitis (NEC). While rare in full term babies, this microbial infection exploits pre-term infant vulnerabilities destroying gut tissue leading to severe complications; two out of five cases are fatal.

NEC is caused by a range of different bacterial species. One that causes especially sudden and severe disease is Clostridium perfringens.

First identified in association with gas gangrene in World War I soldiers, C. perfringens was later recognised as a major cause of foodborne illness.

It is found in many different environments and non-disease-causing strains can live in healthy human guts; they have even been found in the mummified Neolithic ‘Tyrolean Iceman’ known as Ötzi, found in an Alpine glacier in 1991.

We’ve lived alongside these bacteria for thousands of years; so why do some C. perfringens strains cause NEC?

Whole Genome Sequencing has provided some answers in adults by reading the entire genetic instructions of gastroenteritis-associated strains to work out how they use a range of toxins and other factors to invade tissues and cause damage.

Professor Lindsay Hall and Dr Raymond Kiu from the Quadram Institute and University of East Anglia have now led the first major study on C. perfringens genomes from preterm babies, including some babies with NEC.

The research was supported by the Biotechnology and Biological Sciences Research Council, part of UKRI, and the Wellcome Trust. Working with Dr Stephen Robinson’s group in Quadram and colleagues at Imperial College, London, the University of Glasgow, the University of Cambridge, Newcastle University and Northumbria University, they analysed C. perfringens genomes from the faecal samples of 70 babies admitted to five UK Neonatal Intensive Care Units (NICUs).

After grouping them based on genomic similarities, they found one set were less virulent, i.e. they had a lower capacity to cause disease. This provided an opportunity to compare these strains with the more virulent ones.

The less virulent group lacked genes responsible for production of a toxin called PFO (perfringolysin O), which is also associated with gas gangrene. Experiments comparing strains with and without PFO toxin genes supported its role in growth of C. perfringens with disease-causing properties. The less virulent lineage also lacked other factors needed for colonisation and survival, suggesting they were incapable of causing disease and more likely to be harmless or commensal within the gut.

This study, published in the journal Nature Microbiology, has begun to construct genomic signatures for C. perfringens associated with healthy preterm babies and those with necrotising enterocolitis.

“Exploring genomic signatures from hundreds of Clostridium perfringens genomes has allowed us potentially to discriminate between ‘good’ bacterial strains that live harmlessly in the preterm gut, and ‘bad’ ones associated with the devastating and deadly disease necrotising enterocolitis” said Prof. Lindsay Hall. “We hope the findings will help with ‘tracking’ deadly C. perfringens strains in a very vulnerable group of patients – preterm babies.”

Virulent strains have enhanced spore-forming and germination abilities that may help them survive and grow following disinfection. Larger studies, across more sites and with more samples may be needed but this could help identify better ways to control NEC.

Previous studies by Prof. Lindsay Hall, working alongside Prof. Paul Clarke and clinical colleagues in the Neonatal Intensive Care Unit at Norfolk and Norwich University Hospital, have demonstrated the benefits of providing neonatal babies with probiotic supplements. The enterocolitis gut microbiome of neonatal infants is significantly disrupted, making it susceptible to C. perfringens overgrowth.

“Our genomic study gives us more data that we can use in the fight against bacteria that cause disease in babies – where we are harnessing the benefits of another microbial resident, Bifidobacterium, to provide at-risk babies with the best possible start in life,” said Prof. Hall

Dr Raymond Kiu from the Quadram Institute said “We were surprised to discover a new lineage of less virulent Clostridium perfringens strains in healthy babies. This sheds new light on why C. perfringens can exist as a commensal bacterium in the wider population, while virulent strains cause disease in preterm guts.”

“Importantly, this study also highlights Whole Genome Sequencing as a powerful tool for identifying new bacterial lineages and determining bacterial virulence factors at strain level which enables us to better understand disease.”

Reference: ‘Particular genomic and virulence traits associated with preterm infant-derived toxigenic Clostridium perfringens strains’ Raymond Kiu et al., will be published in Nature Microbiology on 25 May 2023 at 16:00 (London time), 25 May 2023 at 11:00 (US Eastern Time) DOI: 10.1038/s41564-023-01385-z

This article was originally posted by our partner, Quadram Institute, on their website here.

Main Image: Clostridium perfringens bacterial cells (false-colured green) and their spores (red). SEM by Kathryn Cross, the Quadram Institute

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