In brief

A metagenomic analysis of gut samples from healthy carriers of CPE bacteria links long-term CPE colonisation with microbial diversity loss and potential resistance gene transfer between disease-causing species.

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Hidden threats from benign colonisers

3 Oct 2023

Genomic profiles of the human gut microbiome reveal the hidden impacts of asymptomatic, antibiotic-resistant bacterial infections, as well as potential solutions for their reversal.

During World War II, the brown tree snake was accidentally introduced to the island of Guam. With no natural predators, the snake population exploded, and the brown tree snake soon became Guam’s dominant predator, causing the extinction of several native species.

There’s a similar concern about a class of antibiotic-resistant bacteria called carbapenemase-producing Enterobacteriaceae, or CPE. These bacteria carry resistance genes that can spread easily to other close relatives, opening the door to life-threatening infections that most current antibiotics can do little to fight.

Sometimes, CPE hides among the natural gut microflora of healthy individuals without causing visible effects. Though most of these asymptomatic carriers clear the bacteria over time, the long-term health impact of CPE colonisation isn’t fully understood, said Niranjan Nagarajan, Associate Director and Senior Group Leader at the Genome Institute of Singapore (GIS).

Nagarajan’s team collaborated with researchers from the National University of Singapore (NUS) and the Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital, to investigate the dynamics of the gut microbiome when colonised by CPE, and to find potential solutions to reverse this colonisation.

Using a technique called shotgun metagenomics, the team tracked changes in the gut microbiomes of 46 asymptomatic CPE carriers and their family members over a year by profiling genetic material in gut samples from each individual.

The researchers found that gut colonisation by CPE was combined with a loss of microbial diversity and the enrichment of microbial functions that promote inflammation. Conversely, in some individuals where CPE spontaneously decolonised, the team found gut microbial diversity restored and key beneficial bacteria known to modulate the immune system and reduce inflammation to return.

The study further showed that the abundance of CPE was unstable, with levels of different bacterial species such as Escherichia coli and Klebsiella pneumoniae fluctuating wildly over time. Concerningly, there were also signs that resistance genes had potentially crossed between colonies of E. coli and K. pneumoniae, despite the bacteria being different species.

“It’s worrying what this could mean in long-term colonisation, with trillions of gut bacteria that can potentially receive those resistance genes,” said Nagarajan.

In light of their findings, the team proposed that microbiome therapeutics might offer a safer, more effective alternative to antibiotics as a CPE decolonisation strategy. “More importantly, these approaches would reduce the amount of antibiotics administered in general, which directly addresses a leading cause of CPE prevalence,” added Nagarajan.

The team was awarded the highly competitive Open Fund-Large Collaborative Grant (OF-LCG) from the National Medical Research Council to further their groundbreaking work on CPEs. The researchers are currently looking for more ways to combat CPE colonisation in collaboration with colleagues at NUS, the National Centre for Infectious Diseases and the Lee Kong Chian School of Medicine.

The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore (GIS).

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Kang, J.T.L., Teo, J.J.Y., Bertrand, D., Ng, A., Ravikrishnan, A., et al.  Long-term ecological and evolutionary dynamics in the gut microbiomes of carbapenemase-producing Enterobacteriaceae colonized subjects. Nature Microbiology 7, 1516–1524 (2022). | article

About the Researcher

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Niranjan Nagarajan

Associate Director and Senior Group Leader

Genome Institute of Singapore
Niranjan Nagarajan is an Associate Director and Senior Group Leader at the Genome Institute of Singapore (GIS). He is also an Associate Professor in the Department of Medicine and Department of Computer Science at the National University of Singapore (NUS). Nagarajan received a BA in Computer Science and Mathematics from Ohio Wesleyan University in 2000, and a PhD in Computer Science from Cornell University in 2006. He did his postdoctoral work at the Center for Bioinformatics and Computational Biology at the University of Maryland working on problems in genome assembly and metagenomics. Currently, his research focuses on developing cutting-edge genome analytic tools and using them to study the role of microbial communities in human health. His team conducts research at the interface of genetics, computer science and microbiology, focusing on using a systems biology approach to understand host-microbiome-pathogen interactions in various disease conditions.

This article was made for A*STAR Research by Wildtype Media Group