Recent discovery about C. difficile could pave the way for new treatments

By Sally Robertson, B.Sc.Nov 25 2019

Researchers at the Icahn School of Medicine at Mount Sinai have found that a process called sporulation, which helps the dangerous bacterium Clostridum difficile (C. difficile) survive and spread, is regulated by epigenetics.

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Epigenetics refers to the factors beyond the genetic code that influence gene expression.

This is the first time that epigenetics has been shown to regulate sporulation in a bacterium, and the finding could pave the way for new life-saving treatments.

C. difficile, which infects almost half a million people every year, causes severe diarrhea and claims the lives of just under 10% of those aged over 65 who contract it.

C. difficile spores are extremely resilient

Spores of C. difficile, which are spread via fecal matter, are extremely hardy. They can survive inhospitable conditions outside of the body for weeks or months and infect people who come into contact with contaminated surfaces.

Given how common and dangerous this bacterium is, its genome has been well studied, but the senior author of the current study, Gang Fang, says his team decided to use a different approach.

We wanted to study beyond the genetic code of the bacteria and look at what chemical modifications were being made to the genome,"

Senior author Gang Fang, Mount Sinai

These modifications, referred to as methylation, do not alter a gene's sequence, but they can make a more or less active, which strongly influences an organism's function.

What did Fang's team do?

In 2012, Fang and the team started using third-generation DNA sequencing to map epigenetic factors in bacteria, and in 2015, they began looking at the epigenetics of C. difficile.

The researchers isolated C. difficile from fecal samples taken from 36 intensive care unit (ICU) patients at Mount Sinai Hospital.

On analyzing the samples, they discovered a certain epigenetic pattern that was highly conserved across all of the samples.

Next, the team analyzed approximately 300 C. difficile genomes stored in GenBank, the National Institute of Health's databank of genetic sequences.

As reported in the journal Nature Microbiology, the researchers discovered that all of the genomes contained a particular gene that was responsible for the epigenetic pattern identified in the 36 ICU patients.

Suspecting that this epigenetic pattern was essential to the function of C. difficile, the team decided to collaborate on two other studies looking at C. difficile sporulation. One study was at the lab of Aimee Shen at Tufts University Medical School, and the other was at the lab of Rita Tamayo, University of North Carolina.

In one study investigating infected mice, the researchers found that inhibiting the gene that was responsible for the epigenetic pattern reduced the number of bacteria by a 100 times after six days, compared with when the gene was not inhibited.

The findings underscore the importance of epigenetics in studies of bacteria

Fang says the findings demonstrate how important epigenetics is in the study of bacteria and the development of drugs to treat the infection.

As well as providing new insights into the epigenetic characteristics of C. difficile and potentially establishing new targets for drug development, Fang hopes the research will prompt others to investigate the epigenetics of bacteria.

"This is just the beginning of our understanding of epigenetic regulation in bacteria; there are still so many questions yet to be answered," he says… "We hope this exciting discovery will encourage further interdisciplinary collaborations to investigate epigenetics of bacteria and how we can use these new insights to develop life-saving treatments for infection."