How is a common food additive linked to deadly C. difficile infections?
Clostridium difficile is a bacterium capable of causing life-threatening diarrhea, colitis, toxic megacolon, organ failure, and death.
According to the Centers for Disease Control and Prevention (CDC), C. difficile is currently "the most common microbial cause of healthcare-associated infections in U.S. hospitals and costs up to $4.8 billion each year."
In fact, C. difficile causes half a million infections and kills 15,000 people each year, the majority of whom are seniors. Yet these numbers used to be much lower.
Exactly why the past 20 years have seen a rising epidemic of C. difficile infections has remained a mystery — until now.
Writing in the journal Nature recently, researchers from Baylor College of Medicine in Houston, TX, and colleagues at the University of Oregon in Eugene, Leiden Medical Center in the Netherlands, and the Wellcome Trust Sanger Institute in Hinxton, United Kingdom, might have located the missing piece in the puzzle.
They point the finger squarely at a food additive, the simple sugar trehalose, which is widely used by the food industry.
The rise of C. difficile
The turn of the century saw the emergence of epidemic strains of C. difficile, explains Jimmy D. Ballard — a professor in the Department of Microbiology and Immunology at the University of Oklahoma in Oklahoma City — in an accompanying article in the journal Nature.
Prof. Ballard explains that most of these strains originated from a single source: a type of C. difficile known as ribotype 027 (RT027), which spread from the U.S., Canada, and Europe around the world.
In 2013, the CDC classed the threat level of C. difficile as urgent, putting the bug in the top 3 of 18 drug-resistant microbes — well above tuberculosis and MRSA.
"Of particular concern has been the correlation between RT027 and a dramatic increase in deaths related to C. difficile. The mystery of why this ribotype and a second one, RT078, became so prevalent apparently out of thin air has remained largely unsolved."
Prof. Jimmy D. Ballard
Robert A. Britton — who is a professor of molecular virology and microbiology at Baylor College of Medicine — and his team have been on the hunt for the answer for a number of years.
Prof. Britton pointed me in the direction of a study that the team published back in 2014, which showed that RT027 can outcompete other C. difficile strains in laboratory and animal models.
Based on this work, they decided to delve deeper to get to the bottom of what gives RT027 this advantage.
Hunt for the missing link
"To begin to ask this question we screened [around] 200 sugars and other carbon sources for their ability to support growth of RT027 strains better than other ribotypes," Prof. Britton explained.
"Through this screen," he continued, "we found that RT027 and a second hypervirulent, epidemic ribotype (ribotype 078) were able to grow on low concentrations of trehalose that do not support the growth of other C. difficile strains."
Trehalose is a naturally occurring sugar. It is a disaccharide, meaning that it is made up of two individual sugar molecules — in this case glucose. Trehalose can be found in fungi, algae, and other plants. The food industry uses the sugar to improve the texture and stability of food products.
Prof. Britton explains in his article that the use of trehalose was somewhat limited before the turn of the century; it cost approximately $7,000 to produce just 1 kilogram. However, the discovery of an enzymatic process that allows trehalose to be extracted from corn starch brought this number down to just $3 per kilogram.
"Granted [the] 'generally recognized as safe' status by the U.S. Food and Drug Administration [FDA] in 2000 and approved for use in food in Europe in 2001," Prof. Britton reports, "reported expected usage ranges from concentrations of 2 percent to 11.25 percent for foods including pasta, ground beef, and ice cream."
"The widespread adoption and use of trehalose in the diet coincides with the emergence of both RT027 and RT078 outbreaks."
Prof. Robert A. Britton
Connecting the dots
Prof. Britton and his team put the two strains of C. difficile to the test in order to find out what gives them the edge over other C. difficile strains when it comes to trehalose metabolism.
Interestingly, RT027 and RT078 achieve this in different ways. The RT027 strain has one mutation in a protein that normally represses the trehalose-metabolizing enzyme phosphotrehalase. This mutation switches off the repressor protein, allowing RT027 to use low levels of trehalose.
On the flipside, RT078 has four extra genes that support trehalose metabolism and allow it to grow much better in environments with low levels of trehalose than other strains.
Commenting on the results, Prof. Britton told me that "the most surprising finding of this work is that a dietary additive impacted the emergence of epidemic strains of C. difficile that have caused increased morbidity and mortality."
"The other surprise," he added, "is the fact that trehalose appears to directly increase the virulence of C. difficile." In fact, the team's research shows that while trehalose does not necessarily increase the number of RT027 bacteria, it does allow the bugs to produce significantly more bacterial toxins, which are responsible for the gut-wrenching symptoms that many patients experience.
But how much trehalose would I need to consume to allow these potentially deadly bugs to take a foothold in my gut?
In the study, the scientists tested fluid collected from the small intestine of three volunteers who consume a normal diet. The results revealed that there was enough trehalose to support the growth of RT027 but not other strains of C. difficile.
Does this mean that I should be looking to reduce my trehalose consumption?
The 'unexpected culprit'
I asked Prof. Britton whether he thought that the use of trehalose in food will be restricted based on these data. He didn't think so.
"What this work does suggest is that if a hospital or long-term nursing care facility has an outbreak of C. difficile caused by a RT027 or RT078 strain, then patients' diets should be modified to restrict trehalose consumption," he suggested instead.
The biggest group of people at risk of C. difficile infection are over 65s, and particularly those who are taking antibiotics and find themselves in a healthcare setting such as a hospital.
For the rest of the population, C. difficile poses less of a threat. However, the CDC are very clear in their objective that "preventing C. difficile is a national priority."
Prof. Britton and his colleagues are certainly doing their bit. "We are working now to understand how trehalose increases disease severity of C. difficile strains that can metabolize low concentrations of trehalose," he told me.
"We are also screening," he continued, "emerging C. difficile strains from hospitals for their ability to consume trehalose and other dietary sugars to further investigate the link between the diet and C. difficile infection."
While there are many questions still to be answered by the scientists, the link between trehalose and C. difficile is part of an emerging theme showing that our diet seems to play an increasingly crucial role in how our gut microbes behave in sickness and health.
"It is impossible to know all the details of events surrounding the recent C. difficile epidemics, but the circumstantial and experimental evidence points to trehalose as an unexpected culprit."
Prof. Jimmy D. Ballard