The C.difficile epidemic. Sugar rush?

Clostridium difficile

Clostridium difficle features high on the list of public (health) enemies, being a notorious cause of life-threatening hospital-associated infection, particularly in the elderly.

The rise of C.difficile infection from being an occasional complication of hospitalisation to full-on epidemic in Europe and North America in less than a decade coincides with the appearance of more dangerous strains, readily identifiable through differences in the genes that encode for ribosomes, the macromolecular complexes that translate genetic information into proteins.

Ribosmal gene fingerprints (“ribotypes”) indicate that, from the early to mid-2000s, the appearance of strains of two particular C.difficile ribotypes, 027 (also known as NAP1) and 028, correlated with a steep increase in severe C.difficile infection and death. These so-called “hypervirulent” strains are much studied and while certain characteristics explain their propensity to cause severe infection, including toxin production, greater adherence to human gut cells and prolific spore formation, the reason for the sudden appearance of the 027 and 028 strains remains an epidemiological mystery.

An international research group centred at Baylor College of Medicine has raised the intriguing possibility that the C.difficile epidemic may be in fact self-inflicted, with the rise in hypervirulent infection being fuelled by an  increase in dietary trehalose, a food additive which hit the mass market in the early 2000s.

Trehalose, a natural sugar, has the handy properties of being able to survive high temperatures without browning while preserving cell structure on freezing. Low cost manufacture of this sugar resulted in trehalose becoming ubiquitous in processed foods, jam, fruit juice and ice-cream (with some brands containing over 10% trehalose).

  

The hypervirulent 027 and 028 C. difficile strains are capable of thriving on low concentrations of trehalose as their only source of carbon. Sequencing has revealed a genetic variation in 027 strains and the presence of additional genes in 028 strains, each of these differences from “normal” C.difficile strains conferring the ability to utilise low concentrations of trehalose.

Knocking out the genetic variant in a 027 strain reduced its virulence in mice, while adding trehalose to the diet of infected mice resulted in increased mortality, possibly through increased toxin production rather than an increased rate of bacterial overgrowth. Fluid collected from the small intestines of three volunteers on normal diets contained sufficient trehalose to trigger expression of the trehalose-metabolising gene in 027 strains, but not in other C.diffcile strains.

Although circumstantial, the discovery that hypervirulent C.difficile stains are uniquely adapted to make good use of low trehalose levels, together with the close temporal fit between the spread of these strains and the upswing in dietary trehalose makes for a compelling story.

On the other hand, increased trehalose consumption alone does not explain national differences in the appearance and dominance of hypervirulent strains, nor the rapid decline of these strains in the UK and other countries. A history of antibiotic use is an established risk factor for severe C.difficile infection and it’s possible that antibiotic-induced changes to the gut microbiome confer a selective advantage to hypervirulent strains.

And it’s far too early to start worrying rationally about trehalose, although minimizing intake in those with established risk factors for C.difficile infection might be worth consideration.

Photo credit: CDC/ James Archer

Dietary trehalose enhances virulence of epidemic Clostridium difficile. Collins, J et al. Nature 553, 291–294 (online 3^rd January 2018).

And apologies for covering something which I know has been blogged about extensively elsewhere, but a dose of ‘flu has left me reliant on my (small) reserve of half-baked blog pieces.