From the Journals

Common food additive makes C. difficile more virulent


Key clinical point: Metabolizing trehalose increases the virulence and mortality of C. difficile ribotype 027 (RT027).

Major finding: The ability to metabolize trehalose with the phosphotrehalase enzyme (TreA) increases mortality in RT027.

Study details: Experimental mouse models and an analysis of ileostomy effluent from three anonymous donors.

Disclosures: All authors had no financial disclosures to report.

Source: Collins J et al. Nature. 2018 Jan 3. doi: 10.1038/nature25178.



The ability of Clostridium difficile ribotype 027 (RT027) to metabolize the sugar trehalose, a common food additive, has increased the virulence of C. difficile infections, a study showed.

“Out of several carbon sources identified that supported CD2015 growth [epidemic RT027 isolate], we found the disaccharide trehalose increased the growth yield of CD2015 by approximately fivefold, compared with a non-RT027 strain,” according to James Collins, PhD, of Baylor University, Houston, and his colleagues. The increased growth of the epidemic strain of C. difficile observed by Dr. Collins and his team demonstrates that trehalose is a robust carbon source for C. difficile bacterium.

cjc2nd/Wikimedia Commons/CC ASA-3.0
After Dr. Collins and his team determined that trehalose is an excellent food source for C. difficile, they tested whether trehalose metabolism effected disease severity.

In one experiment, mice with humanized microbiota were infected with two strains of RT027, either R20291 (n = 27) or R20291-delta treA (n = 28), a phosphotrehalase enzyme (TreA) deletion mutant that cannot metabolize trehalose. Mice were then given 5 mM of trehalose ad libitum in their drinking water. Researchers observed that the mice infected with R20291-delta treA had much lower mortality rates than the R20291 group (33.3% vs.78.6%). These findings were then reinforced with a second experiment using mice with humanized microbiota, in which trehalose addition increased mortality in RT027 mice, compared with RT027-infected mice that were not given dietary trehalose.

While Dr. Collins and his team demonstrated the effect of trehalose on C. difficile in mice, they also conducted a limited analysis of ileostomy effluent from three human donors. The researchers found that in two of three samples, treA was strongly induced in CD2015, but not in another ribotype, CD2048. This demonstrates that amounts of trehalose found in food are high enough to be metabolized by certain epidemic strains of C. difficile in humans.

Prior to 2000, trehalose use was limited by a relatively high cost of production, approximately $700 per kilogram. A production innovation that utilized a novel enzymatic method that yielded trehalose from starch brought the price of trehalose to approximately $3 per kilogram, making it a commercially viable food supplement. After being considered “generally recognized as safe” by the U.S. Food and Drug Administration in 2000 and approved for use in Europe, the trehalose concentrations in food skyrocketed from around 2% to 11.25%, and trehalose became widely used in several foods, including ice cream, pasta, and ground beef.

Dr. Collins and his associates said that there is considerable evidence that the widespread use of dietary trehalose has contributed to the spread of epidemic C. difficile ribotypes. First, strains RT027 and RT078 have always had the ability to metabolize trehalose, as evidenced by outbreaks of nonepidemic C. difficile in the 1980s. But no epidemic outbreaks were reported until after 2003, several years after trehalose was approved by the FDA. Second, RT027 and RT078 are phylogenetically distant, but independently evolved the ability to metabolize low levels of trehalose. Third, increased severity of the RT027 strain, which metabolizes trehalose in mice, is consistent with increased virulence of RT078 and RT027 in human patients. Fourth, a competitive advantage is conferred to C. difficile being able to metabolize trehalose in low concentrations in a diverse intestinal setting. Finally, the levels of trehalose in ileostomy fluid from patients who eat a normal diet are high enough to be utilized by RT027 strains.

“On the basis of these observations, we propose that the widespread adoption and use of the disaccharide trehalose in the human diet has played a significant role in the emergence of these epidemic and hypervirulent strains,” Dr. Collins and his colleagues wrote in their article in Nature.

The authors of the study had no relevant financial disclosures to report.

SOURCE: Collins J et al. Nature. 2018 Jan 3. doi: 10.1038/nature25178.

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