Clostridium difficile (C diff) prevalence is enhanced by dietary trhalose-containing foods !!

Between 2001 and 2006, epidemic strains of the bacterium Clostridium difficile (C.diff) –– which can persist in some patient’s bowel and cause dangerous diarrhea, unexpectedly emerged in the United States, Canada, and several European countries. Most of these strains originated from a single lineage of C. diff known as ribotype 027 (RT027), which has now spread around the world. Of par­ticular concern has been the correlation between RT027 and dramatic increases 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. Authors [see attached] raise the possibility that the seemingly harmless addition of a sugar called trehalose to the food supply might have contributed to this disease epidemic.

Whole-genome sequencing (WGS) analysis of C. diff RT027 strains demonstrated that two independent lineages had emerged in North America between 2000 and 2003. Comparison with historic pre-epidemic RT027 strains showed that both epidemic lineages had acquired a mutation in the gyrA gene, leading to increased resistance to fluoroquinolone antibiotics. While the development of fluoroquinolone resistance has almost certainly played a role in the spread of RT027 strains, fluoroquinolone resistance has also been observed in non-epidemic C. diff ribotypes and has been identified in strains dating back to the mid-1980s. Thus, other factors must have contributed to the emergence of epidemic RT027 strains.

The prevalence of a second C. diff ribotype, RT078, increased 10-fold in hospitals and clinics from 1995 to 2007 and was associated with enhanced disease severity. It is noteworthy that the RT027 and RT078 lineages are phylogenetically distant from one another, indicating that the evolutionary changes leading to concurrent increases in epidemics and disease severity might have emerged by independent mechanisms. Authors show that the two epidemic ribotypes (RT027 and RT078) have acquired unique mechanisms to metabolize low concentrations of the disaccharide trehalose –– which reflects a single point-mutation in the trehalose repressor gene (gyrA), which increases sensitivity of this ribotype to trehalose by more than 500-fold. Dietary trehalose was also shown to increase virulence of a RT027 strain in a mouse model of infection.

It so happens that RT078 strains acquired a cluster of four genes involved in trehalose metabolism, including a “PTS permease” (phosphotransferase system, or PTS, is a distinct method used by bacteria for sugar uptake in which the source of energy is from phosphoenolpyruvate (PEP); this multicomponent system always involves enzymes of the plasma membrane and cytoplasm) –– that is both necessary and sufficient for growth on low concentrations of trehalose. Authors propose that implementation of trehalose as a food additive into the human diet, which occurred shortly before the emergence of these two epidemic lineages, might have helped these bacteria to select for their emergence (i.e. “evolutionary survival”) and contributed to the observed hypervirulence.

Nature 18 Jan 2o18; 553: 291–294 & News-N-Views ed pp 285–286

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