Imagine a city street on a busy morning: office workers dashing to get to work on time, traffic zooming by and students on the way to school. Similarly, ‘cities’ of bacteria, fungi and other microorganisms make up the gut microbiome. Still, external influences can disrupt this network of peacefully coexisting microflora with potentially dangerous consequences.
Take the yeast C. albicans for example. The ordinarily harmless fungus inhabits the gastrointestinal tract alongside other microbes in the form of an oval-shaped yeast. However, using broad-spectrum antibiotics has been associated with increased incidences of fatal C. albicans infections.
One widely accepted explanation for this phenomenon is that antibiotics kill beneficial gut bacteria, freeing up resources that favor the fungus’ growth. Yet, studies have shown that introducing C. albicans cells to mice with guts cleared of bacteria does not result in infection.
“These results indicate that removing commensal bacteria alone does not promote candidiasis, contradicting the general view [of scientists],” commented Yue Wang, a Principal Investigator at A*STAR’s Institute of Molecular and Cell Biology (IMCB).
To uncover how broad-spectrum antibiotics turn a typically benign yeast into a dangerous enemy, Wang and his colleagues took a closer look at the relationship between β-lactam antibiotics and gut flora.
In a series of experiments, Wang and colleagues found that β-lactam antibiotics caused trillions of gut bacteria to shed significant quantities of peptidoglycan (PGN) fragments, key components of the bacterial cell wall. This phenomenon was unique to broad-spectrum β-lactam antibiotics—other antimicrobials did not set off this PGN storm.
Interestingly, the team identified the flood of PGN fragments as the root cause of C. albicans pathogenicity by showing that purified PGN prompted the yeast to morph into long, thin, threadlike structures called hyphae that can invade gut tissues and cause life-threatening infections in immunocompromised patients. Accordingly, numerous pathogenic C. albicans hyphae were later found in the intestinal tract and feces of mice given β-lactam antibiotics.
“When a patient takes β-lactam antibiotics, the drug blocks bacterial peptidoglycan synthesis and forces them to produce and release significant quantities of subunits promoting C. albicans hyphal growth,” explained Wang. “These molecules flood the gut and convert the habitat from favoring yeast cells of C. albicans to cultivating its invasive hyphae, which penetrate the intestinal epithelium to invade deep tissues.”
Moving forward, the team plans to collaborate with physicians to investigate how other classes of antibiotics influence the development of C. albicans infections. “This kind of data is required to convince clinicians to modify antibiotic regimen selection to minimize C. albicans infection and support our proposed model,” concluded Wang.
The A*STAR affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB).
