Infections caused by Candida albicans are a growing concern in hospital settings, particularly in immunocompromised patients. Despite taking preventive antibiotics and antifungals, many cancer patients suffer from these life-threatening fungal infections. Infectious disease physician Derek Bays from the University of California, Davis, uncovered that these infections might be linked not to antibiotic resistance but to a breakdown in the gut’s protective mechanisms, known as colonization resistance.
Colonization resistance occurs when the gut’s normal microbiota prevents the growth of harmful microbes. However, antibiotics can deplete these beneficial bacteria, paving the way for pathogens like C. albicans to flourish. The resulting invasive infections, which can reach the bloodstream, have a high mortality rate of 49%. While the mechanism driving these fungal blooms remained unclear, Bays and colleagues discovered that increased oxygen levels in the gut, caused by antibiotics, play a pivotal role.
The researchers found that when gut bacteria are eliminated by antibiotics, oxygen levels rise, providing C. albicans with the conditions it needs to grow. This discovery could lead to new methods for managing fungal overgrowth in patients undergoing antibiotic treatments. Andrew Koh, a pediatric oncologist and infectious disease expert at The University of Texas Southwestern Medical Center, emphasized the importance of the host’s environment in maintaining microbial balance, which the study highlights.
Previously, studies showed that C. albicans is tightly regulated in healthy mice, where certain gut bacteria, such as Clostridia, inhibit its growth by consuming sugars that the fungus relies on. However, when antibiotics deplete these bacteria, the protective effect is lost, and C. albicans proliferates. Bays and his team sought an alternative strategy to curb this overgrowth by focusing on the role of oxygen in promoting fungal expansion.
Hypoxia, or low oxygen levels, is a characteristic feature of healthy gut environments. Bacteria in the gut help maintain this low-oxygen state by producing metabolites that signal to intestinal cells to keep oxygen levels down. Antibiotics, however, disrupt this balance, raising oxygen levels and creating an environment conducive to C. albicans growth.
To test their hypothesis, the researchers introduced different strains of Escherichia coli to antibiotic-treated mice. Some strains could metabolize oxygen, while others could not. They found that mice with higher oxygen levels, due to the presence of E. coli strains that did not consume oxygen, had a higher abundance of C. albicans. This confirmed that oxygen availability plays a key role in fungal proliferation.
Building on these findings, the team turned to 5-aminosalicylic acid (5-ASA), a drug known to restore anaerobic conditions in the intestines. By treating antibiotic-treated mice with 5-ASA, they observed a reduction in C. albicans growth and a restoration of colonization resistance. This suggests that 5-ASA could be used to counteract the negative effects of antibiotics on gut oxygen levels and fungal growth.
Bays and his team are now testing 5-ASA in mouse models with weakened immune systems to simulate the conditions seen in cancer patients. Their results could provide a new approach to preventing fungal infections in vulnerable individuals, offering an alternative to traditional antifungal treatments.
For Bäumler, the study underscores the importance of the gut environment in preventing infections. “Candida cannot become resistant against hypoxia,” he stated. “By using a drug that restores hypoxia, you’re ending the arms race.” This research paves the way for novel therapeutic strategies to maintain microbial balance and prevent harmful fungal infections in patients undergoing antibiotic treatments.
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