When Derek Bays, an infectious disease physician at the University of California Davis Medical Centre, treated individuals with cancer, he knew that their weakened immune system increased their risk of microbial disease. So, Bays put them on prophylactic antibiotics and antifungals but noticed something unexpected. Despite the preventive medicines, the patients acquired life-threatening infections caused by the fungus Candida albicans.
On digging into this issue, Bays discovered that what seemed like a case of resistant candidiasis was in fact a breakdown of the protective mechanism called colonization resistance: a phenomenon whereby the normal gut microbiota limits the introduction of pathogens and expansion of already present opportunistic microbes.1
When gut homeostasis is disturbed by antibiotics, bacterial defenses plummet, leaving room for pathogens like C. albicans to flourish. Invasive C. albicans infections that reach the bloodstream are one of the most common hospital-acquired infections, with a high mortality rate of 49 percent.2 However, the mechanism driving this fungal bloom is unknown. Now, in a study published in Cell Host and Microbe, Bays and his colleagues showed that oxygen is a key resource that promotes fungal growth in a post-antibiotic gut environment.3 This finding could pave the way for improved preventive and treatment measures to control overgrowth of C. albicans in vulnerable individuals.
“What’s interesting about this study is that it emphasizes the fact that the host environmental milieu is so important for colonization resistance,” said Andrew Koh, a pediatric oncologist and infectious disease physician at The University of Texas Southwestern Medical Center, who was not involved in the study.
Researchers have previously shown that in healthy mice guts, various factors tightly regulate C. albicans. The fungus thrives on carbohydrates and sugar alcohols, both of which are consumed by bacteria such as Clostridia.4 Additionally, Clostridia also produces short-chain fatty acids that inhibit the growth of C. albicans. When scientists depleted Clostridia using antibiotics, they observed a drop in colonization resistance against C. albicans.5 It is also established that trying to restore the defenses against C. albicans with probiotic bacterial species that are susceptible to the administered antibiotics is ineffective. So, Bays needed an alternative strategy. He collaborated with Andreas Bäumler, a microbiologist at the University of California, Davis, to test if depriving C. albicans of resources during antibiotic treatment dampens its growth.
The team first analyzed the range of metabolites used by C. albicans. They compared the intestinal contents of mice inoculated with C. albicans with those of healthy mice and identified various carbohydrates and alcoholic sugars that were reduced in the presence of the fungus. Next, they investigated if bacterial scavenging of any of these resources would curb the growth of C. albicans after the gut flora is depleted. For this, Bays and his colleagues focused on sorbitol, one of the alcoholic sugars that C. albicans uses. They inoculated antibiotic-treated mice with two Escherichia coli strains: one that could metabolize sorbitol and one that couldn’t. When they challenged these mice with C. albicans, the researchers observed no difference between the abundance of C. albicans in the intestines of both groups.
After pondering over different explanations for these results, Bays had a moment of clarity. “We realized we were looking at the wrong nutrient source,” he said.
Healthy guts are hypoxic. Gut bacteria produce metabolites that bind to intestinal cell receptors and signal maintenance of low oxygen levels. This, in turn, is crucial to maintenance of microbial homeostasis. Antibiotic treatment drains these essential molecules, thus raising the oxygen level in the intestines. Keeping this in mind, the authors hypothesized that an oxygen-rich environment could enable C. albicans to metabolize the newly available nutrients after antibiotics kill the bacterial competitors. To confirm their theory, they inoculated one group of antibiotic-treated mice with E. coli that could grow aerobically, and thus scavenge the oxygen in the gut, and another group with a strain that couldn’t do so. When the team challenged these mice with C. albicans, they recovered substantially higher numbers of the fungi in the oxygen-rich guts of mice with the E. coli strain that could not utilize oxygen.
“Whenever there's oxygen, whoever uses oxygen will grow faster or divide faster than everybody else and take over the community,” said Bäumler. “These rules apply anywhere on this planet, including the large intestine.”
Next, Bays wanted to develop an intervention that could restore colonization resistance in the aftermath of antibiotics. Baumler had previously reported that the molecule 5-aminosalicylic acid (5-ASA) restores anaerobic conditions in the intestines of mice with colitis by binding to a receptor on the gut epithelial cells. When Bays and his colleagues tested the effects of 5-ASA on fungal bloom after antibiotic treatment, they observed that the drug could improve colonization resistance and blunt C. albicans growth. The team visually confirmed the restoration of hypoxia after 5-ASA treatment by using a chemical that specifically binds to cells with less than one percent oxygen. Importantly, when they transplanted the microbiome of an antibiotic and 5-ASA treated mouse to one without gut flora, they observed colonization resistance against C. albicans, showing that the drug can functionally replace Clostridia.
Bays is now testing this treatment in mouse models with a weakened immune system and disrupted gastrointestinal tract—a situation that resembles the one observed in cancer patients. For Bäumler, these findings highlight the importance of the host in maintaining colonization resistance in the face of antibiotic treatment and developing a regimen that is shielded from resistance. “Candida cannot become resistant against hypoxia,” he said. “By using a drug that restores hypoxia, you're ending the arms race.”
- Lawley TD, Walker AW. Intestinal colonization resistance. Immunology. 2013;138(1):1-11.
- Morgan J, et al. Excess mortality, hospital stay, and cost due to candidemia: A case-control study using data from population-based candidemia surveillance. Infect Control Hosp Epidemiol. 2005;26(6):540-547.
- Savage HP, et al. Epithelial hypoxia maintains colonization resistance against Candida albicans. Cell Host & Microbe. 2024;32(7);1103-1113.
- Tiffany CR, et al. The metabolic footprint of Clostridia and Erysipelotrichia reveals their role in depleting sugar alcohols in the cecum. Microbiome. 2021;9(1):174.
- Huang D, et al. Antibiotic-induced depletion of Clostridium species increases the risk of secondary fungal infections in preterm infants. Front Cell Infect Microbiol. 2022;12.
