Tag: Candida albicans

Damaging Candida Strains in Inflammatory Bowel Disease

Anatomy of the gut
Source: Pixabay CC0

In the human gut, individual strains of Candida albicans are incredibly varied, and some C. albicans strains may damage the gut of patients with inflammatory bowel disease (IBD), according to a new study published in Nature. The findings suggest a possible way to tailor treatments to individual patients in the future.

The researchers used an array of techniques to study Candida strains from the colons of people with or without ulcerative colitis, a chronic, relapsing and remitting inflammatory disorder of the colon and rectum and one of the main forms of IBD. They found that certain strains, which they call “high-damaging,” produce candidalysin, a potent toxin that damages immune cells.

“Such strains retained their “high-damaging” properties when they were removed from the patient’s gut and triggered pro-inflammatory immunity when colonised in mice, replicating certain disease hallmarks,” said senior author Dr Iliyan Iliev, an associate professor of immunology in medicine at Weill Cornell Medicine.

IBD is estimated to affect between one in 11 and one in 26 people worldwide. The condition can significantly impact patients’ quality of life. There are a handful of available therapies, but treatments may not always be effective. The study showed that steroids, one of the common treatments, may not work. Treating mice with steroids to suppress intestinal inflammation failed in the presence of “high-damaging” C. albicans strains.

“Our findings suggest that C. albicans strains do not cause spontaneous intestinal inflammation in a host with intact immunity,” Dr Iliev said. “But they do expand in the intestines when inflammation is present and can be a factor that influences response to therapy in our models and perhaps in patients.”

Most studies of the human microbiome in healthy individuals and those with IBD have focused on bacteria and viruses, but recent studies  by Dr Iliev and others has highlighted the role of fungi. Intestinal fungi play an important role in regulating immunity at surfaces exposed to the outside, such as the intestines and lungs, due to their potent immune-stimulating characteristics. While the mycobiota – the body’s fungi community – has been linked to IBD, the pro-inflammatory of gut the mycobiota was not understood.

In the new study, the investigators initially found that Candida strains, while highly diverse in the intestines of both patients with and without colitis, were on average more abundant in the patients with IBD. But that did not explain disease outcomes in individual patients. So, the investigators set out to identify the characteristics of these strains that cause damage and how they relate to individual patients.

The researchers observed that in the patients with ulcerative colitis, severe disease was associated with the presence of “high-damaging” Candida strains, all of which produce the candidalysin toxin. The scientists showed that the toxin damages immune cells called macrophages, prompting a storm of the pro-inflammatory cytokine IL-1β.

The researchers then grew macrophages in the presence of Candida strains and found that the ability of the strains to induce IL-1β corresponded closely to the severity of colitis in the patients.

“Our finding shows that a cell-damaging toxin candidalysin released by “high damaging” C. albicans strains during the yeast-hyphae morphogenesis triggers pathogenic immunological responses in the gut,” said first author Dr Xin Li.

Experiments in mice delineated that candidalysin-producing “high-damaging” strains induced the expansion of a population of T cells called Th17 cells and other inflammation-associated immune cells, such as neutrophils.

“Neutrophils contribute to tissue damage and their accumulation is a hallmark of active IBD,” said Dr Ellen Scherl, a professor of inflammatory bowel disease. “The indication that these processes might in part be driven by a fungal toxin released by yeast strains in specific patients could potentially inform personalized treatment approaches.”

Consistent with this finding, blocking IL-1β signalling had a dramatic effect in reducing colitis signs in mice that harboured these highly pro-inflammatory strains. The researchers noted that other recent studies have linked IBD to IL-1β in a general way, prompting ongoing investigations of drugs targeting related pathways as potential IBD therapies.

“We do not know whether specific strains are acquired by specific patients during the course of disease or whether they have been always there and become a problem during episodes of active disease” Dr Iliev said. “Nevertheless, our findings highlight a mechanism by which commensal fungal strains can turn against their host and overdrive inflammation.”

The team’s next steps are to investigate the persistence candidalysin-producing strains in the inflamed colon of specific IBD patients, as well as ways to choose patients for mycobiome therapy.

Source: Weill Cornell Medicine

An Unexpected Ally: Pathogen Enhances Antifungal Drug

Scanning Electron Micrograph of Pseudomonas aeruginosa.
Credit: CDC/Janice Carr

While pathogens usually work against drug treatments, sometimes, they can actually strengthen them, according to a new University of Maine study published in the journal Infection and Immunity.

Polymicrobial infections, which are a combination of bacteria, viruses, fungi and parasites, are challenging to treat because it is not well understood how pathogens interact during infection and how these interactions affect the drugs treating them.

In a study published in Infection and Immunity, University of Maine researchers examined two common pathogens that often occur at similar sites, particularly in cystic fibrosis and mechanically ventilated patients: Candida albicans and Pseudomonas aeruginosa.

Candida is the fourth most common hospital-acquired pathogen, and many antifungal agents only slow it rather than kill it outright. Meanwhile, P. aeruginosa infects 90% of all adult cystic fibrosis patients. Combined, C. albicans and P. aeruginosa cause more serious disease in cystic fibrosis and ventilated patients.

The researchers investigated the effectiveness of the antifungal drug fluconazole in vitro and then during infection of the zebrafish with both pathogens. Fluconazole slows fungal growth, but Candida can become tolerant to the drug and not only survive, but also evolve tolerance that leads to therapy failure and, potentially, death.

The results showed that P. aeruginosa in fact works with fluconazole to eliminate drug tolerance and clear the C. albicans infection in the culture and the zebrafish.

“Polymicrobial infections are challenging to treat not only because of the lack of understanding of how invading microorganisms interact but also because we don’t know how these interactions affect treatment efficacy. Our work demonstrates that polymicrobial interactions can indeed affect treatment efficacy and, most importantly, it highlights the importance of nutrient availability in the environment -; such as iron in our study -; and how it modulates treatment efficacy,” explained Siham Hattab, lead author of the study.

What’s more, the bacteria also enhance the drug’s ability against a second pathogenic Candida species that tends to be more resistant to the drug.

The increased effectiveness of the drug suggests to the researchers that there is still much more to learn about how current drugs work when targeting these dangerous and complex polymicrobial infections.

Senior study author, Robert Wheeler, associate professor of microbiology said: “We are really excited to have revealed that sometimes drugs against fungal infection can work even better in a more ‘real-world’ situation than in the test tube. There is still a lot to learn about how pathogens interact during infection, and it will be interesting to see how the bacteria manage to work with the drugs to target Candida.”

Source: University of Maine