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People with cystic fibrosis (CF) spend their entire lives fighting against chronic lung infections that are notoriously resistant to antibiotics. Yet, according to a new study by researchers at the University of California San Diego School of Medicine and the Skaggs School of Pharmacy, a unique approach to eliminating the bacteria in question may not be the best approach for all patients with the disease. Pharmaceutical Sciences.
Instead, the researchers discovered that refining other factors in a lung model with CF, such as pH balance and oxygen, contributed to eradicate pathogenic bacteria while minimizing the risks of antibiotic resistance and proliferation of other microorganisms.
The study is published on September 26 Progress of science.
"We think antibiotics cause" scorched earth "simply by wiping out an unknown part of healthy bacteria and, hopefully, bad bacteria, but we do not understand what happens to their microbiota when people take antibiotics cystic fibrosis, "said Pieter Dorrestein, PhD, professor at the Faculty of Pharmacy and Pharmaceutical Sciences of Skaggs and the Departments of Pharmacology and Pediatrics of the Faculty of Medicine and Professor at the Microbiome Innovation Center of the Faculty of Medicine. San Diego UC. Dorrestein led the study with Robert Quinn, PhD, who was a science project assistant at UC San Diego at the time of the study and who is now an assistant professor at Michigan State University.
Due to the genetic abnormality at the base of CF, thick, sticky mucus is formed in the lungs of patients with CF. Mucus helps microorganisms grow. A particularly problematic bacterium Pseudomonas aeruginosa, also forms a biofilm in the lungs, which makes it difficult for the immune system and antibiotics to penetrate. These lung infections are a serious and chronic problem in many people with CF. Currently, infections are largely managed by trial and error with a combination of antibiotics, antifungals and anti-inflammatory molecules.
"It is amazing to think that disease management by expert clinicians (which we are not) by trial and error has increased the average lifespan of people with cystic fibrosis from two years in the 1930s to around 45 in the United States and 55 in Canada, and yet we do not quite understand how such treatments affect the microbial communities living in people with cystic fibrosis, "said Dorrestein.
In biomedical research, scientists generally study bacterial infections by analyzing a specific type of bacterium, such as P. aeruginosa, and perhaps its interactions with human cells. But Quinn's background is in environmental microbiology. It examines the whole CF lung, living in a unique environment in which a particular bacterium does not work alone, but interacts with other microbes in the community, the human cells that make up the lung, as well as in other parts of the body. other molecules, chemicals and metabolites, and all behave like an ecosystem.
Quinn has therefore approached the lungs as any other environment, such as soil or seawater. He has developed a system that he calls WinCF, partly named in l & # 39; honor of the 19th century microbial ecologist, Sergei Winogradsky. Winogradsky invented a gradient system for studying microbes in the soil. Similarly, the Quinn WinCF system provides pH and oxygen gradients that mimic the narrow tubes that make up human lung bronchioles.
Quinn and his team collected sputum samples from 18 patients with cystic fibrosis and applied them to the WinCF system in their laboratory. Next, they modified factors such as pH, oxygen levels and antibiotics to map about 600 different lung diseases of cystic fibrosis.
Because of these pH and oxygen gradients, researchers have found that microbes in cystic fibrosis lungs are divided into two distinct communities: 1) known pathogens, microbes that can cause health problems, 2) anaerobes, microbes that thrive in areas with low oxygen and low pH.
"This stratification is important because it can affect the treatment of patients with cystic fibrosis," Quinn said. "For example, some bacteria can survive antibiotic treatment because they can hide deeper in the lungs mucus.In the meantime, killed bacteria can free up space for that. other microbes are developing, potentially creating a new set of problems. "
That's what the researchers saw when they addedP. aeruginosa tobramycin, an antibiotic at the top of the culture in their WinCF model, simulating inhalation into the airways with mucus-clogged bronchioles, as occurs in cystic fibrosis. The antibiotic has resulted in radical changes in the microbial composition of the system. Some bacterial species were killed in all areas of the column, others in the highest and most oxygen rich layers, but survived at lower depths, while others continued to thrive at lower depths. Quinn said that he was particularly surprised to see flowers from Aspergillus mushrooms grow in areas previously occupied by killed bacteria. Aspergillosis, the infection caused by this fungus, is not uncommon in patients with cystic fibrosis treated with antibiotics.
Not only has the antibiotic altered the microbial balance in the lung model of cystic fibrosis, but the chemical structure of the antibiotic itself has been altered by microbes. This alteration may help bacteria to resist its effect.
"Antibiotics alter the overall structure and relationships in a vibrant community, and not always in a way that benefits the patient," Quinn said. "We do not yet know the" rules "to tip the balance in favor of a beneficial microbial balance."
In contrast, when researchers simply lowered the pH of cystic fibrosis mucus by one unit in the WinCF system, the bacterial composition of the sample increased from 70% P. aeruginosa essentially to none of these particularly troublesome bacteria.
"In some cases, antibiotics may not even be as effective as the simple pH change suggested by our laboratory experience, which deserves clinical exploration," Dorrestein said.
To be clear, the WinCF model is not a perfect replica of the lungs of human cystic fibrosis. It does not contain human cells or components of the immune system that would also help shape the actual microbial composition of a person's lungs.
Thus, although this system should not yet be used to influence patient care, Dorrestein said the ultimate goal was to create a "precision care" clinic for cystic fibrosis patients. In this scenario, doctors and technicians could quickly analyze the sputum of each patient to look for unique molecular and microbial profiles and test different combinations of laboratory treatment options – pH change, oxygen level, antibiotics – before prescribing them to the patient.
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