Interaction between human gut and immune system increases infection risk in critically ill patients

Twenty to 50 per cent of all critically ill patients contract potentially deadly infections during their stay in the intensive care unit (ICU) or in hospital after being in the ICU — markedly increasing the risk of death.

Despite the use of antibiotics, “hospital-acquired infections are a major clinical problem that persists to be a huge issue for which we don’t have good solutions,” says Dr. Braedon McDonald, MD'13, PhD'13, an ICU physician and assistant professor in the Department of Critical Care Medicine at the Cumming School of Medicine (CSM) and member of the Snyder Institute for Chronic Diseases at the University of Calgary.

Now, a two-year study led by McDonald in collaboration with UCalgary colleagues has found that the high rates of infection in critically ill patients are linked with abnormalities of the microbiome, or human gut, in conjunction with an impaired immune system. Collectively, this microbiome-immune system dysfunction lowers the body’s ability to fight infections.

“The signal that we’ve seen in our research is that a family of bacteria seems to be important for directing the immune system, and in this context they’re causing problems with the immune system,” McDonald says. “This information is important because it gives us a whole new avenue to start thinking about not just ways to treat infections, but prevent them.”

The team’s study, involving 51 critically ill adult patients newly admitted to the ICU, found that patients who experienced an abnormal increase in the gut of a family of bacteria called Enterobacteriaceae were at the highest risk of severe infections. This abnormal increase of bacteria in the gut is called a “bloom.” The researchers discovered that a bloom of these bacteria was driving dysfunction of the immune system.

The Enterobacteriaceae family includes the well-known E.coli bacteria that naturally occur in the gut (and in the environment), along with other species from the same family that can cause serious infections. Previous studies in mouse models and in cancer patients have shown a link between microbiome abnormalities and problems in the immune system.

This new study is among the first to uncover the link between Enterobacteriaceae and immune-system impairment associated with increased infection risk in critically ill patients. The team’s study, conducted in the ICU and in the International Microbiome Centre (IMC) at UCalgary, is titled “Dysbiosis of a microbiota-immune metasystem in critical illness is associated with nosocomial infections,” and has been published in Nature Medicine.

“Holistic” approach to problem needed

The researchers ran a systemic analysis of fecal samples from critically ill patients. They integrated this with a systems-level analysis of immune and inflammatory responses using single cells in each patient’s bloodstream. Patients were studied over the first week of acute critical illness.

The research showed that the gut microbiota and systemic immunity work together as a dynamic “metasystem,” in which problems with gut microbes and immune system dysfunction are associated with significantly increased rates of hospital-acquired infections. Gene-sequencing analysis revealed this metasystem is driven by the expansion of Enterobacteriaceae in the gut, resulting in abnormal cell responses and increased inflammation.

“The microbiome becomes injured in critical illness, in a way that allows these bacteria — these bad actors — to start taking over because the mechanisms that are usually there to keep them at bay are lost,” McDonald explains.

Jared Schlechte, BSc'21, a PhD candidate in McDonald’s lab in the immunology program and first author of the study, led and conducted the data analysis for the study. “This was a combination of finding informative ways to integrate multiple data sets and patient information into a single ‘metasystem,’ as well as using cutting-edge analyses to identify the distinct signal we observed in our patients showing an enrichment of Enterobacteriaceae,” Schlechte says.

McDonald says the study’s findings “suggest to us that, if we want to fight infection, we can’t just target these bad bacteria in isolation and the immune system in isolation. We really need to have a more holistic view of how things are functioning.”

The systemic approach used in the study, and the fact it followed critically ill patients over a week, indicates this specific microbiome-immune system dysfunction is not unique to one group of critically ill patients or one type of disease, McDonald says. “This means developing therapies has the potential to benefit across the entire spectrum of critically ill patients,” he says.

UCalgary faculty collaborators and study co-authors included Dr. Christopher Doig, MSc'96, MD; Dr. Mary Dunbar, MSc'12, MD'12, MSc'21; and IMC director Dr. Kathy McCoy, PhD. Amanda Zucoloto, a PhD candidate, along with research technician and laboratory manager Ian-Ling Yu, also co-authored the study. The study was supported by the Canadian Institutes of Health Research and the Alberta Health Services Critical Care Strategic Clinical Network.

Clinical trial in patients planned

As a next step, McDonald and the team plan to launch a randomized, controlled clinical trial, based on a precision medicine approach. Patients who agree to participate will be given engineered microbiomes aimed at suppressing the Enterobacteriaceae and the immune system dysfunction that comes with it.

The approach borrows from probiotics therapy, but utilizes multiple different bacteria engineered to specifically target the Enterobacteriaceae expansion in the patient’s gut. “What we’re trying to do is restore the normal mechanism that works when we’re healthy, and take advantage of that to help protect people from infections,” McDonald says.

To ensure their engineered microbiomes are safe and effective, the team is taking microbiome samples from critically ill human patients and applying them to germ-free mice, to test and prove different precision methods and targeted therapies before moving to human patients.