Critical but overlooked: ICU patients’ gut bacteria

In pursuit of restorative treatments, researchers are examining changes to the microbiomes of critically ill patients.

Our bodies are full of bacteria, and when we get sick, those microbial populations change. Hospitals monitor patients’ bloodwork and vitals, so why not track the makeup of their microbiomes too? Paul Wischmeyer and his collaborators are conducting research that could allow them to do just that, opening the door for microbiome diagnostic indicators and probiotic measures to restore patients’ normal bacterial signatures. The first publication of data from the project appeared this week in the journal mSphere. We asked him about the research, and what he’s learned so far.

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ResearchGate: How did you first get involved in this field?

Paul Wischmeyer: My passion for the research I do started when I was a teenager. At 15, I was diagnosed with inflammatory bowel disease. I had been a very healthy kid until I took antibiotics for strep throat and began to bleed and had other gastrointestinal symptoms. I was diagnosed with ulcerative colitis shortly thereafter, and it progressed rapidly. I spent six months in the hospital and was given steroids and other medicines that never really made me better. I ultimately ended up losing my colon, getting quite sick, and being put in the ICU. Many surgeries later, it's still a part of my life. But it was at that age that I realized I wanted to study treatments that worked with the body, not against it, and to find ways to restore normalcy to the body after illness. When I started university, I focused my studies on how the gut, disease, recovery, and nutrition are interconnected.

RG: And what was the impetus for this particular study of microbiomes of ICU patients?

Wischmeyer: Any of us who work with the microbiome will say we're far more bacterial as humans than we are human as humans. More than 50 percent of the cells that exist in our body are bacterial cells, and 99 percent of the genetic material in our body is bacterial rather than human. So the role those organisms play in who we are as healthy or sick individuals is probably enormous.

Over years of nutrition and gut research, we began to realize that there were clearly major disturbances going on in the gut microbiomes of critically ill patients. We took the data we had and proposed a very large clinical trial of Lactobacillus-GG to prevent infection and sepsis to the NIH. They came back to us and—rightfully so—said it's hard for us to believe that one bacterium could define a therapeutic agent for all the different patients and different diagnoses that come into an intensive care unit. We’d like for you to define for us what exactly changes in the microbiome when severe illness occurs, to explore which bacteria need to be put back, and what kind of synthetic probiotic or synthetic stool transplant could restore health-promoting bacteria and fight off dysbiosis, the adverse bacterial colonies that grow in the gut when we're sick.

So I reached out to Rob Knight and explained that we have this large nutrition research platform with Daren Heyland in a number of hospitals that collect quite a bit of data, and do it largely for free. I said we’d love to start collecting microbial samples along with the other data, and we really can't do that without someone who's a true microbiome expert like he is. Rob and his lab said, that’s great, because we have thousands of healthy people’s data from the American Gut Project, but we don't know much about disease and how it changes the microbiome. And so the collaboration began. With essentially no funding, we worked together to initiate a project involving four medical centers across the US and Canada and multiple ICUs, generating an initial data set of 115 patients. It appears right now to be the largest survey of the microbiome in critical illness published to date. Studies in this field tend to be very small: 10-15 patients, for the most part in just one treatment center.

“We're far more bacterial as humans than we are human as humans.”

RG: And how did you collect the samples?

Wischmeyer: In each of the participating hospitals, if patients had been on a ventilator for 48 hours and were expected to stay in the ICU at least three days, they met inclusion criteria and we collected samples from them, anonymizing the data. The samples were collected by nurses and dieticians at the hospitals using techniques that mimic those of the American Gut Project. The American Gut Project is crowd-funded citizen science project, where you can go on the internet and for $99 you can send your poop, or your dog’s poop, or your friend’s poop to Rob, and he’ll analyze it and send you your microbiome results. They have a very standardized way of collecting samples with swabs, and so we tried to replicate that quite closely, because we knew that would be the large control group we’d compare against.

We collected the first sample at around 48-72 hours after ICU admission, and we’d collect another sample at discharge from the ICU, or day 10, to look for change over time. It was basically a small swab of the stool of the patient, a small swab of the oropharyngeal region—avoiding the teeth, which have quite a distinct microbiome—and then a skin swab across the forehead, looking at changes in the skin microbiome. We outlined this process in standardized procedure manual, and the participating hospitals collected the samples and sent them to Rob’s lab for processing. It’s a very inexpensive collection process and something you can teach anyone to do. So it’s a very realistic way to do this kind of study on a larger scale.

RG: And what have you learned so far?

Wischmeyer: Our hypothesis was that critical illness would lead to a loss of diversity of the microbiome and that this loss of diversity would correlate with adverse outcomes, or perhaps even predict them. That was really the goal of the project: to use the microbiome diagnostically to identify patients who are at risk for bad outcomes, then ultimately guide us in replacing the healthy bacterial population to drive recovery.

Our initial results have really supported that hypothesis. Patients lose significant, significant amounts of their normal flora, the families of bacterial species that make up a healthy gut or oropharynx. They’re largely replaced by pathogens or proteobacteria; like staph, proteus, and other bacteria we associate with GI-associated bacterial translocation. Under normal circumstances, the human gut is made up of many different species. The most abundant bacterial family might make up 25 or 35 percent, and there are many others present. Our patients often start out with that normal appearance, but within just a few days we saw that in some patients 95 percent of bacteria in the gut were one taxa, and often this was a pathogen that dominated. One bacterial taxa overwhelms the rest, or grows because the others have been wiped out by antibiotics or other interventions. The lack of diversity that can occur is severe.

“One bacterial taxa overwhelms the rest, or grows because the others have been wiped out by antibiotics or other interventions.”

One of the bacteria we noted was quite depleted in the sick patients is a Faecalibacterium, which is a very important bacterium that makes short-chain fatty acids and helps nourish and protect the gut under normal and stress circumstances. It’s been shown to be deficient in inflammatory bowel disease, and probably plays a role in controlling inflammation in the gut. Significant depletion of this bacterium had not to our knowledge been well-described before in critical illness, so that’s one of the first results. Faecalibacterium is likely a bacterial species we should be studying as a replacement for our patients, because it probably plays a key role physiologically, and it becomes quite depleted in acute illness.

The microbiomes of critically ill patients also mirrored some known bacterial compositions in ways that were often quite unexpected. In many patients, the bacteria began to revert back to what an early neonatal gut looks like. In other cases, the gut and the mouth—especially the gut—would resemble samples taken from corpses found at outdoor crime scenes or around autopsy sites.

RG: Does the type of illness matter in terms of the expected impact on the microbiome?

Wischmeyer: That’s another question we’re trying to answer. At the moment, we aren’t seeing those patterns emerge yet. This is very initial, but it appears that perhaps the microbiome’s response to illness is not necessarily related to the disease we have, but may also be linked to other factors, such as the types of antibiotics people are treated with. In our study, 100 percent of patients received antibiotics at some point in their ICU stay, which is quite shocking. Of course, these are people who had high disease severity classification scores with reasonable risk of death, so all of them getting antibiotics was not perhaps as shocking as if they were less sick, but nevertheless striking. We think antibiotics are a major factor. In some of the more recent research we’ve done, we used a standardized score that quantitated some of the pressures that different antibiotics exert—some are much more broad in their killing activities than others—and it appears that antibiotic pressure may relate to some of the bacterial changes we’re seeing. It doesn’t appear to be all antibiotic related, but the treatments we give are fairly common across different diagnoses of patients, and do seem to drive some of these changes.

There are other factors as well: an 18-year-old trauma patient who was hit by a car and had never been sick a day in their life probably does look different for some period of time in the ICU than a 60-year-old patient who’s had cancer and been in the hospital for a month prior to entering the ICU. That’s one of the next steps: to look at the data and really break out diagnoses groups and identify the trends that actually drive microbiome patterns. As I move my research program to Duke University’s Department of Anesthesiology, we hope to embark on answering many of these questions.

“We need to ask ourselves in ICU care, ‘Are we creating
survivors or victims?’”

RG: Do you think the composition of the microbiome could become the standard way we look at illness in ICUs?

Wischmeyer: We hope it becomes part of it. I think you could imagine a day where we follow patients’ microbiomes on a daily or weekly basis. As the technology evolves, we’re actually not that far from being able to follow changes to the microbiome on a regular basis, much like we would blood cultures, blood pressure, or other laboratory markers. This could allow us to predict which ICU patients are at risk for adverse outcomes or have undiagnosed infections. It could also tell us who needs to be treated aggressively and early with restoration therapies—we call it “resodding the lawn.” We could tell individually, patient to patient, what bacteria need to be given back based on a sample collected at admission.

We can save just about anybody in the ICU from just about anything and get them out of the hospital. But the reality is these patients are so depleted, they’re never able to go back to their lives as normal. Many of them, because of their weakened state and the other things we’ve done to their bodies and microbiomes, will die within a year, never having held their grandkids again, never having walked down the street with their spouse again. With all of our advances in critical care, we must ask ourselves, are we creating survivors or are we creating victims, people who will never really go home and back to the quality of life they had before? Now that we’ve gotten good enough to save people from severe disease and injury, we need to work on ways of restoring health and life and normalcy. By creating effective methods of restoring the microbiome, together with nutrition and exercise, we hope we can begin to give people their lives back.

Featured image courtesy of J. van Rosmalen.