As a gastrointestinal surgeon and critical care specialist, John Alverdy has treated many patients in the intensive care unit (ICU) who have had very big operations, such as major organ reconstructions. “There is a race between making the patient better, fixing the bleeding, and how long they will be sick, exposed to dialysis or ventilators. The less time patients spend in there the better off they are.”
For patients who spend several weeks in the ICU, that race is sometimes lost to late-onset sepsis, a condition where patients succumb to a systemic infection that causes immune system dysfunction and multi-organ failure. Alverdy had a hunch that gut microbes might play a critical and culpable role in this process.
Fifteen years ago, Alverdy teamed up with Olga Zaborina, a microbiologist, to study the gut microflora found in critically ill hospital patients. Based at University of Chicago, they hypothesize that it’s the ‘abnormal’ gut microbes, those that survive the extreme amount of antibiotics thrown at these patients that eventually turn deadly.
“Nobody had asked what happens to bacteria in the gut when the host gets really sick,” says Alverdy. And as symbiotic gut microbes continuously sensing the state of their host, they know when you get sick, he says. “They know if you are hot, if you’ve been exercising and are sweaty, if you ate well that day and they are constantly adjusting.”
But what happens to that ongoing molecular conversation between the host and gut microbes in the ‘hostile environment’ of the ICU, which includes scads of antimicrobial drugs, low nutrition, and pain relief from morphine?
Zaborina and Alverdy decided to catalog the surviving gut microbes, find out who they are and—more importantly it turns out—how they are behaving in these patients at risk for sepsis.
They surveyed stool samples from 14 patients with long ICU stays, including six people who stayed more than a month. Using next-generation sequencing of the microbes’ ribosomal RNA 16S subunit, the team found that four of these patients had gut microbe communities of only two species. Typically, the two members consisted of a Candida strain of infectious yeast and an antibiotic-resistant pathogenic bacterial strain, such as Enterococcus faecium or Staphylococcus aureus, the researchers report in mBio® this week.
In marked contrast, fecal samples taken from five healthy volunteers harbored a large and diverse array of microbes which were overwhelmingly nonpathogenic and beneficial.
“The mere presence of bad guys doesn’t tell you who is going to live or die,” notes Alverdy. Two ICU patients with long stays were discharged home, while three others died of sepsis—and yet all of them carried pathogenic intestinal microbes. “It is not only which microbes are there, but how they are behaving.”
In the lab, Zaborina could test that behavior in a clever way using the tiny worm, Caenorhabditis elegans, which likes to feast upon microbes. The team grew up cultures of the ICU patients’ gut communities to feed the worms—both in the yeast-plus-bacteria pairs and separately. When the worms eat virulent pathogens, they are effectively poisoned from the inside out.
Using the worm ‘guinea pigs’, the team showed that often, the yeast alone would kill the worms, but when fed alongside its bacterial partner, the yeast was not harmful. “If you do something to one of those partners, then that can change their behavior” from peaceful coexistence, or commensalism, to virulence, says Zaborina.
Next, she added an opioid drug to the mix fed to the worms to mimic stress signals that are released in the gut in response to injury and illness. Including the opioid also provoked some yeast-bacterial pairs to switch from commensal to virulent behavior. However, the researchers could reverse this and prevent virulence by feeding the worms a molecule that created high phosphate levels in their gut—a signal that might trick microbes into sensing that ‘all is well’ with their host.
Giving ICU patients a similar phosphate-bound molecule might help keep their remaining gut microbes from turning virulent. Zaborina adds that doctors should pursue ways to stabilize and diversify the gut microbes of ICU patients.
“We are taking the sickest patients in the hospital and wiping their microbiome out,” says Alverdy. “This study tells us there’s got to be a better way.”