Microbiome information found in feces helps predict infections in liver transplant patients

In a new study, researchers at the University of Chicago were able to predict postoperative infections in liver transplant patients by analyzing molecules present in their stool. Their analysis represents a big step forward in exploring the link between the gut microbiome – the bacteria that inhabit the human body – and overall health.

“Antibiotic resistance is increasing every year and getting worse. Without effective antibiotics, we cannot do things like perform surgeries, protect premature babies, or treat cancer,” said Christopher Lehmann, MD, assistant professor of medicine at UChicago Medicine and lead author of the study. “It turns out that the human microbiome, particularly the gut microbiome, has adapted to fight drug-resistant bacteria throughout history. We need to try to understand how it works to fight these drug-resistant infections. “

Liver transplant patients are particularly susceptible to drug-resistant infections. So Lehmann and his fellow researchers analyzed fecal samples from more than 100 liver transplant patients to see if the microbiome could influence their risk of infection.

Healthy or unhealthy microbiomes

Researchers discovered a wide range of microbiome compositions in different patients.

“A healthy microbiome would be made up of over a trillion bacterial cells, with thousands of unique species, like a diverse rainforest,” Lehmann explained. “Some patients see this whole ecosystem wiped out. They still have over a trillion cells, but there’s only one bacterial species, usually a bad drug-resistant species. It would be like clear-cutting the rainforest and plant only one noxious weed species.

Researchers have found that healthy microbiomes produce several key metabolites, which are molecules produced by digestion or other chemical processes within an organism. These metabolites include short-chain fatty acids, which are beneficial to human hosts, as well as secondary bile acids produced when bacteria modify human bile acids to meet their own needs.

It turned out that in a diverse microbiome, these needs include fighting drug-resistant bacteria. Some bile acids are highly toxic to bacteria such as vancomycin-resistant enterococci (VRE), a type of antibiotic-resistant bacteria that commonly causes infections in patients who have undergone surgery, cancer treatment, or healthcare. intensive.

The predictive power of droppings

Next, the researchers looked at their data to see if there was a correlation between microbiome composition and postoperative infections.

“It turned out that the amount of drug-resistant pathogens in the microbiome predicted postoperative infections with an accuracy that we normally look for in a clinical test,” Lehmann said.

The team then went even further. Rather than sequence genomes to identify specific bacterial species, they decided to look only at metabolites present in patients’ feces to see if these molecules offered the same predictive value. The metabolites alone allowed them to sort patients into two categories: healthy microbiomes and unhealthy microbiomes. Taking the final analytical step, scientists discovered they could use the metabolites to predict whether a patient would get an infection.

“We can go directly from metabolites to predicting a clinical outcome,” Lehmann said. “This is important because metabolomic analysis can be performed very quickly, whereas sequencing is relatively slow.”

The analytical algorithm is currently very complicated and would require extensive validation before being used as a diagnostic or predictive test in clinical practice. However, these findings lay the foundation for future studies that could solidify the link between infection and metabolites present in feces, as well as explore potential causal relationships.

The next step: repairing microbiomes to prevent infection

“The next step in this research will be to determine whether we can use these results to correct human microbiomes,” Lehmann said. Patients who have unhealthy, monospecific gut microbiomes and are at high risk for infection could potentially receive healthy gut bacteria from external sources and restore the production of healthy metabolites, including molecules like secondary bile acids that may help to protect against drug-resistant infections.

In 2023, the FDA approved two microbiome restoration products. “Restoring the microbiome is not in the distant future; it is already in the present,” Lehmann said.

UChicago’s Division of Biological Sciences already has a biobank containing thousands of bacteria, all of which have been analyzed and classified based on their genome and the metabolites they produce. UChicago is building a Good Manufacturing Practices (GMP) compliant facility that will allow scientists to produce, filter and freeze-dry key gut bacteria derived from healthy donors and package them into pharmaceutical-grade capsules that people can take like pills.

“We’ve already created a handful of cocktails of bacteria that were absent in patients who had poor outcomes, but were present in patients who had good outcomes,” Lehmann said. “These bacteria can work together to make the metabolites that were missing in infected patients, and then they can inhabit the gut and theoretically defend against future negative outcomes.”

In patients who have received broad-spectrum antibiotic treatment, these capsules could be used to repopulate healthy gut bacteria that have been eliminated. In patients at high risk of drug-resistant bacterial infections, supplementing metabolites from their microbiome may provide some protection.

“We have lost the battle against several drug-resistant bacteria, so we desperately need more weapons,” Lehmann said. “Understanding the microbiome, testing its health, and restoring the microbiome are all crucial new tools we can add to our arsenal. »

The study titled “Fecal metabolite profiling identifies liver transplant recipients at risk for postoperative infection” was published in Cellular host and microbe in December 2023. Co-authors include Nicholas P. Dylla, Matthew Odenwald, Ravi Nayak, Maryam Khalid, Jaye Boissiere, Jackelyn Cantoral, Emerald Adler, Matthew R. Stutz, Mark Dela Cruz, Angelica Moran, Huaiying Lin, Anitha Sundararajan, Ashley M. Sidebottom, Jessica Cleary, Eric G. Pamer, Andrew Aronsohn, John Fung, Talia B. Baker, and Aalok Kacha.