In a new study, researchers at the University of Chicago were able to predict postoperative infections in liver transplant patients by analyzing their intestinal microbiome. Their analysis represents a critical step forward in exploring the connection between the gut microbiome, the bacteria that populate the human body, and overall health.
The results of research were published in Cell Host & Microbo.
Intestinal microbiome: how can it help in liver transplants?
“Antibiotic resistance is growing every year and getting worse. Without antibiotics that work, we can't 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 whether the microbiome might influence the risk of infection.
The researchers discovered a wide range of microbiome compositions in different patients.
“A healthy microbiome would be composed of over a trillion bacterial cells, with thousands of unique species, like a diverse rainforest,” Lehmann explained. “Some patients see their entire ecosystem wiped out.” They still have more than a trillion cells, but there is only one bacterial species, usually harmful and resistant to drugs. It would be like cutting down the rainforest and planting just one species of noxious weed.”
Researchers have found that healthy microbiomes produce several key metabolites, which are molecules produced through 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 suit their own needs.
It turns out that in a diverse microbiome, those needs include fighting drug-resistant bacteria. Some of the bile acids are highly toxic to bacteria such as vancomycin-resistant enterococcus (VRE), a type of antibiotic-resistant bacteria that often causes infections in patients undergoing surgery, cancer treatment, or intensive care.
Next, the researchers examined their data to see if there was a correlation between the composition of the microbiome and postoperative infections.
“It turned out that the amount of drug-resistant pathogens in the microbiome predicted postoperative infections with an accuracy that we would normally look for in a clinical trial,” Lehmann said.
The team then took it a step further. Instead of sequencing genomes to identify specific bacterial species, they decided to look only at metabolites in the patients' bacteria to see if those molecules offered the same predictive value.
Metabolites alone allowed them to classify patients into two categories: healthy microbiomes and unhealthy microbiomes. Making the final analytical leap, the scientists discovered that they could use metabolites to predict whether a patient would contract an infection.
“We can go directly from metabolites to predicting a clinical outcome,” he said. Lehmann said. “This is important because metabolomic analysis can be performed very quickly, while 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 on the gut microbiome lay the foundation for future studies that could solidify the connection between infection and metabolites in feces, as well as explore potential causal relationships.
“The next step in this course of research will be to investigate whether we can use these findings to fix people's microbiomes,” the researcher said. Lehmann said. Patients who have unhealthy, single-species gut microbiomes and are at high risk for infection could potentially receive healthy gut bacteria from external sources to restore the production of healthy metabolites, including molecules such as secondary bile acids that can help protect against drug-resistant infections .
In 2023, the FDA approved two products for microbiome restoration. “Restoring the microbiome is not in the distant future; it's already in the present,” Lehmann said.
The University of Chicago's Division of Biological Sciences already has a biobank containing thousands of bacteria, all analyzed and classified based on their genomes 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 gut microbiome bacteria derived from healthy donors and package them into pharmaceutical-grade capsules that people can take like pills.
“We have already created a handful of cocktails of microbiome bacteria that are missing in patients who have had poor outcomes, but are present in patients who have good outcomes,” the researcher said. Lehmann said. “Those bacteria can work together to produce metabolites that were missing in patients who contracted infections, and therefore can inhabit the gut and theoretically defend against future adverse outcomes.”
In patients who have received broad-spectrum antibiotic treatment, such capsules could be used to repopulate healthy gut microbiome bacteria that have been wiped out. In patients at high risk for drug-resistant bacterial infections, supplementation of microbiome metabolites may be able to provide some protection.
“We have lost the battle against multiple drug-resistant bacteria, so we desperately need more weapons,” Lehmann said. “Understanding the microbiome, testing its health, and restoring it are all crucial new tools we can add to our arsenal.”
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