Studying the microbiome’s effects on the liver is critical for human health. The liver is the organ (only second to the intestine) most directly impacted by the composition of the intestinal microbiome. In addition, liver transplantation is complicated by high rates of infection that have been linked to the intestinal microbiome. Many liver transplant patients are colonized with multidrug-resistant organisms (MDROs), which is associated with reduced microbiota diversity.

Now, researchers analyzed fecal samples from over 100 liver transplant patients to see if the microbiome could be influencing their risk of postoperative infection. By quantifying fecal metabolites from 107 patients undergoing liver transplantation, they could correlate these with fecal microbiome compositions, pathobiont expansion, and postoperative infections. Their analysis was able to predict postoperative infections in liver transplant patients by analyzing their fecal microbiome.

This work is published in Cell Host & Microbe in the paper, “Fecal metabolite profiling identifies liver transplant recipients at risk for postoperative infection.”

“Antibiotic resistance is growing every year and getting worse. Without antibiotics that work, we can’t do things like perform surgeries, protect premature infants, or treat cancer,” said Christopher Lehmann, MD, assistant professor of medicine at UChicago Medicine. “It turns out the human microbiome, particularly the gut microbiome, has adapted to fight off drug-resistant bacteria over the course of history. We need to try to understand how that works to fight off these drug-resistant infections.”

Healthy microbiomes, the researchers found, produce several key metabolites, including short-chain fatty acids, which are beneficial to human hosts, as well as secondary bile acids produced when the bacteria modify human bile acids to fit their own needs. Some of the bile acids are highly toxic to bacteria such as vancomycin-resistant Enterococcus (VRE), a type of antibiotic-resistant bacteria that frequently causes infections in patients who have undergone surgery, cancer treatment, or intensive care.

The researchers examined 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 we’d normally be looking for in a clinical test,” Lehmann said.

The team then analyzed just the metabolites in the samples to see if they offered the same predictive value. The scientists found they could use the metabolites to predict whether a patient would get an infection at all.

More specifically, the authors wrote, “Consistent with experimental studies implicating microbiome-derived metabolites with host-mediated antimicrobial defenses, reduced fecal concentrations of short- and branched-chain fatty acids, secondary bile acids, and tryptophan metabolites correlate with compositional microbiome dysbiosis in LT [liver transplantation] patients and the relative risk of postoperative infection.”

“We can go straight 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 too complicated to be used as a diagnostic or predictive test in clinical practice. However, these findings lay the groundwork for future studies that could solidify the connection between infection and metabolites in fecal samples, as well as exploring potential causal relationships.

“The next step of this course of research will be investigating whether we can use these findings to correct people’s microbiomes,” Lehmann said. Patients who have unhealthy, single-species gut microbiomes and are at high risk of infection could potentially receive healthy gut bacteria from external sources and restore production of healthy metabolites, including molecules like the secondary bile acids that can help protect against drug-resistant infections.

In 2023, FDA approved two microbiome restoration products. “Microbiome restoration isn’t in the far-off future; it’s already in the present,” Lehmann said.

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

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