In a study that one microbiome researcher calls “one of the most important papers that has come out in the entire microbiome field,” a team of scientists has cataloged how dominant species of microbes living in our guts metabolize some two-thirds of common drugs that treat a wide assortment of human diseases. The findings suggest that how well an oral drug works may not just be a function of how well our bodies absorb it, but what our intestinal microbes do to it (Nature 2019, DOI: 10.1038/s41586-019-1291-3).
Bacteria do more to drugs than what most people think, says University of Miami scientist Nichole Klatt, who studies how gut microbes metabolize HIV drugs and who was not involved in the research. She says these findings, coupled with previous smaller studies on single drugs, signify how critical it’s becoming for drugmakers to consider the microbiome when designing and testing new medications. “I think that it’s going to take a while for this to really be incorporated and be part of people’s consideration. But I think that is where the field is going to move,” she says.
To study how gut microbes metabolize different drugs, the research team, led by Andrew Goodman at the Yale University School of Medicine, tested 271 small molecule drugs against 76 bacterial strains representing the most dominant groups of bacteria in the human gut, including Clostridia and Bacteroides. They tested medicines like imatinib, a cancer drug sold as Gleevec; fluoxetine, sold as Prozac; levonorgestrel, sold as the emergency birth control Plan B; and diltiazem, an antihypertensive drug sold as Cartizem.
Two-thirds of the drugs were metabolized by the bacteria in lab culture tests, some by a handful of species, others by many. Through mass spectrometry, the team could classify the metabolites that the bacteria spit out after dining on the drugs. They could match different species of bacteria to specific metabolites, giving the researchers ammunition to chase down the enzymes the bacteria were using to metabolize the drugs.
For example, Bacteroides species liked to chop up ester and amide groups. The team found that, in general, the bacterial species they tested preferentially metabolized drugs with lactones, nitro groups, azo groups, and urea groups.
Identifying the metabolites produced by the bacteria is important, says Maria Zimmermann-Kogadeeva, a computational biologist who conducted much of the work, because it underscores the difference between how our livers and gut bacteria metabolize drugs. The liver metabolizes drugs for elimination from the body and tends not to make toxic by-products. But bacteria use these small molecules as food—they take what they need and what they leave behind could be toxic, affecting a drug’s safety, if not its efficacy.
The scientists also tested some drugs in mice to determine how bacteria in an actual gut treated the molecules. The team could control which bacterial species were in the mouse guts by working with animals born without intestinal bacteria and then inoculating them with different species. In one case, they found that a bacterial deacetylating enzyme was responsible for metabolizing diltiazem. Meanwhile, a bacterial hydrolase seemed to metabolize many different drugs.
The researchers also studied human fecal samples to determine if similar metabolism occurred in people. They found, for example, an association between the number of bacterial species carrying genes for a deacetylase and the amount of acetyl-containing drug molecules that had been metabolized.
The research team envisions a future in which doctors screen a patient’s microbiome before receiving treatment to determine what medications might work best, or, if none works, whether a fecal transplant of a specific bacterial species might help.
But that future is still far away, says Jeremy Nicholson of Murdoch University, a human metabolism expert. The human body is complex. Gut bacteria exist in communities that change over time. The human diet influences what’s in our guts, he says, and all this possibly influences how drugs get metabolized.
Nicholson calls the new study “long overdue,” but preliminary.
Goodman agrees. “I would say these are very early days in this research,” he says. He thinks microbiome testing during drug development could save companies a lot of frustration in the long run.“What we hope is that this information is helpful in identifying compounds in the preclinical stage that are most likely to work well.”