Our bodies need neurotransmitters and hormones to stay healthy, but too much or too little can cause conditions such as breast cancer or Parkinson’s disease. Normally, excess neurotransmitters and hormones in the body are removed through excretion via the gut. A team of scientists has discovered a new class of enzymes from bacteria in our guts that can alter levels of serotonin, the “feel good” neurotransmitter, and estradiol, a sex hormone, among other compounds. The scientists also found that certain FDA-approved drugs can inhibit these bacterial enzymes. In this way, a cancer drug may inadvertently cause depression in some people by interfering with excretion and thereby initiating a change in their serotonin levels.
These surprising findings could explain why some people respond well to certain drugs and other people don’t, leading the way to more personalized drug dosing based on genomic analysis of the patient and the microbes in their gut. The researchers used the Advanced Photon Source (APS), a U.S. Department of Energy (DOE) Office of Science user facility at DOE’s Argonne National Laboratory.
Our bodies maintain equilibrium in part by ensuring that detrimental substances, such as environmental toxins or excess molecules created naturally when we eat too much turkey at Thanksgiving, are flushed away. To do this, the liver attaches a sugar to the unwanted molecule that serves as a “tag” for trafficking it to the gut for excretion.
For the past 10-15 years, many scientists have focused their investigations on one detrimental substance in particular—drugs that cause adverse reactions in the GI tract—to discover what makes them toxic. They found that certain microbes living in the gut feed off the sugar attached to the detrimental substance by using an enzyme that removes the sugar for microbial growth. Rather than being excreted, the detrimental substance, freed of its sugar – or “reactivated,” in scientific language – remained in the body, causing off-target effects, from irritable bowel syndrome to Crohn’s disease.
Little was known, however, about how gut microbes were behaving toward naturally-occurring molecules like hormones or neurotransmitters. To fill that gap, the research team turned their attention to dopamine and serotonin, as well as estradiol and thyroid hormones, to see if the gut microbes were processing them the way they processed toxic drugs.
A primary question was: Why do the bacteria have these enzymes in the first place?
Through structural biology, in vitro biochemistry, multi-omics, and in vivo studies, the team showed that specific enzymes in the gut acted on these naturally occurring molecules in the same way they processed man-made molecules like drugs. This suggested to the scientists that sugar-linked natural chemicals like hormones and neurotransmitters play an important role in the microbial evolution of an enzyme that allows gut bacteria to take advantage of this resident food supply.
The enzyme in question is called GUS, or beta-glucuronidase. Previous research had shown that certain types of FDA-approved drugs, including those that fight cancer and depression, inhibit a specific subset of gut microbial GUS enzymes. Different people have different types of microbes in their guts and, therefore, different GUS enzymes. The scientists wondered whether this could explain why different people react differently to these drugs: Might the difference lie in which enzymes were being inhibited and which enzymes were left to interfere with the body’s natural chemical balance, or homeostasis?
The key answers lay in detailed studies using structural biology, a field that investigates how complex biological macromolecules do their job. Drugs usually have one target, but in the expansive gut microbiome, hundreds of different proteins can all do the same job. The scientists set out to understand on an atomic level why some GUS are more active than others.
Using the National Institute of General Medical Sciences and National Cancer Institute Structural Biology Facility (GM/CA) beamlines at 23-ID-B and 23-ID-D at the APS, the team collected data that enabled them to solve the crystal structures of various species of gut microbes in complex with various anticancer and antidepressant drugs. What they found not only surprised them but also doubled the pool of enzymes that matter – they’d discovered that a whole other class of enzymes, called C-Terminal Domain GUS (CTD), are critically efficient at processing the sugar-attached molecules and are very potently inhibited by certain drugs.
Read more on Argonne website
Image: Simpson et al. pinpoint the gut microbial enzymes (green) that reactivate neurotransmitters and hormones (yellow, orange, and purple) essential to homeostasis and to diseases ranging from cancer to anxiety. They also show that a range of FDA-approved drugs (blue) inhibit these enzymes and impact local and systemic hormone and neurotransmitters levels. The study highlights the indispensable role of gut microbes in endobiotic homeostasis and indicates that therapeutic disruption of this role promotes interindividual variabilities in drug response.
