Published 24th November 2022

Gut bugs and drugs: How medicines and microbes mix

Although scientists have designed and tested an impressive collection of medicines that have saved countless lives, there are still unanswered questions.

For instance, a drug might be incredibly effective for some people and might not work at all for others. Why?

Similarly, some people might experience terrible side effects from a particular medicine, while others have no such trouble. What’s going on?

We all respond to drugs differently. And this can be due to a range of factors. 

Scientists now know that some of these personalized responses might be due to your gut microbiome — the trillions of microbes in your gut.

Experts in this emerging field of study, pharmacomicrobiomics, hope that in the future, understanding the interactions between drugs and bugs might help reduce side effects and make medicines more effective.

Here, we’ll outline some of what we know so far about this complicated and fascinating topic.

A varied response

As we mentioned, how well a drug works can vary substantially between people, and the same goes for side effects.

For instance, adverse drug reactions were responsible for an estimated 3.5% of hospital admissions in Europe from 2000 to 2014. And on average, 10% of patients experienced an adverse reaction to a drug during their stay at a hospital.

Coming to grips with why drugs behave differently in different bodies is important work.

And it likely involves many factors, including underlying health conditions, age, sex, diet, interactions with other medications, and whether the individual took the drug as prescribed. Genes can also play a role.

The role of genes

Before we jump into the role of gut bacteria in how you respond to drugs, we should mention genetics.

Although scientists don't have the full picture yet, they’ve identified some important examples of how certain genes influence some drugs.

One case is the antiretroviral agent abacavir. Doctors often prescribe it to people with HIV.

Around 10% of white people and 20% of people in India carry a genetic variant that gives them a 1 in 2 chance of experiencing a life-threatening allergic reaction to the drug.

Interestingly, less than 3% of people in Africa and East Asia have this genetic variant.

So far, scientists have identified about 20 genes that can predict different responses to around 80–100 drugs. This search through the genome continues, but genes don’t tell the whole story.

Enter the gut bugs

Trillions of microorganisms call your gut home. Although they're famous for helping you digest food, their influence goes way beyond meals and snacks.

Some scientists think these tiny, single-celled critters might help explain why some drugs only work for some people — and why some medications cause side effects for some folks but not others.

So, how might your onboard microbes be influencing these things? Let’s have a look at what might happen when a theoretical medicine enters the realm of microbes.

When you swallow a drug, it may end up in your large intestine, where most of your gut bacteria live. 

Once there, the drug might alter the microbiome, or the microbiome might alter the drug. We’ll look at both of these scenarios in a little more detail later, but here’s a brief overview:

Drug alters the microbiome

Once in your gut, a drug might slightly change the environment within your intestines. 

This could alter some gut bacteria’s metabolism or influence their growth, which might increase the populations of certain species while reining in others. 

Microbiome alters the drug

Alternately, gut bacteria might interact with the drug. Microbes have countless enzymes that we lack, and these might chemically alter the drug in ways our bodies can’t.

And here’s another dash of complexity: Once your digestive system breaks down a drug into different compounds, these can enter your circulation and travel around your body. They can end up in various places, and some can even end up back in your gut

If they return, these metabolites have another chance to interact with your gut bacteria and potentially produce even more compounds.

So, it’s a complicated story to unpick. 

Next, we’ll look at some examples of how specific drugs influence gut bacteria in a bit more detail. Then, we’ll switch things around and look at how gut bugs affect how drugs work.

Drugs influencing gut bugs

Your gut microbiome is unique. And, incredibly, one study concluded that 10% of the variation between people’s gut microbiomes can be explained by the drugs they’ve taken.

Because scientists know that the gut microbiome is important for overall health, altering it can surely influence our health.

The best-understood drugs in this regard are antibiotics. Because antibiotics are excellent at killing harmful bacteria, it’s no surprise that they also kill our gut bacteria.

Researchers have shown that antibiotics can cause dysbiosis — a general gut microbiome imbalance. 

Broad-spectrum antibiotics, which can kill a range of bacteria, can reduce the populations of 30% of species in the gut.

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Aside from antibiotics, other drugs can also influence the gut microbiome. One study identified 19 groups of drugs associated with changes to the gut microbiome. 

These included proton pump inhibitors (PPIs), metformin, statins, and laxatives. 

Let’s look at PPIs in more detail because scientists have figured out how they influence our gut bugs.

Before diving in, we should clarify that you shouldn’t stop taking any medication that your doctor has prescribed.

PPIs and gut bugs

PPIs help treat conditions like stomach ulcers and gastroesophageal reflux disease (GERD). 

Normally, the bottom of the esophagus — the tube between your mouth and stomach — only opens to let food and drink into your stomach. GERD can develop if the bottom of the esophagus instead hangs open frequently or for a long time.

This allows stomach acid to rise up and damage the esophagus. PPIs inhibit the production of stomach acid, allowing the damaged tissues to heal.

So how do PPIs change the gut microbiome?

Because there’s less acid in your stomach, more bacteria from your mouth can make the trip down to your intestines. Usually, they’d be destroyed before they arrived.

This also means that disease-causing bacteria are more likely to reach your gut. Because of this, people who take these drugs have a higher risk of developing Clostridium difficile infections.

But not all medicine–gut bug interactions are negative. Let’s look at metformin.

Metformin and short-chain fatty acids

Doctors commonly prescribe metformin to treat type 2 diabetes. 

Scientists have shown that the drug encourages the growth of certain gut bacteria, which leads to increased production of short-chain fatty acids (SCFAs).

SCFAs are important for your health in several ways. For instance, they nourish your gut lining, reduce inflammation, and help improve glucose control.

Some experts believe that metformin’s ability to encourage SCFA-producing gut bacteria might help explain how the drug treats type 2 diabetes.

Gut bugs influencing how drugs work

OK, now we’ll flip it around. We’ve looked at how drugs influence the gut microbiome, now let’s look at how gut bugs interact with drugs.

To recap, gut bacteria have a huge selection of enzymes that humans lack. And some of these enzymes can affect drugs.

Sometimes the enzymes change the way a drug works, produce new compounds from the drug, or even stop it from working.

To date, scientists have identified a number of drugs that gut bacteria can alter with their enzymes. Let’s look at a couple of examples.

Activated by microbes

Amazingly, scientists identified the first case of a drug being influenced by gut bugs in the 1930s.

The drug in question is an antibiotic that doctors once used to treat a type of Streptococcus infection. 

Called prontosil, this antibiotic doesn’t kill bacteria when it’s tested outside of the body. 

But when it’s inside a human, gut bacteria chop it up, producing sulfanilamide, which does kill Streptococcus bacteria. Without the gut bacterial interaction, the drug doesn’t work at all.

Deactivated by microbes

Doctors prescribe digoxin to treat various cardiovascular troubles. However, in some people, the drug is broken down into digoxin reduction products (DRPs), which don’t treat the problem.

In the 1980s, a group of researchers recruited people who didn’t respond to digoxin to figure out why.

The team found that after a course of antibiotics, the drugs did work for these people. Their bodies had stopped turning the digoxin into DRPs.

Later studies identified the culprit: a bacterium called Eggerthella lenta that split digoxin into DRPs.

As an interesting aside, ZOE’s research has shown that these bacteria are also associated with poorer health outcomes.

Looking at cancer

One of the most recent approaches to treating cancer is immunotherapy. This treatment helps bolster the immune system’s attack on cancer cells.

Immunotherapy is promising, and it works well for some people. But for others, it’s not particularly effective. 

Why is there such variability in responses? As scientists dig into this question, some are looking to gut bacteria.

Initial hints that the gut microbiome might influence immunotherapy came from mouse studies.

For instance, a study in 2015 showed that Bifidobacterium — a common type of “good” gut bacteria — boosted the animals’ immune response against tumors.

Following this finding, a group of researchers recruited 112 people with melanoma who were receiving immunotherapy. Melanoma is the most deadly form of skin cancer. 

For some of these participants, immunotherapy was effective, but for others, it wasn’t. So, the scientists compared their gut microbiomes.

They found that those who responded well to the treatment had a more diverse microbiome and more Clostridiales, Ruminococcaceae, or Faecalibacterium bacteria.

Along with lower diversity, non-responders had higher levels of Bacteroidales.

Further evidence came from a study in 2018 that included people with epithelial tumors, a type of cancer that affects the ovaries.

As with the previous study, the scientists found differences between the gut microbiomes of people who responded to the treatment and people who didn’t.

They also found that avoiding antibiotics, which can kill off gut bacteria, during treatment improved participants’ responses.

These kinds of studies show an association rather than causation. In other words, they tell us that people with certain species of gut bacteria are more likely to respond to these drugs. But they don’t prove that the bacteria are actively helping the drugs to work.

In another part of the 2018 study, the scientists went some way toward demonstrating causation. 

They took poop samples from responders and non-responders and put them in germ-free mice. These animals are reared so that they have no gut bacteria.

The researchers found that poop from responders improved the mice’s immune response to the tumor. And poop from non-responders didn’t. 

A long road ahead

Whether drugs and gut bacteria interact is no longer just a theory, it’s a well-documented fact. But the precise relationships will take a good while to unravel.

After all, there are thousands of prescription drugs out there and hundreds of species of bacteria in your gut. And each person’s gut microbiome is unique. 

To add to the confusion, trillions of viruses also live in your gut, alongside fungi and other microbes. Do they affect the way a given drug works? We don’t know.

And as we’ve seen, genetic differences and a range of other factors can also influence how medications act.

Unsurprisingly, there’s a long road ahead. But thankfully, it will be a fascinating and potentially lifesaving journey.

Sources

Antibiotics and the human gut microbiome: Dysbioses and accumulation of resistances. Frontiers in Microbiology. (2015). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4709861/ 

Chemical transformation of xenobiotics by the human gut microbiota. Science. (2018). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5534341/ 

Clinical and economic burden of adverse drug reactions. Journal of Pharmacology and Pharmacotherapeutics. (2013). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3853675/ 

Clinical application of pharmacogenetics. Trends in Molecular Medicine. (2001). https://www.sciencedirect.com/science/article/abs/pii/S1471491401019864 

Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. (2015). https://pubmed.ncbi.nlm.nih.gov/26541606/ 

Contribution of the gut microbiome to drug disposition, pharmacokinetic and pharmacodynamic variability. Clinical Pharmacokinetics. (2021). https://link.springer.com/article/10.1007/s40262-021-01032-y 

Disentangling the effects of type 2 diabetes and metformin on the human gut microbiota. Nature. (2016). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681099/ 

Epidemiology of adverse drug reactions in Europe: A review of recent observational studies. Drug Safety. (2015). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4412588/ 

Fact Sheet: FDA at a glance. (2021). https://www.fda.gov/about-fda/fda-basics/fact-sheet-fda-glance 

Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. (2018). https://pubmed.ncbi.nlm.nih.gov/29097494/ 

Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science. (2018). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827966/ 

Immunotherapy to treat cancer. (2019). https://www.cancer.gov/about-cancer/treatment/types/immunotherapy 

Inactivation of digoxin by the gut flora: Reversal by antibiotic therapy. The New England Journal of Medicine. (1981). https://pubmed.ncbi.nlm.nih.gov/7266632/ 

Is p-aminobenzenesulphonamide the active agent in prontosil therapy?. The Lancet. (1937). https://www.sciencedirect.com/science/article/abs/pii/S0140673600974476 

Microbiome signatures of nutrients, foods and dietary patterns: Potential for personalized nutrition from the PREDICT 1 study. Current Developments in Nutrition. (2020). https://www.nature.com/articles/s41591-020-01183-8 

Predicting and manipulating cardiac drug inactivation by the human gut bacterium Eggerthella lenta. Science. (2013). https://pubmed.ncbi.nlm.nih.gov/23869020/ 

Proton pump inhibitors affect the gut microbiome. Gut. (2016). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853569/ 

Pharmacogenetics: The right drug for you. Nature. (2016). https://www.nature.com/articles/537S60a 

Pharmacomicrobiomics: A novel route towards personalized medicine? Protein and Cell. (2018). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5960471/ 

Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science. (2016). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5240844/ 

Population-level analysis of gut microbiome variation. Science. (2016). https://www.science.org/doi/abs/10.1126/science.aad3503 

Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: Cohort and case–control studies. CMAJ. (2004). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC437681/ 

Species-level analysis of human gut microbiota with metataxonomics. Frontiers in Microbiology. (2020). https://www.frontiersin.org/articles/10.3389/fmicb.2020.02029/full

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