The microbiome’s influence on human health explored by NIEHS grantee

I recently had an in-depth talk with Peter Dedon, M.D., Ph.D., an NIEHS grantee whose research into the microbiome is helping to uncover the complex and vital roles it plays in human health. The microbiome refers to all of the bacteria, fungi, and viruses that live on us and inside us. We explored how some environmental exposures may disrupt the gut microbiome and influence irritable bowel syndrome, brain disorders, and other conditions. Dr. Dedon is Underwood-Prescott Professor of Biological Engineering at the Massachusetts Institute of Technology (MIT).

Understanding the microbiome is increasingly important in environmental health. As we learn more about these microbial communities, it is clear that they are not mere passengers in the body but rather active participants in health and disease states, in many intricate ways. So, it is critical to assess how environmental factors may alter that delicate balance.

Among his other efforts, Dr. Dedon has sought to determine whether certain bacterial DNA changes can make an individual more sensitive to things like diet, inflammation, and other environmental stressors, internal or external. Such increased sensitivity could pave the way for a variety of poor health outcomes, ranging from schizophrenia to obesity. In addition to discussing his recent research, Dr. Dedon also shared what inspired him to become a scientist and how “happy accidents” in his career have led to exciting discoveries.

New scientific frontier

Rick Woychik: What exactly is the microbiome?

Peter Dedon: It’s the new frontier in human health and disease, in my view. The microbiome includes more than 5,000 different kinds of bacteria that inhabit every surface of your body. The biggest concentration is in your intestines.

And the microbiome is more than just bacteria. It also includes fungi and viruses, including a significant amount of bacteriophage. Those are viruses that attack bacteria. They require bacteria as a food source and to replicate themselves.

So, there is a constant sort of warfare between bacteria and bacteriophage. And they all have defense mechanisms to keep fighting off one another. One of my aims has been to better understand one of these mechanisms — DNA modifications that function like an immune system. The goal has been to shed light on how those modifications relate to human health.

Producing essential chemicals

RW: Why is the microbiome an important factor in human health?

PD: In years past, nobody considered that the microbiome was important to human health. In fact, most people thought of bacteria simply as things you want to wash away. Today, we know that is not the case, and these and other microorganisms throughout your body are essential to life.

Every human requires them, and they are so important that we can almost view them as another organ in the body. Emerging research shows that gut bacteria produce chemicals that are essential to cognitive function, heart function, and every form of metabolism in the body.

We don’t yet know the full spectrum of the tens of thousands of chemicals that bugs in the human gut make. The chemicals are absorbed into the bloodstream, they circulate around, and they get metabolized just like drugs, but they’re essential for bodily functions. In fact, many of these chemicals are considered vitamins — essential chemicals that humans can’t make — that are produced by the bugs in the gut, skin, and airways. And they are essential compounds for human physiology and for human health.

Demonstrating microbiome’s importance

RW: Back when I was a graduate student, I, like many others, thought that bacteria were just things we needed to get rid of. But part of the problem was that we didn’t know a lot about them because we didn’t have methods to actually detect them. So, what innovations brought the microbiome forward as an important element of health?

PD: Well, some people might first say “omics” — the science of measuring thousands of different molecules and proteins at the same time, like metabolomics and proteomics. But actually, the first technological breakthrough was the ability to make germ-free mice, which lack any microbes in them. Such mice helped to show that these bugs can influence health in major ways, and that is because germ-free mice are not healthy at all.

Consider inflammatory bowel disease. Many people are afflicted with this condition, and we now know that the microbiome plays a huge role. Germ-free mice don’t get inflammatory bowel disease — you can’t make them get it by genetics, or by treating with chemicals. So, that was a major discovery, and it came about because of innovation in rodent models.

Also, years ago, a seminal study by Dr. Jeffrey Gordon showed a strong connection between obesity and the microbiome. If you have obese rodents and transplant their microbiome into non-obese mice, those mice will experience obesity. This indicates the microbiome is having some effect on metabolism, food intake, caloric consumption, and metabolic physiology.

Gigantic revolution

RW: What kinds of technologies does your team use to advance microbiome research?

PD: Today, a big breakthrough is that we can take DNA from a stool sample, which contains fragments of genomes from the thousands of bacteria in the gut, and do what is called metagenomics research. That is where we determine the genetic code in each piece of that DNA with cutting-edge sequencing, computational, and informatic tools, and then assign the pieces of DNA to specific bacteria. This is a gigantic revolution that has allowed us to know what bugs are inside you.

Then we look at the realm of metabolomics, which involves measuring all the small chemical molecules in your blood and body. With just a stool sample, for example, we can measure the spectrum of molecules produced by the gut microbes and confirm that they are different molecules than what are in humans themselves. And right now, I’m looking at RNA modifications and DNA modifications in those microbes to determine how such changes may influence the composition and function of the microbiome, especially in response to stressors.

Gut-brain connections

RW: Can you share some of your most exciting discoveries?

PD: Sure. Earlier, I mentioned that the microbiome produces compounds that are essential to human health. It turns out that people can’t make queuine, a chemical that is necessary for an important biological modification that helps cells respond to stress, both internal and external.

Queuine is basically a vitamin that humans can’t make. However, bacteria in your gut microbiome do make it, and it is found in certain foods, including yogurt. From mouse studies, we have seen that too little queuine can result in brain disorders like schizophrenia.

So, there appears to be an important connection between the gut microbiome and mental health, but more research is needed going forward. My colleagues and I are busy now trying to more clearly demonstrate the gut-brain connection. We want to shed light on what happens when environmental exposures disrupt the microbiome’s supply of queuine.

In addition, our team wants to better understand how exposures may affect the balance of phosphorothioate-containing bacteria, which we have linked to gut inflammation. Phosphorothioate refers to an important type of DNA modification where sulfur gets incorporated into the DNA backbone. A major feature of inflammatory bowel disease is disruption of sulfur metabolism. Phosphorothioate-containing bacteria overgrow, which may damage the gut lining and contribute to the inflammation that is the hallmark of the disease.

Environmental influences

RW: What kinds of exposures might affect the microbiome?

PD: Diet has a huge influence in terms of bringing small-molecule metabolites, fats, carbohydrates, and proteins into the intestines. The gut microbiome is swimming in these nutrients, and different microbes will use whatever’s in the diet for their own advantage.

Also, a classic exposure is arsenic in drinking water. We’ve done some work on that. Arsenic affects human cells, yes, but it also affects microbes in ways that we don’t fully appreciate, with much of the same kind of toxicology that we see in humans. Bacterial cells will take up arsenic and incorporate it in different functions, and that can disrupt them significantly.

Ultimately, any chemical that is in the air, food, and water is going to influence the microbiome. For example, I was just looking up dimethyl sulfoxide [DMSO], a solvent that we use in the lab all the time. Well, there are bugs in your gut that actually have dimethyl sulfoxide reductases, which means that the bugs can live on DMSO. So, if you have an exposure to this substance, is that going to cause an overgrowth of these bugs, and what are the consequences of that?

We can start to think about every environmental chemical in a similar manner. Going forward, it will be critical for the scientific community to address these and other related questions.