Reader, it’s a phrase that’s been used for thousands of years, used as a code of conduct during ancient wartimes, and written by everyone from the Ancient Greeks to Shakespeare: “Don’t shoot the messenger!” This timeless metaphor persists because it gets at something fundamental in our nature: when we hear news, whether good or bad, we often react with strong emotions—and when it’s bad, we have an impulse towards blame. In recent weeks, this metaphor has become increasingly relevant on a national scale. With politics being as dysfunctional as they are, and talk of impeachment framing the headlines, some have an impulse to blame the modern messengers of our day: the journalists. We get angry when we hear messages we don’t like—and that emotion stems from a deeper place than just irritation at perceived biases in the media – perhaps it stems from our anxiety over the deteriorating quality of communication between our political leaders – which threatens the very health of our democratic republic. This toxic multimedia “crosstalk” can begin to affect our emotional health. Simply put, this continuous communication begins to chip away at the very fabric of our emotional well-being. And since we feel emotionally threatened, we may want to lash out at the messenger – perhaps a reporter, newspaper or loved one with a different point of view.
If you’ve been following this blog series, you know what question comes next: “Dr. Bruce, how could this possibly relate to my mental health?” It’s simple. “Don’t kill the messenger” relates directly to the workings of our own body. Our microbiome’s “crosstalk” naturally creates millions of “messengers” that report the “news” out to our 32 trillion cells, down to the level of our very DNA. And just as the news can alter our minds and beliefs, the “news” being delivered to our cells has the epigenetic power to change the expression of our genes – to turn them on, turn them off, or regulate them in other ways. And when our gut bugs are in dysbiosis (when they are not healthy), our genetic expression can be changed for the worse, negatively affecting the production of trillions of essential molecules inside each cell. How does our microbiome have such power to change our DNA? Let’s dig in to find out!
What is Epigenetics?
While our DNA may seem like the most stable thing about us, how it expresses itself – what it produces – is in fact anything but certain. Each and every one of our genes can be turned on or off based on triggers found in our environment—including the rich environment that lives inside our own bodies. The change that can occur in gene functionality is known as “epigenesis”, and the field that studies those changes is called “epigenetics”.
The role external and internal factors can play in modifying the expression of our genes—and the power we have to harness those factors to benefit our mental and physical health—is so important to the future of precision medicine that we’ve not only dedicated blogs to epigenetics, but have used the term to frame entire blog series. However, while we have discussed epigenetics broadly on the blog, we’ve not taken a look into the specific mechanisms that allow a gene to change its expression. To use our messenger metaphor, you can’t send a letter without a mailbox to receive it on the other end, and you can’t share the news without an active listener. If “messengers” are sent from the microbiome to our cells, what mechanism is receiving them and processing their important messages?
In this blog, I want to focus on two biological factors that can lead to epigenesis: DNA methylation and histone modification. DNA methylation can downregulate or turn off the expression of a gene. DNA demethylation reverses this process to upregulate or turn on the expression of a gene. Histone modifications are changes occurring to a cell’s histones—proteins that DNA coils around to form chromosomes—which can in turn lead to activation/inactivation of a gene and other epigenetic outcomes. These two factors create the foundation for epigenesis, and epigenesis itself can turn on genes that lead to health outcomes ranging from addiction and substance abuse to higher rates of depression and stress.
Now that we understand the “receiving” mechanism for epigenetics, let’s take a look at the messengers themselves: those little microscopic entities that arise from our gut microbiome and help shape our DNA destiny.
How Your Microbiome’s Messenger Microbes Play a Role in Epigenetics
As we’ve read in prior blogs in this series, the trillions of bugs comprising our gut microbiome play a significant role in our mental and physical health. Those gut bugs are capable of “speaking” to our brain through the Gut Brain Connection, and, as numerous studies have indicated, the messages sent from a healthy microbiome are significantly different from those sent from a microbiome in dysbiosis. Our body “listens” to those messages about our gut through the process of epigenesis—but who, exactly, is doing the talking and what are they saying?
Our gut bacteria are hugely efficient manufacturing plants, and among their many products are “microbial metabolites.” Two examples of these metabolites are B vitamins, and short chain fatty acids, or SCFAs. Each of these metabolites is a “messenger” that plays a role in the epigenetic modification of our genes. Our body’s own cells cannot manufacture B vitamins—instead, we rely on our microbiome to synthesize them for us. B vitamins, including riboflavin, niacin, biotin, and folate, are produced by our gut bugs—and each acts as a unique cofactor of enzymes that modify histones in our chromosomes. Specific B vitamins—riboflavin and folate—also impact MTHFR, which plays a large role in epigenetic regulation through DNA methylation. Low levels of MTHFR can lead to lower production of serotonin, dopamine and norepinephrine – contributing to a greater vulnerability to developing depression —and low levels of riboflavin and folate lead to low levels of MTHFR. And what leads to low levels of B vitamins in our gut? An unhealthy gut microbiome – one that is in dysbiosis!
If you’ll recall from a recent blog, SCFAs are what our microbes produce after we feed them food they like, namely prebiotics. These SCFAs become an important energy source to increase energy production in our cells. They also act epigenetically on histones to turn on genetic production. A reduction of SCFAs has been associated with diseases such as depression, bipolar disorder, obesity, diabetes, autoimmunity, chronic inflammation, and intestinal diseases such as ulcerative colitis (UC), Crohn’s disease (CD), and colon cancer. One SCFA in particular called butyrate has garnered significant attention for its role in epigenesis. Butyrate is a key enzyme known to regulate gene expression through histone modification—and low levels of butyrate produced by our gut can lead both to variances in gene expression and to an increased intestinal permeability also known as “leaky gut”. Decreased levels of butyrate have also been implicated in obesity—which has its own mental health implications.
SCFAs and B Vitamins each play messenger roles and “talk to” the DNA inside our cells —and our genes respond and produce more or fewer molecules essential for the maintenance of life itself. Like any messenger, these microbial metabolites shouldn’t be blamed for poor health outcomes—instead, the fundamental problem lies in the society from which they arise: namely, a dysregulated gut. A healthy microbiome simply sends different messengers to our chromosomes than a microbiome in dysbiosis. And a good place to start if you want your gut messengers to convey happier news is to take care of your microbiome and treat it kindly—by feeding it what it likes (like prebiotics!) and by sending in those probiotic “troops” to help get it into shape if needed.
Taking advantage of the power of epigenetics to optimize our health is the future of medicine—and paying attention to which messages from our gut bugs promote healthier genetic expression is already becoming a crucial tool in the psychiatrist’s toolbox. For better or for worse, our gut microbiome is constantly speaking to us—and we’d do well to listen to exactly what it is saying!
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*Although lessons learned from the treatment of actual patients are included in the patient stories on this website and blogsite, the historical events and facts represented have been changed to protect the identities of any real patients and to protect their confidentiality. For example, the names, ages, careers, the number and sex of their children, as well as the careers of the patients’ parents have been deliberately altered, as well as other alterations that have been made. Consequently, all characters appearing on these sites are fictitious. Any resemblance to real persons, living or dead, is purely coincidental.
**Author’s financial disclosure: Genomind and Potomac Psychiatry have an ongoing marketing collaboration aimed at raising visibility for Genomind pharmacogenomics services and Potomac Psychiatry’s Genetic Testing Consultations. Dr. Kehr holds no ownership interest in Genomind and receives no consulting fees.