My Dear Reader, congratulations! By the time you read this, you’ll have made it through another Thanksgiving. This uniquely American holiday is perhaps most famously idealized by the Norman Rockwell painting of a perfectly roasted turkey being set on a table full of food, shared by people looking perfectly relaxed and contented. The Rockwell scene makes Thanksgiving look all too easy—but for those of us who have been in the kitchen as the feast is being prepared, we know it can be anything but. In many families, it seems the stress of preparation falls to one person who spends hours frenetically boiling potatoes, compiling the green bean casserole, stuffing the turkey, rolling the pie dough, and setting the table. Does that sound familiar to you? If it does, you surely know what follows: after the meal has been cleared and the leftovers stored away in the fridge, the frantic chef is often the first to fall asleep after the tryptophan in the turkey kicks in! For Thanksgiving guests, the holiday is all about relaxing and enjoying the company of loved ones—but for the host, it can be a day of pure chaos, stress, and exhaustion, from the moment they awaken to the moment their head hits the pillow. It’s a real act of love to host Thanksgiving, because ultimately the host misses out on the most enjoyable moments of the day. These momentary stresses of living compromise our near-term contentment, yet we can quickly bounce back. Yet what if that stress becomes chronic? Reader, when our body is in a state of chronic stress, our overactive “fight, flight or freeze” response not only leads to chronic immune system problems (chronic inflammation) it can also damage our microbiome, leading to outcomes far more dangerous and long-lasting. This week, I want to review the significance of chronic inflammation to our health, and how both our microbiomes and our genes play a role.

The Consequences of Chronic Inflammation

In small doses, acute inflammation is a crucial part of our biological defense system in fighting off bacteria, viruses, or other antigens that create damage in the body and brain—and in our brains the cells leading the charge are called the microglia. When the microglia cells sense danger present, they swoop in and clear things up and repair the damage. They do this by “upregulating”, feeding off the same energy sources that are used to power nearby cells, in order to do their good work. This works wonderfully over short time frames. But when our microglial cells get stuck in upregulation, the result is oxidative stress and chronic inflammation, which ultimately does as much or more damage to our bodies and brains than the damage that acute inflammation is supposed to prevent! As we have learned in prior blogs, chronic inflammation can lead to a multitude of negative mental health outcomes—including “inflammaging” and Alzheimer’s Disease. So how does our body become chronically inflamed? For many, it can start in the microbiome.

Can a Leaky Gut Inflame your Brain?

 The trillions of gut bacteria living within your intestinal tract regulate digestion—but they also play a role in our metabolism, our hormones, and our inflammatory response. When your microbiome is healthy and diverse, the lining of your gut is leak-free, allowing for safe passage into the bloodstream of numerous important nutrients, neurotransmitters, hormones, and more. When your microbiome is less diversified or otherwise thrown out of equilibrium, it enters what is known as a dysbiotic state, in which the lining of your intestines become more permeable, or “leaky”, allowing bacteria, incompletely digested food molecules, and toxic metabolites that should stay well within the gut to leak through and enter your bloodstream (think of “sewage” entering your bloodstream and circulating throughout your body and brain). As you can imagine, once your body recognizes molecules have snuck into a space where they don’t belong, thereby becoming antigens, your immune system is not very happy about it. Recognizing the presence of malevolent foreign bodies in its system, your immune cells call in the guards, and the process of inflammation begins. Low-grade inflammation caused by a leaky gut in turn causes a leaky brain whereby the blood-brain barrier becomes permeable, which allows damaging molecules to leak into and inflame the brain itself.

Chronic inflammation is a significant side effect of a leaky, dysbiotic gut and can wreak havoc on your brain—and when a leaky gut is paired with certain risk genes, the impact can be even more consequential.

CD33, TREM2, and Inflammation

The microbiome is one of the root causes of chronic inflammation—and your CD33 and TREM2 genes may add to the problem, if you carry certain variants of these genes as assayed in Genomind’s Mindful DNA test. Microglia in the brain fight damage, and CD33 and TREM2 gene variants are both involved in manufacturing receptors that are expressed on the surface of your microglia. These receptors help regulate the activities of those microglia. As such, they both help to regulate your brain’s neuroinflammatory pathway. Here is an image that may help you understand, (where “AD” stands for Alzheimer’s Disease)…

TREM2 is a microglial surface receptor that plays an essential role in removing toxic debris from the brain. The failure of this receptor to function normally is one of a group of core components that may lead to Alzheimer’s progression. One variant in particular confers down expression, which pushes your microglia to the dark side, making neuroinflammation more common and causing a three- to four-fold increase in the odds of developing Alzheimer’s.

CD33 encodes for a protein found on the surface of microglial cells that act as an essential regulator for microglial activity. Think of your microglia as the Thanksgiving host. In the frenzy of the holiday, the host can usually be found in one of two states: completely stressed or completely at rest. Your microglia are much the same. When the microglia are in a constant state of activity, they don’t have much time for anything else. This is your microglia in an inflammatory state—which can lead to both oxidative stress and neuronal damage. When your microglia rest, on the other hand, they’re in what is known as the monophagocytic state. This rejuvenating state actually helps to clear the toxic debris found in the brain. CD33, then, is the “on-off” switch between these two states. If you have a resilient CD33 gene that confers a down expression, your microglia are switched “off” more often, leading to a more effective clearance system—and a 10 percent reduced odds of developing Alzheimer’s. A risk gene, however, can lead your microglia to be chronically inflamed, resulting in poor clearance and a dangerous buildup of waste products that can light your brain on fire through oxidative stress and the destruction of cell membranes and many cellular functions.

A Healthy Microbiome, Fecal Transplants, and Brain Inflammation

As we discussed in an earlier blog, someday soon fecal transplants may revolutionize the treatment of dementia. But let’s try to prevent that dementia from developing in the first place. A dysbiotic gut and risk variants of your TREM2 and CD33 genes may increase your chances of developing chronic brain inflammation—but there are things you can do right now to reduce those chances. As we’ve discussed in prior blogs, dysbiosis or a leaky gut can significantly benefit from probiotics and prebiotics; and microdose lithium, vitamin D supplementation, olive oil, omega 3, and a Mediterranean Diet can give your brain a jump start in protecting against dementia. Taking a genetic test like Genomind’s Mindful DNA can provide you with crucial information about what gene variants you’re working with and can provide valuable information to further your defenses in the fight against brain inflammation and its destructive effects on mood, anxiety, and cognition.

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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.

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