In this presentation Dr. David Perlmutter argues that depression should be viewed as a low‑grade inflammatory disorder. He cites a 2013 British medical journal study that identifies elevated inflammatory markers in depressed patients and notes that commonly prescribed SSRIs have anti‑inflammatory properties, suggesting this may be part of their therapeutic effect. The talk then shifts to gut permeability—"leaky gut"—as a primary source of systemic inflammation. Perlmutter explains the two pathways of nutrient absorption (transcellular and paracellular) and describes how the tight‑junctions between gut epithelial cells can be disrupted by stress, infection, certain drugs, toxins, gliadin, and advanced glycation end‑products (AGEs). This disruption allows bacterial components such as lipopolysaccharide (LPS) to enter the bloodstream, activating immune cells and driving inflammation. He presents data from a 2009 study showing markedly higher LPS levels in individuals with major depressive disorder compared with healthy controls, and notes similar elevations in ALS, Alzheimer’s disease, and autism, indicating a broader link between gut leakiness and neurological conditions. Finally, Perlmutter emphasizes practical steps to protect gut integrity: limiting unnecessary antibiotic use, avoiding chlorinated water, and reducing exposure to environmental toxins, all of which can disturb the microbiome and increase gut permeability.
Chapters
One of the things I explore in depth in Brain Maker is the notion that even depression is now considered an inflammatory disorder. We now understand that, for example, inflammatory markers, markers of inflammation that we see elevated in heart disease, for example, are also seen to be elevated in the depressed patient. So the question would be then, if depression is an inflammatory disorder, where does this inflammation come from? And in fact, more or less, that's That's the title of a new study that was just published. Let's have a look. So this is a study published in a British medical journal in 2013, in fact called So Depression Is an Inflammatory Disease, But Where Does the Inflammation Come From? And they in fact indicate that depression is a low-grade inflammatory response and it's caused by activation of those cells that lead to inflammatory production. Interestingly enough, they call to our attention the fact that the SSRIs, and those are the very common Widely prescribed antidepressant medications are actually anti-inflammatory, and it might well be that that's how they work. So they looked at in this study a variety of factors that are common in depressed patients, things like stress, dietary issues, etc. Let's take a look at them. Again, stress and trauma, diet, exercise, obesity, smoking, and even gut permeability and the microbiome, the very bacteria that live within the gut are now looked upon as possibly having a causal role in the inflammation that underlies depression. Now, let's specifically focus for a moment on this notion of gut permeability, the so-called leaky gut, and talk about how that relates to the bacteria that live within the gut. We have 2 ways of absorbing nutrients from the gut into the systemic circulation: through the cell, which is called transcellular, And between the gut lining cells, which is called paracellular. The gut lining cells are kept tightly together by what's called the tight junction. But we now understand that a variety of factors like stress, infection, drugs, toxins, gliadin, and even AGEs, which are proteins bound to sugar, can ultimately lead to destruction of that tight junction, and that leads to separation of these cells and makes the gut leaky. We then have the ability for various proteins to gain entrance into the systemic circulation, and when they do so, they stimulate various immune cells, and that leads to inflammation. So this is the mechanism by which various factors like stress, like elevated blood sugar, like toxins in the environment lead to what's called a leaky gut And that is now thought to be associated with depression. But let's take this a bit further. Let's look at the measurement of a marker of leaky gut called lipopolysaccharide, or LPS, and see how that correlates with major depressive disorder. Here you see in a study that was published in 2009, a strong correlation with high levels of LPS when comparing major depressive disorder with healthy controls in terms of gut leakiness. We also see this related to Lou Gehrig's disease or ALS, and even with progression of ALS. We see it with Alzheimer's disease, and we even see it with autism. So we're seeing then that elevated LPS levels, an indication of gut leakiness, are really pervasive in a lot of neurological conditions like autism, Alzheimer's, Lou Gehrig's, and even in depression. And I began by talking to you about the role of inflammation in depression. We've talked at length in the past about the role of inflammation in Alzheimer's, but now we're understanding that the mechanism is really leakiness of the gut, and that can be brought on by a number of factors, most importantly by disturbance of the balance of gut bacteria. And this is the reason it's so important to avoid, for example, overusage of antibiotics, of drinking chlorinated water, for example, of exposing yourself to potentially toxic chemicals. These all play a role in changing the dynamics of the gut, increasing leakiness, which we now see is strongly correlated to some very important neurologic conditions. I'm Dr. David Perlmutter.
