Today’s post covers how endotoxemia and a “leaky gut” negatively impact the hormonal or endocrine system known as the hypothalamic-pituitary-adrenal axis (HPA).

The HPA axis is a negative-feedback circuit between the hypothalamus, the pituitary gland and the adrenals. Using hormones and the nervous system, these structures are in constant communication with one another to regulate certain bodily systems.

But before I detail how endotoxemia and increased intestinal permeability impacts this system, let me begin by briefly detailing what these glands do.

The hypothalamus is an almond-sized part of the brain that has the chief function of linking the central nervous system to the endocrine system via the pituitary gland. It produces a number of hormones that target distant tissues and the anterior pituitary gland.

The pituitary gland is a pea-sized protrusion attached to the hypothalamus composed of the posterior and hormone-producing anterior pituitary gland. It is known as the master endocrine gland and along with the hypothalamus is responsible for a number of physiological functions, including growth rate, appetite and weight regulation, blood pressure, breast milk production, mood, sleep, sex hormones, fertility, uterine contractions, kidney function, thyroid function, thirst, water balance and body temperature.

The adrenals are two hormonal glands that sit atop each of your kidneys. Each gland has an inner section called the medulla, and an outer section called the adrenal cortex.

The adrenal medulla is where the fight or flight hormones epinephrine (adrenaline) and norepinephrine are produced. That feeling you get when you’ve had a near miss while driving or the heart pounding you experience when you realize it’s too late to get off of that crazy-ass roller coaster you’re on, are the result of the hormones produced here.

The adrenal cortex is itself divided into three separate zones that each produce different hormones.

The outermost layer of the adrenal cortex is called the zona glomerulosa and the major hormone produced here is aldosterone. Aldosterone is the main hormone regulating blood pressure by its actions on the kidneys. The more aldosterone produced, the higher your blood pressure.

The innermost layer of the outer cortex is called the zona reticularis and here androstenedione, a precursor to sex hormones, is produced from cholesterol.

Sandwiched between the outer and inner layer of the adrenal cortex is the zona fasciculata which is where I want to focus my attention today. Here are produced what are known as the glucocorticoids, a class of steroid hormones. These hormones regulate glucose metabolism throughout the body hence their name.

Another important function of these steroid hormones is to reduce inflammation by suppressing immune function. Remember, inflammation is how the immune system handles infections and threats; however, too much inflammation can cause damage, some of it irreversible, to surrounding tissue and cellular structures. For this reason modern medicine uses these types of steroids to treat chronic inflammatory conditions.

Of the glucocorticoids, cortisol is by far the most important. Cortisol has a number of functions when released in the body:

  • Metabolism: when cortisol production is increased, glucose output in the liver goes up and glucose uptake by muscle, fat and other tissue goes down resulting in a rise in blood-glucose levels. In order to increase glucose production in the liver, it breaks down protein and fat so the liver can produce glucose from these building blocks. Doing so mobilizes energy for the brain and the heart which makes sense in an emergency, but is harmful to health if cortisol production is chronically elevated over long periods of time.
  • Blood Pressure Regulation: cortisol maintains the responsiveness of the smooth muscle tissue of your blood vessels to other hormones responsible for proper blood pressure regulation. Without it you would experience severely low and potentially life-threatening blood pressure. However, too much can chronically raise blood pressure.
  • Immune System: cortisol inhibits immune function by suppressing precursors to prostaglandins, lowers nitric oxide and decreases the number of immune T4 cells and cytokines. This is fine in the short term to shuttle energy from the immune system to the brain and heart, but not so great over the long term if you want to ward off infections.
  • Central Nervous System: cortisol directly impacts the electrical activity of neurons including those responsible for memory. It decreases REM sleep but increases shallow sleep or time spent awake which makes sense if there is an external threat. In the stone-age, your ancestors avoided being eaten by marauding beasts because they could stay awake to defend themselves. However, chronically elevated cortisol is not ideal if you want to get some sleep. I’ll return to this topic when I write a future post on insomnia.

What has become clear over the last decade from the results of numerous rodent studies is that this HPA axis is affected by gut pathogens as illustrated in the following graphic:

 

Courtesy: Regulation of the stress response by the gut microbiota

 

I realize this graphic seems a bit daunting, but I promise it’s not that difficult to understand so bear with me for a minute.

Let’s start at the lower-right-hand corner. Here we notice gut pathogens that have breached the intestinal gut wall and have provoked an immune response shown by the green arrow pointing towards the area labeled immune system. These pathogens, by the way, are none other than our old “friends” gram-negative bacteria and their cell-wall remnants lipopolysaccharides (LPS).

Let me interject here that gut pathogens are not the only substances capable of provoking an immune response. Gluten, other food proteins, alcohol, plant lectins, omega-6 fats, Candida albicans, viruses–all can produce immune stimulation in the presence of a compromised gut barrier function. Since gluten grains produce inflammatory gluten peptides upon digestion and contain wheat germ agglutinin, they are particularly effective at causing gut permeability and inflammation. So too omega-6 vegetable oils which are ubiquitous in the food supply.

Each of these factors can amplify the effects of the other. The key point here is that anything that increases intestinal permeability will provoke an immune response. However, I’ll just concentrate on the immune response provoked by gram-negative bacteria for now.

You’ll notice two green arrows leading away from the immune system. Let’s first look at the arrow pointing towards the hypothalamus.

Here we notice an increase in the production of the cytokines interleukin 1 and 6 affecting the hypothalamus, although there are other cytokines not shown that also impact it like tumor necrosis factor alpha. Cytokines, as you may recall, are signaling proteins used by the immune system to regulate inflammatory responses.

In response to these immune signals, the hypothalamus produces the hormones CRH (corticotrophin-releasing hormone) and AVP (arginine vasopressin) that then act on the anterior pituitary gland. Keep in mind that these inflammatory cytokines can, over time, damage the hypothalamus potentially affecting any and all systems regulated by it. Moreover, notice that serotonin (5-HT) and noradrenaline (NA) also cause the hypothalamus to produce CRH and AVP.

The pituitary, in response to both CRH and AVP, produces adrenocorticotropic hormone or ACTH. ACTH directly acts on the adrenals to increase cortisol production. The more ACTH produced the higher the production of cortisol.

Once cortisol is produced it signals back to both the hypothalamus and pituitary gland to suppress the production of CRH, AVP and ACTH to curtail its further production. This is represented by the red arrows and completes the negative-feedback loop.

Finally note that endorphins, which are produced when exercising, will also decrease cortisol production by acting directly on the hypothalamus. This is one reason exercise is good for you.

However, the immune system does not only stimulate cortisol production via cytokine signaling. It also increases cortisol via the synthesis of prostaglandin PGE2. This arm of the immune system is represented by the second green arrow emanating from the immune system in the diagram.

Therefore, the more endotoxins provoke an immune response, the more cortisol will be produced. And since the immune response affects both the HPA axis and the adrenals directly, the more likely it is that the signals responsible for lowering cortisol will be overwhelmed by the signals that increase it.

While this diagram only details the effects of endotoxemia on the production of cortisol, I need to stress (pun intended) that the increases in ACTH produced by the actions of both the hypothalamus and the pituitary gland and the direct stimulation of the adrenals by prostaglandins impacts all hormone-producing areas of the adrenal glands, not just that producing cortisol. This has implications for sex hormone production, blood pressure regulation, thyroid function and regulation of the fight or flight response including anxiety disorders.

Another point I want to make is that stress itself causes “leaky gut”. Increased cortisol will cause openings in the tight junctions that span the distance between the cells lining the gut wall. Just as gluten or pathogens open these gateways, so too cortisol.

As seen in the following diagram, cortisol can directly increase intestinal permeability which then directly impacts the HPA axis via the production of cytokines as seen on the right. However, note that inflammation also acts upon the liver and reduces tryptophan levels in the brain:

 

Courtesy: Regulation of the stress response by the gut microbiota

 

Tryptophan is an essential amino acid that is a precursor to the neurotransmitter serotonin (5-HT). Serotonin produced outside of the gut is used to regulate mood and appetite. It is also important in sleep regulation as melatonin is made from it. Serotonin is also involved in cognitive functions, including memory and learning. Alter tryptophan and you alter serotonin and everything it regulates.

Finally notice that probiotics block all of this mayhem by strengthening gut barrier defenses and preventing bacterial translocation.

Now that you know how endotoxemia and “leaky gut” affect the HPA axis, the upcoming post will cover the link between endotoxemia and severe depression.

 

References:

Dinan T. G. and Cryan J. F. (2012). Regulation of the stress response by the gut microbiota: Implications for psychoneuroendocrinology. Psychoneuroendocrinology, 37: 1369-1378.

Mitrovic, I. Introduction to the Hypothalamo-Pituitary-Adrenal (HPA) Axis (Lecture). https://docs.google.com

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