The most essential cornerstone to optimize testosterone that cannot be overlooked

All roads lead to Rome…or at least in this case…to the gut.

As Hippocrates said: “All disease start in the gut”.

The gut is overlooked all too often when it comes to a topics such as testosterone.

When it comes to testosterone, people want to know what secret stacks or hacks they should be doing or applying, but if the gut isn’t sorted out yet, then those other hacks don’t really do much.

The gut and what happens in the gut influences the testicles and subsequent testosterone production.

“Well, I don’t have gut issues”, you might think. However, gut issues aren’t always obvious. If your gut isn’t in a good place or you’re eating something that is irritating your gut or absorbing undesirable things through a leaky gut, you can experience symptoms such as joint pains, brain fog, chronic low-grade inflammation, skin issues (such as psoriasis, eczema, cystic acne, etc.) as well as low libido, erectile issues and low testosterone.

Almost 40% of Americans are obese and even more are overweight. Most people that are overweight or obese have low testosterone. When it gets very low, it’s called testosterone deficiency.

Testosterone deficiency (TD), characterized by low testosterone levels and relevant clinical symptoms and signs, is estimated to affect up to 6% of men, with projections estimating that 6.5 million American men will develop symptomatic TD by 2025.

However, the lower limit for testosterone is so low, that you’re basically experiencing hypogonadal symptoms even while being in the “normal range”. It’s not “normal”, it’s just so widespread that it seems normal. Just because most people have low T doesn’t mean it’s normal.

The gut-testicular axis

The gut and testicles are connected. Whatever is happening in the gut is affecting testosterone production.

Two things that potently influences testosterone production negatively is serotonin and endotoxins.

Serotonin and testosterone

Serotonin in the gut

More than 90% of all serotonin in the body is produced in the gut. Whenever the gut isn’t happy, it produces more serotonin to promote diarrhea to get rid of the gut irritant. However, if you’re chronically eating problematic foods that are increasing serotonin in the gut, you’ll end up with chronically elevated serotonin, which leads to all kinds of issues.

Too much serotonin in the body promotes inflammation, immune reactions, platelet aggregation (blood clotting), bone breakdown, vascular leakage and vasoconstriction as of other things (R).

Germ-free mice, which have no gut bacteria, have significantly less circulating serotonin and they are resistant to weight gain and metabolic syndrome (R, R).

Only a small amount of bacteria in the gut produces serotonin. However, the short-chain fatty acids produced by the bacteria stimulate the enzyme tryptophan hydroxylase, which then produces serotonin. More gut bacteria = more short-chain fatty acids = more serotonin.

Serotonin in the body and testes

Circulating serotonin reaches the testes where it acts as an autocrine regulator of testosterone secretion.

Serotonin suppresses testosterone production and is inversely correlated with fertility (R, R, R).

On the other hand, blocking serotonin receptors 5-HT2A and 5-HT2C with ketanserin is able to increase testosterone (R). Also, inhibiting serotonin synthesis from tryptophan is able to increase testosterone (R).

Furthermore, serotonin enhances aromatase, and estrogen has a negative feedback loop on the hypothalamus and inhibits GnRH and LH release. More estrogen = less testosterone. That’s why obese people, or at least people with a lot of visceral fat (visceral fat has a very high concentration of aromatase), have lower testosterone; and also why giving them an aromatase inhibitor can increase their testosterone levels.

Lastly, serotonin plays a role in regulating inflammation and immunity, acting as a strong chemoattractant to recruit innate immune cells to inflammation sites, modulating the production of cytokines and chemokines and being involved in cell activation and proliferation (R).

Serotonin receptor 5-HT3 up-regulates the endotoxin-induced production of inflammatory markers, such as IL-1beta, IL-6 and IL-8 (R).

Serotonin receptors 5-HT2, 5-HTR4 and 5-HTR7 are also involved in inflammation and fibrosis. This is how serotonin is involved in chronic inflammatory conditions such as psoriasis.

Free serotonin (released by platelets) is also able to promote the recruitment of neutrophils in acute inflammation. Tianeptine promotes serotonin re-uptake and can help lower inflammation, and this is one mechanism through which tianeptine is so potent against asthma.

How to lower gut serotonin

It comes down to avoiding gut irritation, staying away from hard to digest food and lowering excess gram negative bacteria in the gut.

A simple trick is to use natural anti-biotics, such as oregano oil, cinnamon oil, monolaurin, Tulsi, Olive leaf extract, etc., and combine that with activated charcoal so that the charcoal can bind the serotonin and dead gram negative bacteria and remove them from the body.

Endotoxins and testosterone

Endotoxins, also known as lipopolysaccarides (LPS), are also heavily involved in inflammation and low testosterone.

The human intestine contains on average 1.5 kg (over 100 trillion) bacteria, with 70% of these being gram-negative, containing the potent immune stimulant LPS.

This is not really an issue, unless the intestinal wall is compromised (leaky gut) and these endotoxins can enter into the general circulation. This is when immune cells attack the endotoxins and cause an immune response.

And the thing is, most people have compromised intestines. Under stress, blood flow is diverted from the intestine, which makes it permeable. Every time you stress, you absorb endotoxins.

As Sherlock Holmes said: “Stress can ruin every day of your life. Dying can only ruin one.”

LPS causes inflammation and lowers testosterone

It has been well documented that infections as well as experimental administration of endotoxin can produce “sickness behavior” in healthy men, which is characterized by impaired mood, anxiety, and social disconnection (R). This is due to an increase in inflammation and a decrease in testosterone.

Low-dose endotoxin administration in animals induces an acute systemic inflammatory response, as evident from a significant increase in plasma IL-6 and TNF-α concentration. This inflammatory response is followed by a decline in plasma testosterone levels. This drop in testosterone only returns to normal after 24 hours (R).

Now imagine what happens if you’re under chronic exposure of LPS, and not just once. Then you end up with chronic low-grade inflammation and low testosterone.

As a side note, fat tissue itself (especially visceral adipose tissue) is also a major producer of inflammatory cytokines and is a significant driver of inflammation independent of endotoxin exposure (R). Importantly, these fat tissue-derived cytokines are known to impair intestinal tight junction function resulting in an increase in intestinal permeability, which creates the potential for a positive feedback loop generating more endotoxemia and inflammation.

From this study:

Adiposity was positively correlated with endotoxin exposure (LBP) and inflammation (C-reactive protein, IL-6) and negatively correlated with testosterone. Furthermore, endotoxemia (LBP) was negatively correlated with serum testosterone but positively correlated with IL-6. Multivariate analysis revealed a significant, negative correlation between serum IL-6 and free testosterone. In a second interventional study, low-dose endotoxin challenge in lean men produced a transient inflammatory response that was followed by a decline in serum testosterone, without changes in LH or FSH, providing further evidence that endotoxin-driven inflammation may result in impaired Leydig cell function.


Furthermore, inflammation is known to promote aromatase, which converts testosterone into estrogen. Excess levels of estradiol and pro-inflammatory cytokines act at the hypothalamic level to inhibit the neuronal release of Kisspeptin, which will lead to a profound reduction in GnRH signals leading to a sustained state of hypogonadotropic hypogonadism (R).

LPS lowers testosterone, without inflammation

Apart from just promoting inflammation, endotoxins can lower testosterone via an inflammation independent pathway.

It does so by binding to the Toll-like receptor 4 (TLR4) protein. The testes have a high expression of TLR4, which makes the Leydig cells particularly susceptible to direct LPS inhibition.

Also, endotoxin:

  • Decreases androgen receptors and increases estrogen receptor expression in testes (R).
  • Significant reduces enzymes involved in steroidogenesis, such as steroidogenic acute regulatory protein (StAR; the rate-limited step in cholesterol transport into the testes) and 3beta-hydroxysteroid dehydrogenase-Delta4-Delta5 isomerase (3beta-HSD) proteins.
  • Significantly increases lipid peroxidation of Leydig cell membranes.


If you want high testosterone, start with the foundation, which is the gut. Solve gut issues and you’ll experience a significant increase in testosterone. Once the gut is fixed, focus on macros and micros to optimize testosterone.

I discuss how to do all of this in my Alpha Energy Nutrition Course.

Alternatively, you can read the other articles I wrote on how to increase your testosterone:

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