Exercise can be great, but should be done correctly.

If it’s not done correctly, it can lead to chronic low grade inflammation and lots of internal scar tissue, that leads to lots of health problems along the way.

Check out this article to see what exhaustive, strenuous exercise can do to you.

What I want to talk about in this article in exercise induced endotoxin absorption.

Leaky gut

When we’re healthy, we don’t have a leaky gut. Leaky gut is when the epithelial lining of the intestines becomes permeable, which allows for the absorption of intraluminal pathogens and other potentially harmful molecules, such as endotoxins, into the body.

A few things that can induce leaky gut is heat stress, being in a flight or fight situation, low glucose availability, exercise, serotonin, etc.

Endotoxins

Endotoxins, or lipopolysaccharides (LPS), are molecules that reside in the outer membrane of gram-negative bacteria. It consists of a lipid and a polysaccharide composed of O-antigen, outer core and inner core joined by a covalent bond.

There are many different kinds of endotoxins, which stimulate the immune system differently.

Endotoxins bind to their receptor, TLR4, and initiate an immune response.

Endotoxin absorption

Once endotoxins are absorbed into the body, they go through the portal vein to the liver, where they stimulate the kupffer cells to initiate an inflammatory response. Elevated levels of endotoxins in the portal circulation can cause a dose-dependent systemic inflammatory response.

Antagonizing the kupffer cells or enhancing endotoxin clearance will help to prevent inflammation and fibrosis induced by endotoxins.

Exercise, exercise-induced leaky gut and endotoxin absorption

Exercise done right is a potent modulator of intestinal microbiota composition and function, leading to enrichment and bacterial proliferation, improvement of intestinal barrier integrity, and the synthesis of immunomodulatory and antimicrobial agents (R).

But if done in excess, both endurance and resistance training can increase gut permeability, but it’s more common amongst endurance athletes, since they have a high rate of gastrointestinal symptoms.

Even 20 min of exercise (running and cycling) at 80% VO2max can induce a 2.5-3 fold increase in permeability!!! (R, R, R)

One of the major reasons why this happens is because blood flow is directed away from the intestine, to the muscle that is being exercised (due to increased sympathetic tone), and this leads to increased GI permeability. Endurance-trained, sprint-trained, and weightlifter-trained athletes tend to have higher catecholamine concentrations at rest than inactive subjects (R).

When the rate of endotoxin clearance by the liver is overwhelmed by increased translocation after transient damage to the gut, endotoxemia can occur if there are insufficient levels of anti-LPS antibodies to aid in clearance (R).

“A loss of intestinal integrity may result in the passage of luminal endotoxins into the circulation, thereby causing an inflammatory cascade and an exacerbating loss of barrier function. These developments can result in severe systemic effects (4) such as an exertional heat stroke, which is associated with hyperthermia, multiorgan failure, and endotoxemia” (R).

When blood flow is reduced to the gut, it not only causes leaky gut but also causes a reduction in adenosine triphosphate (ATP) synthesis in mitochondrial respiration as well as damages the specialized antimicrobial protein-secreting cells (Paneth cells) and the mucus-producing cells (such as goblet cells) (R).

During running and strength exercises, mechanic effects occur like enhanced intra-abdominal pressure and organs bouncing, which also contributes to leaky gut and/or gastrointestinal symptoms (R).

Together, the above exercise-related responses are associated with lower gastrointestinal symptoms such as flatulence, lower abdominal bloating, urge to defecate, abdominal pain, abnormal defecation, such as diarrhea, and bloody stools (R).

Here’s a part of a study that I really like.

“Among elite athletes involved in cyclic sports, there is often a syndrome of endogenous intoxication that occurs as a result of excessive physical exertion and is accompanied by a change in the rheological properties of blood, hemostasis parameters, impaired microcirculation, damage to biological membranes, and a decrease in the functional state of vital organs and body systems. The deficiency of substrates and oxygen that forms during exercise leads to the appearance of hypoxia with the subsequent development of ischemia, which limits the energy production in the system of mitochondrial oxidative phosphorylation. The destruction of proteins due to the developing ischemia is accompanied by the release of urea, creatinine and ammonia, which causes a shift in the acid-base state towards acidosis, which contributes to the aggregation of platelets, erythrocytes and tissue trophic disorders [1-3]. Such formation and accumulation of endogenous toxic substances creates a vicious circle in which endogenous toxins are the result of metabolic disorders in the cell and at the same time themselves have a damaging effect on cellular structures and metabolic processes. The intake of various endogenous toxic products leads to the activation of the sympathetic-adrenal system, followed by the release of glucocorticoids, catecholamines, cytokines, serotonin, histamine and other biologically active substances. With significant and prolonged physical and psycho-emotional stress, dysfunction of the organs of natural detoxification leads to the development of an immunosuppressive state, accompanied by infectious and inflammatory, allergic, autoimmune and other diseases.” (R)

So all in all, getting leaky gut from exercise is pretty bad if done frequently and in excess.

Some numbers for you

The role of endotoxins during strenuous exercise has been investigated since the 1980s with circulating LPS concentrations of >5 pg·mL⁻¹ being indicative of mild endotoxemia.

Following an 8 hour ultra-triathlon, mean circulating endotoxins concentrations increased to 294 pg·mL⁻¹ (R). Elevated endotoxins are positively correlated with the incidence of cramping of the lower limbs.

But not everyone gets leaky gut though.

• In another early study, the majority (81%) of ultra-marathon runners had increased levels of endotoxins (above 100 pg·mL⁻¹) at the cessation of the race (R).
• Following an Ironman distance triathlon, 68% of athletes exhibited at least 150% increase in endotoxins, however, while the majority (93%) of those athletes also reported GI symptoms, the severity of symptoms was not directly associated with endotoxemia (R).

But in general, it’s very common.

“Over 56% of athletes experienced at least 1 symptom sometimes, often, or always during training and competition and 18.6% had symptoms that sometimes or often interrupted/prevented training. Almost half (45.8%) of athletes and 80.0% of athletes with IBS reported trying nutritional modifications to help ease symptoms.” (R)

Let’s discuss a few solutions

Glycine

Glycine is one of the best amino acids that you can take. Our bodies can produce it, but not in big enough quantities. First off, glycine is involved in motor control and pain tolerance, both of which will immediately improve your exercise performance.

Furthermore, glycine is highly anti-inflammatory and can help to restore the anabolic effect of leucine in an inflamed muscle/body.

The following study looked at alcohol induced leaky gut and endotoxin absorption, which makes it applicable to exercise induced leaky gut as well.

“Ethanol feeding, by promoting intestinal permeability, enables portal influx of bacterial endotoxins. The resulting activation of Kupffer cells exposes hepatocytes to proinflammatory cytokines such as TNF-α that play a key role in induction of steatohepatitis. Glycine antagonises Kupffer cell activation via glycine-gated channels, as previously discussed.” (R)

So glycine can protect against absorbed endotoxins.

Glycine also prevents tissue damage and inflammatory response to endotoxin (R).

Furthermore, glycine can modulate the structure of gut bacteria to reduce the amount of endotoxin they have (it was in vitro study though).

“During various phases of growth, bacteria produce membrane vesicles (MVs) that contain much of the biological content derived from their parent bacterial cells, such as phospholipids, lipopolysaccharides (LPS), proteins, enzymes, toxins, DNA and RNA. … Glycine supplementation also significantly increased the number of MVs with enlarged particle size and altered the protein profile with an increase in the inner membrane and cytoplasmic protein contents as compared to non-induced MVs. … Of note, the endotoxin activity of glycine-induced MVs was approximately eightfold or sixfold lower than that of non-induced MVs when compared at equal protein or lipid concentrations respectively. Glycine is known to induce morphological changes in the outer layer of bacteria, by changing their Bacterial membrane vesicles (MVs).” (R)

Last but not least, glycine also has an antibacterial effect via inhibiting peptidoglycan (PG) synthesis by substitution of glycine for DL-alanine of PG during bacterial growth.

Product: (Amazon) (iHerb)

Dosage: 5g pre-workout. You can also have more during the day, such as an additional 2-5g with breakfast and dinner.

Vitamin B3

Vitamin B3 is great for gut health, reducing inflammation and destructive process and energizing the body. For example, niacinamide helps to increase NAD and inhibit NAD catabolizing enzymes, such as PARP, CD38, iNOS, etc (R).

“In isolated lungs, LPS increased lung weight (LW) to body weight ratio, LW gain, protein and dye tracer leakage, and capillary permeability. The insult also increased NOx, MG, TNFalpha, and IL-1beta in lung perfusate, while decreased adenosine triphosphate (ATP) content with an increase in PARP activity in lung tissue. Pathological examination revealed pulmonary edema with inflammatory cell infiltration. These changes were abrogated by posttreatment (30 min after LPS) with NCA. Following LPS, the inducible NO synthase (iNOS) mRNA expression was increased. NCA (niacinamide) reduced the iNOS expression. Niacinamide exerts protective effects on the organ dysfunction and ALI caused by endotoxin. The mechanisms may be mediated through the inhibition on the PARP activity, iNOS expression and the subsequent suppression of NO, free radicals, and proinflammatory cytokines with restoration of ATP.” (R)

Another great thing about niacinamide is that it energizes the intestine, preventing it from becoming leaky and preventing serotonin excess (A).

Niacin (and this should mean that niacinamide should be able to do it as well) has been shown in this study to prevent the decline in proteins involved in gut integrity, such as claudin-1, claudin-5, and ZO-1 in the distal intestine, whereas nicotinic acid significantly up-regulated these genes (R).

According to this study, microencapsulated delayed-release niacin significantly increased the relative abundance of Bacteroidetes, and this increase was associated with improved biomarkers for systemic insulin sensitivity and metabolic inflammation (R).

Product: (Amazon) (iHerb)

Dosage: 100mg before workout. If you have gut problems, then 500mg-1.5g x2 daily.

Vitamin B2

Riboflavin (vitamin B2), similar to vitamin B3, is extremely important for energy production. One of the important aspects is that it increases FAD, which accepts electrons from glucose and fat metabolism and donates them to the electron transport chain for energy production.

What I find most interesting is the effect it has on the gut.

This study found that just 100mg riboflavin increased the number of butyrate producers, namely Faecalibacterium prausnitzii and Roseburia, per gram of feces in healthy subjects after just 14 days, and also decreased Enterobacteriaceae in patients with inflammatory bowel disease (IBD) (R).

Riboflavin is also highly protective against absorbed endotoxins. “RF (riboflavin) decreased the mortality of endotoxin- and exotoxin-induced shock, gram-negative and gram-positive bacterial infection including long-term treatment. In addition, RF reduced levels of plasma inflammatory cytokines.” (R)

Lastly, riboflavin has also been shown to dramatically enhance bacterial and endotoxin clearance from the body (R).

Product: (Amazon) (iHerb)

Dosage: 100mg pre-workout

Sugar/carbs

Training in a fasted state is a sure way of getting leaky gut fast. Carbs are known to prevent leaky gut. As mentioned earlier, reduced blood flow and reduced glucose bioavailability promote leaky gut. Ischemia (reduced blood flow) depletes glycogen rapidly and this is what causes cellular damage.

So I don’t know why people think fasted training is such a good idea!

“Frequent ad libitum ingestion of glucose (15 g) before and during a 120 min treadmill run at 60% VO₂ max in hot conditions (~35 °C and 27% RH) ameliorates intestinal epithelial injury, small intestine permeability, and enhances anti-endotoxin antibody responses, when compared to water alone [20].” (R).

“Sucrose but not nitrate ingestion lowers intestinal injury evoked during prolonged strenuous cycling. These results suggest that sucrose ingestion, but not nitrate, prevents hypoperfusion-induced gastrointestinal damage during exercise and, as such, may help to lower exercise-related gastrointestinal complaints.” (R)

Dosage: 30-50g carbs before workout and 30-50g during your workout. I generally have 500ml fruit juice (around 60g carbs) as a before and intra-workout.

Creatine

Creatine a great overall supplement to use for enhancing gains. It’s one of the very few supplements that will have the biggest effect on your gains.

Although it hasn’t been shown to directly prevent exercise-induced leaky gut, it can reduce excess body temperature during exercise (overheating) and this may result in protective benefits against heat stress (R). Heat stress contributes to leaky gut, so creatine might help to prevent it.

Product: (Amazon) (iHerb)

Dosage: 5g any time of the day. Creatine stores build up so it really doesn't matter when you take it.

Succinic acid

Succinic acid has been used for a long time by Russian athletes in the product called Cytoflavin. The Russians have studied this compound a lot more than other countries, so most studies are in Russian.

Cytoflavin is a mix of succinic acid, inosine, niacinamide and riboflavin.

“Complete oxidation of one molecule of YaK (succinic acid) in reactions of oxidative phosphorylation can give 5 ATP molecules. Thus, the energy value of succinate is more than 2 times higher than the energy obtained by anaerobic glycolysis” (R).

“It is also one of the components of the antioxidant system, has an anti-inflammatory effect, takes part in the detoxification of xenobiotics and has neurotropic activity. There is evidence that it reduces the level of lactate in the body and promotes its faster excretion, which increases the performance of athletes and accelerates muscle recovery after physical exertion” (R)

Endotoxin depletes glycogen, so having glucose helps to prevent damages.

“In experiments on rats, which were injected with bacterial lipopolysaccharide, simulating experimental endotoxemia, it was demonstrated that UC (succinic acid) dimethyl ester is a potent stimulator of gluconeogenesis in hepatocytes, preventing glycogenolysis, which possibly protects liver cells from the metabolic consequences of endotoxemia” (R)

Succinic acid is a strong adaptogen and helps to protect against the harms of endotoxins, helps to prevent the drop in blood sugar which causes cellular damage and optimize cellular energy production.

Products

• Cytoflavin
• Cardenosine (also an ATP optimizer containing succinic acid, inosine, vitamin B6, ATP and pyroglutamic acid)

Inosine

So all in all, inosine is great against endotoxin induced damage, as well as restoring energy levels.

Product: Inosine

Dosage: 200mg before workout and up to 5-6g total daily (for restoring the energetics of various organs, such as the intestine, liver, kidney, lung, etc.) is safe.
It's good to combine this with succinic acid and vitamin B2 and B3.

Vitamin C

“Supplementation with ascorbic acid (a form of vitamin C) can reduce post-exercise LPS concentration by ~12 fold [31].” (R)

“Supplementation with ascorbic acid, however, abolished the increase in LPS and nitrite but led to a significant increase in the ascorbate radical in plasma. The amelioration of exercise-induced endotoxemia by antioxidant pretreatment implies that it is a free radical-mediated process while the use of the ascorbate radical as a marker of oxidative stress in supplemented systems is limited.” (R)

I would not take vitamin C directly before or after my workout as it might interfere with muscle protein synthesis to a degree.

Dr Ray Peat mentioned that one of the reason not to go too crazy on anti-oxidant supplements such as vitamin C, is because it can cause oxidative stress, by activating metals for example. Such as converting Fe2+ to Fe3+, which is the reactive form of iron, thus creating toxic hydroxyl radicals.

Colostrum

Colostrum at doses of 10-20g per day can reduce exercise induced gut permeability by 70-80% (R).

Product: (Amazon) (iHerb)

Dosage: 10g pre-workout

Zinc carnosine

Any kind of zinc might work as well, but the chelation form might be the best. And this might be because the carnosine enhances the absorption of zinc because of its solubility and delivers zinc to the tissues in a delayed/extended-release manner (R).

Zinc carnosine stabilises small bowel integrity and stimulates gut repair processes (R).

37.5mg of zinc carnosine has been shown to reduce exercise induced leaky gut by 70% (R).

Interestingly, combing (37.5mg) zinc carnosine with (10g) colostrum increased epithelial resistance and the tight junction structure synergistically (R).

Product: (Amazon)

Dosage: 37.5mg, with or without 10g colostrum

Progesterone

Progesterone isn’t a female hormone, as much as estrogen is. Progesterone has many beneficial effects in men, such as improving libido and antagonizing the major effects of stress.

This study found that progesterone protected against the damages of endotoxins and even inactivated endotoxins.

“progesterone was remarkably protective against endotoxin inflammation and lethality, but it also suggests that progesterone may react directly with endotoxin and form a covalent bond” (R; Thanks Haidut for digging up this study).

Dosage: 10-15mg pre-workout

DHEA

DHEA levels decline as we age and DHEA supplement has great health-promoting benefits, such as promoting the clearance of endotoxin and reducing the inflammatory response to them (R).

Keep in mind that dosage over 25mg can spill over to estrogen, which is also undesirable.

Dosage: 5-10mg pre-workout

Conclusion

Every time we expose ourselves to a stressor, our bodies adapt to become more resilient. But like any injury, we get scar tissue in that area; an increase in fibrotic tissue. Accumulation of this in the long term can dramatically reduce our health span and this is why we see increased risk of certain conditions amongst veteran lifters/endurance athletes.

Protecting yourself against endotoxins is a great first step to optimizing long-term health span and minimize the formation of excess collagen in our bodies.

Pre-workout idea:

• 500ml fruit juice
• 10g EAAs (essential amino acids; if you haven’t had a meal before your workout)
• 5g glycine
• 5g creatine
• 1 dose Cytoflavin or Cardenosine + Energin
• 4 drops CortiNon (DHEA and progesterone mix)

If you want to get your diet in check to make sure you’re gut is in optimal health, you’re eating the best nutrient-dense foods, and you’re optimizing your nutrient, you might be interested in the Alpha Energy Nutrition Course.

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