Glutamine - The Unsung Hero of Recovery

 Glutamine – The Unsung Hero of Amino Acids

Immune Health Starts in the Gut

This is where glutamine does its heavy lifting!  Your digestive tract (GI for short) is completely separated from the rest of your body and circulation. Anecdotally, you might hear therapists reference your stomach or GI tract as being “outside of your body” and when you think about it, it really is!  This separation is critical, preventing the entry of toxins, allergens, and other pathogens which are naturally present in your GI, from entering the rest of your body, and for good reason!

We turn our attention now to the intestines, a primary site of nutrient absorption and where glutamine is truly “king”.  Imagine the health and function of this gut barrier along a continuum; like a long, sealed pipe carrying oil from a refinery to a seaport.  You do not want that oil to escape, so the integrity of the pipeline is crucial!  Should it be compromised, oil would seep through - slowly at first - and begin to pollute the surrounding area.  While the amount of oil may not be initially large, if left unchecked this would lead to a serious accumulation and untold environmental damage; not to mention weakening the integrity of the pressurized pipeline!

So too is the failure of your intestinal barrier. In the body, “seepage” of intestinal fluids is known to cause a strong immune response and ramp up inflammation throughout the body. The condition is called gut permeability and more commonly spoken of as “leaky gut”.  (1)

The problem with leaky gut is that it allows bacteria and endotoxin (like lipopolysaccharides (LPS)) to bypass this barrier and get into your circulation. This greatly increases the risk of infection as these pathogens circulate throughout the body and challenge your immune system. (2)

Gut permeability is known to play a critical role in numerous gastrointestinal diseases such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), celiac disease, Crohn’s, and general inflammation. Even more critically, you do not need to have a “condition” to be gut-compromised; should this barrier not be operating effectively, it can impair nutrient absorption and make us more prone to sickness. (3) Lastly, having a poor diet can negatively impact and exacerbate inflammation of this barrier.  This is yet another reason why food quality is such a critical component for everyone, regardless of their exercise practices. 

How Does Glutamine Help?
Remember those epithelial tight junctions I mentioned, which are critical to your intestinal barrier? This is one of the major sites where glutamine plays a vital. It provides energy/fuel for the metabolism, growth, and repair of the specific cells which make up this intestinal barrier (1) In fact, when under extreme duress, studies involving cases of serious GI damage make this point very apparent and are summarized below:

• For those undergoing cancer radiation therapy, serious bowel injury and ulceration occurs. Patients were given 30g of supplemental glutamine daily over a period of 28 days and were found to have improved markers of gut permeability, compared to a control group. (4)

• Several other studies have found a clinical benefit of glutamine in multiple areas, including cancer treatment, sepsis, burn injury, or diarrhea including amongst children. (5)

These “worst case” scenarios while awful to read do markedly show how glutamine makes a significant difference to GI health and accompanying symptoms.

Lymphocytes, neutrophils, and macrophages are the cells that respond to invading bacteria, virus, or other pathogens, and these cells use glutamine at high rates. In fact, they consume glutamine at rates equal to or higher than glucose during catabolic conditions (sepsis, recovery from burns or surgery and malnutrition) which increase the demand for this amino acid. (6)

Fittingly, this research is also where the step from therapeutic health and wellness shifts over to the subject of training recovery.  In addition to the conditions listed above, these critical cells also consumed glutamine at high rates under the demand of high levels of physical exercise and can quickly deplete glutamine stores. (5)(3) Keeping these immune cells topped up with glutamine is important for the overall health and functioning of your immune system and where the oft-used explanation “glutamine heals your muscle” comes from.

Before we fully shift into athletic recovery, glutamine in the gut:

• supports nutrient absorption
• provides maintenance and supports to the 1^st line of defense for your immune system
• provides energy for the individual cells of your immune system

Thus, it controls inflammation and facilities optimal health by keeping our internal “pipeline” sealed.

Glutamine’s Role in Athlete Recovery/Performance 

For starters, anyone who takes their training seriously AND suffers from a compromised GI tract (IBD, IBS, Celiac, Colitis, Crohn’s) needs to make taking care of their stomach a priority!  Why? Not only can this impair your absorption of important nutrients, but studies also show that any disruption in the gut barrier function can be further exacerbated during exercise. This can lead to increased intestinal permeability, which allows increased passage of endotoxins (LPS) into your circulation. (7)

This can lead to some awful side effects, as increased circulating LPS levels in athletes have been associated with GI symptoms including nausea, vomiting and diarrhea (8). Further, it can also impact physical performance (9) or delay recovery (10).

Without doubt, glutamine is a “must” for anyone fitting this category.  But what about the otherwise “healthy” person who is also dedicated to their training?  Is there anything that supports using glutamine in that scenario?  The short answer is “yes”.  Glutamine can potentiate improved recovery and support performance by preventing accumulation of toxic levels of ammonia (which we generate when we breakdown amino acids), lowering muscle damage, preventing dehydration, or supporting the hormetic response to training. (11) (12) (13) 

Too Hot? Glutamine to the Rescue

Interestingly, training in the heat can add extra stress to the gut and induce gut permeability. One of the more intriguing studies had researchers give athletes high dose supplemental glutamine before strenuous exercise in the heat to determine if it would prevent some of the gut permeability this training is known to cause.

• In a double-blind randomized placebo-controlled trial, 10 participants
  
  completed four different exercise trials; and were given supplemental glutamine at increasing doses before 60 minutes of running at 70% of V02max in the heat (30 degrees Celsius). (14)

• Compared to placebo, supplemental glutamine did indeed lower markers of GI permeability. The largest dose (0.9g/kg Fat Free Mass) was most effective but even the small dose
  
  (0.25g/kg FFM) was beneficial.

• Lower Dosing Range: about 21g for a 200lb person @ 10% body fat

• Higher Dose Range: >73g for a 200lb person @ 10% body fat

Based on this, adding some glutamine to your pre-workout stack would be especially helpful to those who perform jobs or sports (running, cycling, triathletes) in the summer or fully geared up.  Intense exercise like this creates a curious dilemma for the body.  You are accumulating inflammation and oxidative stress triggering your body to burning through resources (including glutamine) to control it so that you can continue to perform. The last thing you want is to add more “inflammation to the fire” because of an exercise-induced compromised gut barrier!

Glutamine – A Potential Carb Replacement?

This was a point teased in the intro and while the points previously covered are important, I really want to discuss how relevant glutamine can be for carb insensitive or potential insulin-resistant individuals. This concept was first introduced by the late, great (and way-ahead-of-his time) Charles Poloquin who rightly should be given credit for this consideration.

As you might have surmised, glutamine plays an interesting role in replenishing your stored energy (glycogen). This is one of the reasons why Charles would recommend (higher dose) glutamine to athletes post workout often in place of carbohydrates. In study that (later) validated his actions, a study published in The Journal of Applied Physiology concluded that 8g of post workout glutamine replenished glycogen to a similar level as 61g of a glucose solution! (15) This is quite a shocking finding from where I draw three takeaways:

• It makes it a useful tool for those on a low carb diet or for people who do not handle carbohydrates well (e.g., if someone has excess body fat to lose). Note it could also be superior option to curb excess inflammation (which is known to be present in overweight people).

• When it comes to athletic performance, research is conclusively in support of variation. You must keep your body guessing to encourage continued gains. So instead of using post workout carbohydrates every single time why not occasionally, instead, use high dose glutamine? This forces your body to use alternative metabolic pathways. From an anecdotal standpoint, it also appears to reduce sugar cravings and prevents “crashes” which often stem from high carbohydrate intake.

• It can be effective for maintaining performance during weight cuts, especially when you consider points 1 and 2, and the heightened muscle damage that can occur while in a sustained caloric deficit.

 Reaching for Advil?  Think Twice!

My last point here straddles both athletics and wellness and needs to be mentioned.  Many who train hard and get sore often rely on pain killers, as do those who are in chronic pain due to an injury or illness.  Given that NSAIDS (Ibuprofen) are anti-inflammatory it would be logical to think that they would help with recovery.

• Thought Process: If inflammation is bad, then taking an anti-inflammatory drug should counter this and help my recovery!

First - when used sparingly - these drugs can have merit and be beneficial.  That said, they should not be the first thing you reach for, especially on a consistent basis. Why?  These drugs have a causal link with intestinal permeability. That is

right, these anti-inflammatories are WORSENING your recovery by compromising your gut! And it does not take the chronic use that one might think to experience these side effects! (400mg twice before exercise) (16)

Luckily, glutamine supplementation was found to be beneficial in decreasing intestinal permeability induced by non-steroidal anti-inflammatory drugs like ibuprofen (17). This means the glutamine can be an excellent option for those who use NSAID painkillers for chronic pain, and not solely in an athletic training situation.

Lean Muscle and the Link to Immune Function

I wanted to make a final note on how having adequate lean muscle also supports your immune system. My greatest frustration with this last year is how mainstream media have completely ignored the importance of metabolic health and the therapeutic potential of exercise.

One of the most important sites of glutamine synthesis occurs in skeletal muscle. It turns out that as muscle reduces its contribution to maintaining plasma glutamine, diseases and infections, or risk of subsequent infections worsen (18). Indeed, low blood concentration of glutamine may impair immune cell function, resulting in poor clinical outcomes and increased risk of mortality (19).

So yet again we see a protective effect of muscle as it ‘donates’ energy to the immune system. Those with more muscle have more of this energy to give.

How Does Your Glutamine Supplement Stack Up?

One common thing seen is how many protein supplements mislabel ‘glutamate’ as actual L-Glutamine.  In a typical scoop of protein, glutamate is known as a pre-cursor to glutamine and it is NOT the same and needs to be metabolized into L-Glutamine via a cellular enzyme called glutamine synthetase, which converts glutamate into glutamine.  When you use supplemental L-Glutamine, this amino acid is already in the form that your body needs and requires no conversion, thus you get more. (20 

Some BCAA and Intra Workout products also add glutamine, often in small 1-2g doses.  While I would never say “no” to some extra glutamine during training, know that these doses (while nice) do not meet the standard for a therapeutic or what is best stated as a meaningful dose.  That is why the vast majority of those who supplement with glutamine purchase the stand-alone product.  Depending on your situation, the dose could vary greatly and for that reason I recommend buying it alone. 

Glycine

One exception I would consider is using a Glutamine supplement with some added Glycine.  It is vital for several biological pathways that are synergistic with that of glutamine.

Collagen is the major protein found in skin and joint cartilage and has risen in popularity in the past 4-5 years. Research now confirms that we can build and repair new collagen - with the help of supplemental forms - even as we age. This was previously thought not possible. But this process - the actual synthesis of collagen - requires adequate glycine.  Short on glycine or Vitamin C?  You will not be rebuilding this critical tissue! (21)

Glycine also has powerful antioxidant and anti-inflammatory properties. It is involved in the production of the body’s major antioxidant - glutathione (as is glutamine) (22). Glutathione is important for our immune system and for coping with any conditions of heightened oxidative stress. This includes sickness, chronic illness, or high-volume training or competition. In fact, glutathione is depleted during intense exercise, and while the body can naturally restock it, it requires the proper resources to do so.  Moreover, glycine is also one the 3 building blocks of creatine (along with methionine and arginine) that we produce each day and is critical to the ATP cycle.

The last benefit that I want to touch on is how glycine acts as a calming neurotransmitter in the brain and facilitates the signaling of GABA. As a result, many people experience a calming effect from supplemental glycine. In fact, research shows that supplemental glycine improves sleep quality (likely owing to this mechanism) but also because it lowers the stress-hormone, cortisol. (22)

For this reason, when formulating their L-Glutamine supplement ATP Labs opted to combine these two amino acids together, at a 4:1 ratio.  In each scoop, Glutamed offers 4g of fermented L-glutamine and 1g of Glycine.  These amino acids are vegan friendly, produced with no fillers and being AjiPure sourced, are the cleanest source available, worldwide. 

As a last point, avoid any glutamine supplements which contain ‘glutamine peptides’ as these are often from wheat and not ideal due to gluten content. 

Dosing Suggestions:

Take 1-2 scoops of Glutamed 2-3 x daily to promote gut health, support your immune system, and optimize recovery from hard exercise or injury.

As an example:

• On training days, use 1-2 scoops upon waking, 1-2 scoops intra-workout, and 1-2 scoops before bed.
• On rest days/for general health take 1-2 scoops upon waking, and 1-2 scoops mid-afternoon between meals and 1-2 scoops before bed.

References

1 - Rao R, Samak G. Role of Glutamine in Protection of Intestinal Epithelial Tight Junctions. J Epithel Biol Pharmacol. 2012;5(Suppl 1-M7):47-54. doi:10.2174/1875044301205010047

2- Castell L., Newsholme E. The relation between glutamine and the immunodepression observed in exercise. Amino Acids. 2001;20:49–61. doi: 10.1007/s007260170065.

3 - Cruzat V, Macedo Rogero M, Noel Keane K, Curi R, Newsholme P. Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation. Nutrients. 2018;10(11):1564. Published 2018 Oct 23. doi:10.3390/nu10111564

4 - Yoshida S, Matsui M, Shirouzu Y, Fujita H, Yamana H, Shirouzu K. Effects of glutamine supplements and radiochemotherapy on systemic immune and gut barrier function in patients with advanced esophageal cancer. Ann Surg. 1998 Apr;227(4):485–491.

5 - Newsholme P. Why is l-glutamine metabolism important to cells of the immune system in health, postinjury, surgery or infection? J. Nutr. 2001;131:2514S–2523S. doi: 10.1093/jn/131.9.2515S.

6 - Ardawi M.S.M., Newsholme E.A. Maximum activities of some enzymes of glycolysis, the tricarboxylic acid cycle and ketone-body and glutamine utilization pathways in lymphocytes of the rat. Biochem. J. 1982;208:743–748. doi: 10.1042/bj2080743.

7 - Selkirk GA, McLellan TM, Wright HE, Rhind SG (2008) Mild endotoxemia, NF-kappaB translocation, and cytokine increase during exertional heat stress in trained and untrained individuals. Am J Physiol Regul Integr Comp Physiol 295:R611-623. doi:10.1152/ajpregu.00917.2007

8 - Jeukendrup A, Vet-Joop K, Sturk A, Stegen J, Senden J, Saris W, Wagenmakers  A  (2000)  Relationship  between  gastro-intestinal complaints and endotoxaemia, cytokine release and the acute-phase reaction during and after a long-distance triathlon in highly trained men. Clin Sci 98:47–55. doi:10.1042/Cs19990258

9 - Vargas NT, Marino F (2014) A neuroinflammatory model for acute fatigue during exercise. Sports Med 44:1479–1487

10 - van Wijck K et al. (2013) Dietary protein digestion and absorption are impaired during acute postexercise recovery in young men. Am J Physiol-Regul Integr Comp Physiol 304:R356-R361 doi:10.1152/ajpregu.00294.2012

11 - Bassini-Cameron A., Monteiro A., Gomes A., Werneck-de-Castro J., Cameron L. Glutamine protects against increases in blood ammonia in football players in an exercise intensity-dependent way. Br. J. Sport. Med. 2008;42:260–266. doi: 10.1136/bjsm.2007.040378.

12 - Raizel R., Leite J.S.M., Hypólito T.M., Coqueiro A.Y., Newsholme P., Cruzat V.F., Tirapegui J. Determination of the anti-inflammatory and cytoprotective effects of l-glutamine and l-alanine, or dipeptide, supplementation in rats submitted to resistance exercise. Br. J. Nutr. 2016;116:470–479. doi: 10.1017/S0007114516001999.

13 - Hiscock N, Petersen EW, Krzywkowski K, Boza J, Halkjaer-Kristensen J, Pedersen BK. Glutamine supplementation further enhances exercise-induced plasma IL-6. J Appl Physiol (1985). 2003 Jul;95(1):145-8. doi: 10.1152/japplphysiol.00471.2002. Epub 2003 Feb 28. PMID: 12611772.

14 - Pugh JN, Sage S, Hutson M, Doran DA, Fleming SC, Highton J, Morton JP, Close GL. Glutamine supplementation reduces markers of intestinal permeability during running in the heat in a dose-dependent manner. Eur J Appl Physiol. 2017 Dec;117(12):2569-2577. doi: 10.1007/s00421-017-3744-4. Epub 2017 Oct 20. PMID: 29058112; PMCID: PMC5694515.

15 - Effect of oral glutamine on whole body carbohydrate storage during recovery from exhaustive exercise J. L. Bowtell, K. Gelly, M. L. Jackman, A. Patel, M. Simeoni, and M. J. Rennie Journal of Applied Physiology 1999 86:6, 1770-1777

16 - Van Wijck K, Lenaerts K, Van Bijnen AA, Boonen B, Van Loon LJ, Dejong CH, Buurman WA. Aggravation of exercise-induced intestinal injury by Ibuprofen in athletes. Med Sci Sports Exerc. 2012 Dec;44(12):2257-62. doi: 10.1249/MSS.0b013e318265dd3d. PMID: 22776871.

17 - Hond ED, Peeters M, Hiele M, Bulteel V, Ghoos Y, Rutgeerts P. Effect of glutamine on the intestinal permeability changes induced by indomethacin in humans. Aliment Pharmacol Ther. 1999 May;13(5):679–685.

18 - Oudemans-van Straaten H.M., Bosman R.J., Treskes M., van der Spoel H.J., Zandstra D.F. Plasma glutamine depletion and patient outcome in acute icu admissions. Intensiv. Care Med. 2001;27:84–90. doi: 10.1007/s001340000703.

19 - Rodas P.C., Rooyackers O., Hebert C., Norberg A., Wernerman J. Glutamine and glutathione at icu admission in relation to outcome. Clin. Sci. 2012;122:591–597. doi: 10.1042/CS20110520.

20 - Krebs H.A. Metabolism of amino-acids: The synthesis of glutamine from glutamic acid and ammonia, and the enzymic hydrolysis of glutamine in animal tissues. Biochem. J. 1935;29:1951–1969. doi: 10.1042/bj0291951.

21 - B. X. Yan and Y. Sun Qing, “Glycine residues provide flexibility for enzyme active sites,”

Journal of Biological Chemistry ,vol.272, no. 6, pp. 3190–3194, 1997.

 22- Meerza Abdul Razak, Pathan Shajahan Begum, Buddolla Viswanath, Senthilkumar Rajagopal, "Multifarious Beneficial Effect of Nonessential Amino Acid, Glycine: A Review", Oxidative Medicine and Cellular Longevity, vol. 2017, Article ID 1716701, 8pages, 2017. https://doi.org/10.1155/2017/1716701