L-Ornithine an Anti-Stress Agent: Lower Cortisol, Higher DHEA, Better Sleep W/ Only 400mg of Ornithine Pre-Bed. Plus: Mini-Review of Add. Benefits - Burns, Gut Health, etc.

Stressed? Maybe ornithine can help. Or is this study just a hoax!?

Sounds like marketing shenanigan, right? "Lower Cortisol, Higher DHEA, Better Sleep W/ Only 400mg of Ornithine Pre-Bed." Ok, if it was marketing it would probably say "with only 5g of ornithine." I mean, 400mg that's not enough to generate significant revenues - is it?

But before we get to the marketing side of things, let's first look at the science, researchers from the Research Laboratories for Health Science & Food Technologies present in a recent paper in the Nutrition Journal, an open-access journal which charges scientists a certain fee for processing their papers.

You can learn more about sleep and the circadian rhythm at the SuppVersity

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Pre-Workout Supps Could Ruin Your Sleep

In their 8 week study, Mika Miyake et al. provided fifty-two apparently healthy Japanese adults who had previously felt slightly stressed and fatigue with either L-ornithine (400 mg/day) or placebo capsules.

The participants were advised to take one (400mg) capsule everyday before going to bed for eight weeks. At the end of the study period, all participants arrived at the laboratory fasted for blood sampling and a handful of other tests.

Figure 1: Effect of L-ornithine supplementation on serum stress markers.Means of the change from 0 weeks of each stress marker level (A, DHEA-S; B, cortisol; C, cortisol/DHEA-S) to 2, 4, and 8 weeks: mean ± SE. White circles (○) indicate the placebo and black circles (●) indicate L-ornithine. (Miyake. 2014)

The blood was analyzed for serum cortisol and DHEAS levels. In addition, the perceived mood and quality of sleep were measured by the Profile of Mood States (POMS) tests, the Athens Insomnia Scale (AIS), and Ogri-Shirakawa-Azumi sleep inventory MA version (OSA-MA).

Figure 2: Effect of L-ornithine supplementation on OSA.Means of the change from 0 weeks of each OSA score (A, sleepiness on rising; B, initiation and maintenance of sleep; C, frequent dreaming; D, refreshing; E, sleep length) to 1, 2, 3, 4, 5, 6, 7 and 8 weeks: mean ± SE. White circles (○) indicate the placebo and black circles (●) indicate L-ornithine

Significant changes were observed for serum cortisol levels and the cortisol/DHEA-S ratio. Both were significantly decreased in the L-ornithine group in comparison with the placebo group. The POMS and OSA-MA tests (not shown in Figure 1) revealed that similar beneficial effects occurred for anger (sign. reduced) and perceived sleep quality, which were both improved in the L-ornithine group compared to the placebo group.

Is there anything else ornithine is good for? Sugino et al. report that l-ornithine supplementation (2-6g/day) attenuates physical fatigue in healthy volunteers by modulating lipid and amino acid metabolism (2008). It enhances wound healing in mice and man (Shi. 2002; Coudray-Lucas. 2000). It improves muscle protein synthesis after surgery (Wernerman. 1987). Just like arginine, it holds the potential to improve gut health (Cynober. 1994; de Oca. 1997; Raul. 1995). But it is, unlike arginine, is no insulin secretagogue (=won't trigger an insulin release; Bucci. 1992) - Bottom line: Lots of potential, but nothing that would make it a "must have" supplement.

Quite impressive results, considering the fact that we are talking about a minimal amount of an amino acids fitness enthusiasts know mainly as an ineffective growth hormone booster (Lambert. 1993). What did you say? "Bias"? Well, the product used in the study is produced by the Kyowa Hakko Bio Company a company that is an affiliate of Kirin Company Limited, to which the authors belong, but that does not mean that the results are inaccurate.

Nevertheless, I would advise you to keep it in mind before you buy a 5kg bag of ornithine as an anti-stress treatment for the next 10 years - maybe 25g for an 8-week test-run are a better idea. Not necessarily because of a potential bisa, but rather in view of the small number of study participants  and the fact that we don't know exactly the mechanism that triggers the increase in DHEA, decrease in cortisol and overall anti-stress effect.

Even in animal models, where similar effects on the HPTA have been observed (Kurata. 2012), it is not clear, whether all this may in fact be a result of the  influence L-ornithine has on the urea cycle (converts ammonia to urea in the liver), as some scientists apparently believe. Overall, we are thus dealing with an interesting finding, but one that needs independent confirmation from a larger trials, and one I would have significantly more faith in if I know exactly how it came about (mechanistically) | Comment on Facebook!

References:

• Bucci, L. R., et al. "Ornithine supplementation and insulin release in bodybuilders." International journal of sport nutrition 2.3 (1992): 287-291. 
• Coudray-Lucas, Colette, et al. "Ornithine [alpha]-ketoglutarate improves wound healing in severe burn patients: A prospective randomized double-blind trial versus isonitrogenous controls." Critical care medicine 28.6 (2000): 1772-1776.
• Cynober, L. "Can arginine and ornithine support gut functions?." Gut 35.1 Suppl (1994): S42-S45.
• de Oca, Javier, et al. "Effect Of Oral Supplementation Of Ornithine-[Alpha]-Ketoglutarate On The Intestinal Barrier After Orthotopic Small Bowel Transplantation." Transplantation 63.5 (1997): 636-639.
• Kurata, Koji, et al. "Orally administered l-ornithine reduces restraint stress-induced activation of the hypothalamic-pituitary-adrenal axis in mice." Neuroscience letters 506.2 (2012): 287-291.
• Lambert, M. I., et al. "Failure of commercial oral amino acid supplements to increase serum growth hormone concentrations in male body-builders." International Journal of Sport Nutrition 3.3 (1993): 298-305.
• Miyake, Mika, et al. "Randomised controlled trial of the effects of L-ornithine on stress markers and sleep quality in healthy workers." Nutrition Journal 13.1 (2014): 53.
• Raul, Francis, et al. "Functional and metabolic changes in intestinal mucosa of rats after enteral administration of ornithine α-ketoglutarate salt." Journal of Parenteral and Enteral Nutrition 19.2 (1995): 145-150.
• Shi, Han Ping, et al. "Effect of supplemental ornithine on wound healing." Journal of Surgical Research 106.2 (2002): 299-302.
• Sugino, Tomohiro, et al. "L-ornithine supplementation attenuates physical fatigue in healthy volunteers by modulating lipid and amino acid metabolism." Nutrition research 28.11 (2008): 738-743.
• Wernerman, J., et al. "Ornithine-alpha-ketoglutarate improves skeletal muscle protein synthesis as assessed by ribosome analysis and nitrogen use after surgery." Annals of surgery 206.5 (1987): 674.

Amino Acids for Super Humans. Part II - Arginine, Citrulline and Ornithine: Nitric Oxide and Beyond

This relevant for all of you - regardless of whether you can or cannot spare the time: Tune in live and listen to me @ Carl Lenore's Super Human Radio to learn that amino acids are far more than just the building blocks of the proteins of your body...

Listen live to SHR @ 12:00PM ET

Amino Acids for Super Humans. Part II
(update: click here to download podcast)
Arginine, Citrulline and Ornithine: Nitric Oxide and Beyond

In the second installment of the show we are going to look at the purported and busted NO Booster l-Arginine, its metabolites citrulline and ornithine, malic acid or alpha ketoglutarate binding of this amino acids and their largely overlooked effects on glucose homeostasis, protein synthesis and detoxification.

As usual, I will do my best to provide relevant examples and relate the theory to practical advice. The magic of individual amino acids will be tackled in the shows to come.

Update: The show is now available for download.

Use Glutamine to Heal the Gut and Hinder Your Gut Bacteria from Eating Away Your BCAA, Arginine and Other Aminos

Image 1: Don't do this at home. A pig with cannules that have been dug into its digestive tract to study chemical enzymatic and microbial actions (University of Illinois)

With terms like "the leaky gut syndrome" and the usual quick (and not so quick) fixes a la "solutions for a leaky gut" being all over the blogosphere, I suspect that I am not telling you anything new, when I say that there is reasonable scientific evidence that glutamine is good for your gut (nice alliteration, by the way ;-). That it is yet also "good" for the bacteria in your gut may be news to you. According to a recently published study by scientists from the Laboratory of Gastrointestinal Microbiology, at the Nanjing Agricultural University in Nanjing, China, dietary l-glutamine can exert direct regulatory effects on the amino acid utilization of your gut bacteria - specifically their uptake and use of l-arginine and related amino acids (Dai. 2012).

"Hey, you gut bug, leave my arginine alone!"

It has been known forever that l-glutamine is the most abundant amino acid in the body. It's sheer ubiquitousness and rapid turnover relfect its crucial role in whole body nutrient metabolism and health. While fitness and health enthusiasts have long been mislead to believe that glutamine would exert direct ergogenic effects (cf. Amino Acids for SuperHumans: Part IV - Glutamine), scientists and laymen alike are now zoning in on its protective effects on the integrity and function of the small intestine. In this context it has recently become clear that

... AA [amino acid] metabolism in the small intestine plays important roles in the regulation of whole-body AA homeostasis. [...] Recent studies suggest that bacteria in the small intestine are active in the metabolism of AA, especially lysine, threonine, arginine, glutamate and glutamine. The rapid utilization and metabolism of glutamine by small-intestinal bacteria supports the view that glutamine is a key regulator of the survival and growth of bacteria in the intestine through the regulation of the bacterial metabolism of nitrogenous compounds particularly AA.

The usage of glutamine by your gut bacteria is yet not the only physiologically significant interaction between dietary glutamine and the billions of microorganisms in your gastrointestinal tract. According to Dai et al. glutamine may also affect the utilization and metabolism of other amino acids by small-intestinal bacteria "and metabolism in small-intestinal bacteria, and thusly influence the "the production and profile of nitrogenous compounds in the lumen of small intestine and whole-body amino acid homeostasis."

Complex interactions with a simple solution? Ramp up your glutamine intake!?

As you can see in figure 1 the influence of dietary glutamine on the uptake of nitrogen amino acids by Streptococcus sp., Escherichia coli, Klebsiellasp. and a number of jejunal mixed bacteria or ileal mixed bacteria from the small intestine of pigs (as omnivores they have a very similar digestive tract as humans) was profound, yet dose depended and overall pretty complicated.

Figure 1: Change in utilization [nmol /( 10 cells 3h )] of amino acids from the l-arginine family by small intestinal bacteria subsequent to incubation with 0, 0.5, 1, 2 and 5 mmol/L l-glutamine (data adapted from Dai. 2012)

While the incubation of the bacteria with different amounts of l-glutamine lead to increases and decreases of amino acids from the l-arginine family (cf. figure 1), its addition to a medium with the three BCAAs, leucine, isoleucine and valine (cf. figure 2) led to dose-dependent decreases in all three branched-chain amino acids and may thusly explain why direct ergogenic effects of l-glutamine usually occur in the context of low protein diets, only.

Figure 2: Change in utilization [nmol /( 10 cells 3h )] of branched-chain amino acids by small intestinal bacteria subsequent to incubation with 0, 0.5, 1, 2 and 5 mmol/L l-glutamine (data adapted from Dai. 2012)

The addition of glutamine to low protein diets (and or low dose BCAA supplements) may simply facilitates that the small amount of BCAAs that is present in the die / supplement, will actually make it to the gut border and into your system (and is not "eaten by bacteria" before), where it (and leucine in particular) is then able to exert its mTOR-mediated protein synthetic effects.

Species, dosage and amino acid dependence - further investigations necessary

If you take a look at all the data from the Dai study, it is immediately evident that things are way more complicated than a cursory look at the graphs in figure 1-2 would suggest:

• the net effect on the metabolism of amino acids from the arginine-family is particularly pronounced; the production / conversion of arginine to ornithine and citrulline increased and the overall use of arginine by the bacteria decreased (in some cases profoundly) 
• the increased glutamate production from E. coli could be of particular importance, in view of the multi-faceted function of glutamate in the mammalian (and thusly human, as well) metabolism
• the decrease in the utlization of BCAAs, but also the amino acids from the serine aspartate family, i.e. l-alanine, l-asparagine, l-aspartate, glycine, l-serine and l-threonine allow for a greater uptake and utilization of these physiological important amino acids by the enterocytes

All these factors lead the scientists to conclude that high enough amounts of dietary or supplemental "glutamine [are] not only nutritionally important, but also crucial for maintaining gut health and function", because

• 

  Illustration 1: Potential gut microbiome mediated benefits of higher dietary or supplemental l-glutamine intake; maybe it's still worth taking although it's not a proven ergogenic

  they will fulfill the glutamine requirements of the potential pathogenic bacteria E. coli and Klebsiellasp. and thusly make up for their detrimental effect on the amino acid availability of the host
• the thusly well-nurished and healthy gut lining protects the host (you) from bacterial invasion and infection
• with their role in the intestinal signaling pathways, the increased availability of arginine, amino acids from the arginine family and their related metabolites like agmatine and polyamines can exert direct regulatory effects on gut function and integrity
• there is emerging evidence that the degradation of serine and aspartate, which was reduced in the presence of larger amounts of glutamine, is a major factor contributing to the (over-)colonization of the small intestine with bacteria and the production of virulence factors in the intestine

Despite the fact that these results were obviously obtained by scientists interested in the development of effective feeding strategies for foodstock (ruminents with their large amount of bacteria in particular), the notion that higher glutamine intakes may exert (likely) beneficial effects on both amino acid availability, as well as gastrointestinal integrity and overall health appears to confirm the existing anecdotal evidence that glutamine-rich foods and supplements could make an important, if not essential contribution to your gastro-intestinal and metabolic health.