As research continues to grow, it becomes more evident just how crucial the integrity of the digestive system is to overall health. It is the main barrier and first defense between the outer world and inner body. From this basic standpoint, the importance of maintaining a healthy gut lining is monumental. Here is a closer look at some key nutritional therapeutics for the purpose of enhancing gut health:

L-Glutamine: Maintaining Gut Integrity

L-Glutamine is well known as a major fuel and nitrogen source for colonocytes, as well as a component of glutathione.¹ These factors alone make it clear that the amino acid is a key nutrient in the intestinal mucosa and for combatting oxidative stress. Anecdotally, many practitioners swear by L-glutamine in its ability to heal the digestive tract under inflammatory circumstances and suboptimal gut integrity. However, research surrounding this topic is far from conclusive. Much research has shown L-glutamine to have positive applications in regulating or improving intestinal permeability. A double-blind trial of L-glutamine showed improvement in AIDS-related diarrhea in individuals taking antiretroviral drugs.² Similarly, patients receiving chemotherapy have been shown to benefit from reduced frequency of diarrhea versus control groups without a decrease in the efficacy of chemotherapeutics.^3,4 Testing using the lactulose-manitol ratio test (the preferred measurement for determining the presence or absence of “Leaky Gut Syndrome”) confirmed measureable improvements in intestinal permeability with L-glutamine supplementation in these individuals. Again, in otherwise healthy children suffering from gastroenteritis, L-glutamine supplementation reduced the duration of acute diarrhea by 26% compared to placebo.⁵ Animal studies also show improved intestinal permeability and preserved gut mucosal integrity using L-glutamine, although an extraordinarily high dose of 500 mg/kg/day was administered in one particular study.⁶ It is evident that more research is necessary to determine the exact role that L-glutamine plays in such inflammatory conditions of the digestive tract.

Essential Fatty Acids: Controversial Benefits

There are two types of essential fatty acids (EFA) that the human body cannot synthesize on its own: an omega-3 type, alpha-linolenic acid (ALA), and an omega-6 type, linoleic acid (LA). Both types serve a variety of crucial functions throughout the human physiology, most notably as precursors to various prostaglandins and leukotrienes (thereby regulating inflammatory pathways) and as components of cell membranes.¹³ Although ALA is converted in the body to the biologically active eicosapentaenoic acid (EPA) and docohexaenoic acid (DHA), its conversion rate is quite limited.¹³ As a result, health practitioners often recommend supplementation of EPA and DHA directly in the form of fish oil. Nevertheless, some experts hypothesize that the minimum dose needed for such a condition appears to be quite high (^9,12grams per day), possibly explaining the equivocal results as not all studies reached this dosage.¹ Similarly, research evaluating the efficacy of fish oil in UC patients has shown clinical improvement and decreased medication need,²⁰ yet many studies show disappointing results.²¹ Prospective cohort studies support a possible protective feature of increased omega-3 fatty acid intake for UC .²² A systematic review was performed in 2012 to better evaluate whether omega-3 fatty acids are indeed useful in CD or UC patients. Researchers were unable to come to a conclusion on the recommendations for clinical use based on poor study design features (ie. inappropriate placebo, small number of participants, variable designs). Despite this, they did lean toward the idea that available data does not support the use of omega-3 supplementation for the treatment of active and inactive inflammatory bowel disease.²³ A previous meta-analysis in 2011 came to similar conclusions.²⁴ For completion’s sake, it should be noted that supplementation with omega-6 oils has been shown to be clinically relevant as well, particularly in the form of gamma-linolenic acid (GLA, converted from LA within the body). Animal research has shown GLA to protect against induced ulcers²⁵ and GLA does have antineoplastic activity against hepatocellular carcinoma in vitro.²⁶ Finally, while the trend in modern medicine has been toward high dose omega-3 supplementation to counterbalance the low ratio of omega-3’s to omega-6’s found in today’s diet, some have posed the question of whether we are actually overdosing on omega-3 fatty acids.²⁷ This theory is supported by the fact that EPA and DHA are only converted in small amounts within the body because that is all that we physiologically need. More clinical research must be performed to determine the optimal ratio of EFA’s for supplementation and dietary purposes, as well as the exact role in treating clinical conditions.

Zinc Carnosine: An Anti-ulcer Agent

It has long been known that zinc is essential for the human body in physiological processes such as wound healing, immune function and hormonal regulation .²⁸ However, novel research has examined the role of zinc carnosine ([ZnC], zinc combined with the amino acids beta-alanine and histidine) for its gastroprotective capabilities and potential as a gastric ulcer treatment therapy. In fact, its application as an anti-ulcer drug has been in clinical use for quite some time now in Japan.²⁹ Numerous clinical studies of ZnC examining its anti-ulcer effects have shown great safety and efficacy through endoscopic measures. Optimum healing appears to be achieved after eight weeks of treatment (as high as 72% achieving “remarkable improvement” in one study), although four weeks demonstrates great improvements as well.²⁹ Another study showed that co-administration of ZnC with indomethacin (a Non-Steroidal Anti-Inflammatory Drug [NSAID]) eliminated the increase in gut permeability in humans when the NSAID was given alone. In addition, this coadministration also negated the formation of gastric ulcers in rats versus the damage seen when indomethacin was the sole therapy.30ZnC also shows strong potential as an anti-Helicobacter pylori agent (thereby adding to its role as an anti-ulcer supplement). In a clinical trial examining the efficacy of H. pylori eradication using ZnC in combination with triple therapy (lansoprazole, amoxicillin and clarithromycin), significant improvements were seen when compared to triple therapy alone.³¹ These results have been attributed to its bactericidal, anti-urease and anti-adhesive properties toward H. pylori specifically.³² Aside from anti-bacterial action, the mechanism of action for ZnC appears quite complex and multi-targeted. L-carnosine specifically prevents gastric epithelial injury by inhibiting DNA fragmentation,³³ whereas ZnC together acts as an antioxidant, induces the expression of Heat Shock Protein 72 (HSP72) and inhibits Nuclear Factor kB (NF-kB) in the colonic mucosa.³⁴ This increase in HSP72 activity and decreased NF-kB level has been shown to have cytoprotective effects on digestive organs. Other actions include the restoration of glutathione levels in injured gastric mucosa, promotion of growth factor formation, promotion of polyamine synthesis and inhibition of proinflammatory cytokine production (such as Tumor Necrosis Factor-alpha [TNF-α]) – all of which are essential processes in mucosal protection and ulcer healing in the gut.³⁵ Overall, the actions of ZnC make it a suitable pairing for optimal gut health and protection. As an added benefit, ZnC has also shown application in improving taste sensitivity in cases of idiopathic taste disorders.³⁶

Nitric Oxide: Not Just a Vasodilator

Classically, nitric oxide (NO) has been considered for its cardiovascular role as a potent vasodilator. However, many are unaware that the effects of NO are much more far reaching; it is also a proven anti-microbial, a necessary agent for tissue protection under ischemic circumstances and a gastroprotective agent.³⁷ With this in mind, NO and its precursors (nitrates and nitrites) have tremendous therapeutic potential that is still yet to be fully realized.From a gastroprotective standpoint, research has focused on the ability of NO to prevent and treat gastric ulcers. More specifically, nitrates, nitrites and NO have been shown to mitigate gastric ulcerations commonly caused by non-steroidal anti-inflammatory drugs (NSAIDs), endotracheal intubation and Helicobacter pylorithrough a variety of mechanisms.^38,39,40 NO appears to mitigate epithelial permeability, reduce tissue inflammation, increase gastric mucosal blood flow and, subsequently, increase mucus generation.^38,39 Collectively, these actions provide supportive protection in bacterial overgrowth and they help to offset the depletion of gastric NO due to common medical interventions.⁴¹

Keeping in mind the crucial role that a well-balanced gut microflora plays in our digestive health, NO helps to regulate this ecosystem through its broad-spectrum antibiotic effect. In vitro, NO and nitrites have proven to combat Shigella, Yersinia and Salmonella species, as well as Helicobacter pylori, Clostridium botulinum and Pseudomonas aerguinosa.^40,42,43 This inhibition of H. pylori by nitrites and NO may be a separate and additive protective mechanism for gastric ulcer prevention, while simultaneously promoting healing of the mucosal lining.⁴³Therapeutically, the most effective way to increase NO levels in the body and provide gastrointestinal protection is to deliver nitrates directly and drive the nitrate–nitrite–nitric oxide pathway (also known as the “NOx^3,2,1” pathway). This delivery method holds many advantages over the classic L-arginine-Nitric oxide pathway including stimulation of the entero-salivary nitrate cycle. In the most basic sense, this cycle allows nitrate conversion to nitrite in the oral cavity by commensal bacteria, followed by reduction to NO in the stomach.³⁷ The cycle continues as nitrates and remaining nitrites are rapidly absorbed into the blood stream and recirculated to the salivary glands, where further reduction and activation of NO can take place.³⁷ Interestingly, animal research shows that the gastroprotective effect of nitrate supplementation is eliminated if topical antibiotics are used in the oral cavity to disrupt the oral microflora.⁴⁴ As a final note, administering NO precursors in a clinical setting may be contraindicated in patients suffering from reflux esophagitis, as NO also appears to trigger relaxation of the lower esophageal sphincter.⁴⁵ However, given the gastroprotective effects discussed above, clinical judgment must be exercised, as this aggravating effect is merely theoretical.

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