The gastrointestinal (GI) tract is essentially a system of muscular tubes that propel materials along its length, to enable the absorption of nutrients and the excretion of waste products in and out of the body. The wall of the GI tract is sealed by a layer of intestinal epithelial cells. As well as selectively absorbing nutrients and excreting waste

The GI wall acts as a first line of defense by preventing potentially harmful toxins or bacteria in the gut from entering the blood. Certain conditions and treatments may damage the GI tract, resulting in loss of integrity of the GI wall. Known as intestinal permeability or ‘leaky gut’, this loss of integrity of the GI wall is an abnormal state in which substances that normally do not cross the intestinal wall leak into the blood causing potentially harmful effects¹⁹.

Tight junctions are a key factor in intestinal permeability. Tight junctions are specialized structures made of proteins called claudins that seal the cells (intestinal epithelial cells) of the intestinal wall together. They play a major role in preventing toxic and infectious agents from entering the blood. Intestinal bacteria and inflammation, can activate immune cells that release inflammatory substances (cytokines), which may disrupt the function of tight junctions. Disruption of tight junctions can result in intestinal permeability or ‘leakiness’ in certain areas of the GI wall. This situation allows toxic and infectious material to further exacerbate inflammatory reactions, potentially leading to a vicious cycle of inflammation²⁰.

Certain conditions and treatments may damage the seals in the GI wall. These include inflammatory bowel diseases (Crohn’s disease), intestinal infections (salmonella, norovirus or giardiasis), celiac disease, chemotherapy medication, chronic kidney disease, radiotherapy of the abdomen, immunosuppressants, HIV/AIDS, cystic fibrosis, type 1 diabetes mellitus, sepsis, and complicated GI surgery²¹.

However, natural medicine practitioners also believe that the gut may become ‘leaky’ due to factors ranging from more mild food allergies and tiredness, to more severe factors such as chronic fatigue syndrome, asthma, lupus, rheumatoid arthritis, multiple sclerosis, scleroderma, eczema, and autism²¹.

The ‘leaky gut’ theory is based on the idea that the disruption of tight junctions allows toxic and infectious agents to leak across the gut wall into the blood where they trigger a vicious cycle of inflammation throughout other parts of the body.

Here are some natural options that may help to facilitate healing of the GI wall and offset the effects of a vicious cycle of gut inflammation.

Glutamine

Glutamine is a hypoallergenic amino acid that is safe to ingest at high doses. It plays a role in the integrity and function of the intestinal wall, and is an important source of fuel for the cells lining the intestine (intestinal epithelial cells). Along with another amino acid called arginine, glutamine promotes cell growth and protects against nutrient deprivation, oxidative stress, and inflammation²².

The level of glutamine in the intestinal lining and blood stream is sensitive to inflammation and may become depleted due to inflammatory reactions²³. Improvements in the integrity and function of the GI wall due to the effects of glutamine have been demonstrated in experimental models of intestinal dysfunction^24-26.

Glutamine supplementation has also been shown to help maintain an intact intestinal barrier and reduce the frequency of infections in critically ill human patients ⁽²⁷⁾. In abdominal surgery patients, the mechanism of action for glutamine may involve the reduction of markers of inflammation (endotoxin), histamine metabolism (diamine oxidase), and oxidativestress (malondialdehyde) as well as the improvement of temperature and white blood cell (immune cell) count²⁸.

Butyric Acid

In healthy individuals, butyric acid (esterified form of butyrate), a short chain fatty acid, is produced by the ‘friendly’ bacteriain the gut from the metabolization of non-digestible carbohydrates (i.e. dietary fibre). This 4-carbon fatty acid is the primary source of energy for epithelial cells of the colon (colonocytes), which use butyric acid in preference over glucose to produce 70% of their energy (ATP) requirements²⁹.

Butyric acid has well-documented anti-inflammatory effects, reduces intestinal permeability, and enhances the production of natural anti-microbial agents³⁰. Furthermore, butyric acid enemas have been shown to produce positive effects in the treatment of ulcerative colitis³¹. In a model of LPS-induced inflammation (i.e. inflammation triggered by bacterial agents called lipopolysaccharides [LPS]), butyrate improved intestinal wall integrity and tight junction permeability³².

Butyric acid is rapidly absorbed by colonocytes in the large intestine, although a portion does pass via the hepatic portal vein to the liver²⁹. Once absorbed, butyric acid increases the expression of genes for tight junction proteins, possibly through its activity as an inhibitor of histone deactylase enzymes (HDACs)^29,30—although this is unproven. HDACs removeacetyl groups from genes in DNA, a process that enhances the compaction of DNA, and thus, reduces gene expression. An alternative mechanism may involve butyrate’s interference with LPS-induced inflammatory signaling that otherwise suppresses the synthesis of tight junction proteins³².

Because butyric acid is produced by commensal (‘friendly’) gut bacteria that metabolize non-digestible carbohydrates, butyric acid production depends on the types of bacteria and carbohydrates present in the gut. Butyric acid-producing gut bacteria include Clostridium, Eubacterium, and Butyrivibrio species, while the fibre contained in bananas, onions, asparagus, legumes and whole grain serves as a substrate for butyric acid production by these bacterial species³³.

Zinc-Carnosine Zinc-carnosine is a chelate (metal-binding) compound that combines the mineral zinc with the antioxidant carnosine. This combination has been used as a prescription medication in Japan since 1994. In cellular experiments, zinc-carnosine has been shown to increase the proliferation of human colonic and rat intestinal cells³⁴. Zinc-carnosine was also shown to improve gastric and small intestinal injury in an experimental rat model. In a human clinical trial of 10 healthy volunteers, zinc-carnosine prevented intestinal permeability induced by indomethacin³⁴, a non-steroidal anti-inflammatory drug (NSAID) that may damage the seals between cells of the intestinal wall²¹.

Discussion

Loss of the integrity of the GI wall or ‘leaky gut’ may be caused by, and contribute to a wide range of symptoms. Many of these symptoms share the common theme of infection or inflammation that results in disruption of the seals (tight junctions) between intestinal cells. Restoration of tight junctions is the main rationale behind the use of health supplements for ‘leaky gut’. Glutamine, butyric acid, and zinc-carnosine show promise as alternatives for this condition as they have been shown to have positive effects on infection, inflammation, and intestinal permeability. The potential benefits of eating a diet rich in fibre to support the production of butyric acid by commensal bacteria should also not go unnoticed.