Novel therapeutic uses of Metformin

New research is currently being investigated assessing the role of poor protein metabolism associated with autoimmune diseases. Proteins are large molecules found in a variety of foods such as meat, eggs, soy products, dairy and fish. Some types of protein, such as gluten, are also found in starchy foods, in which case they may be known as glycoproteins.

Proteins tend to be broken down into their constituent parts, amino acids, or into very small groups (chains) of amino acids in the gastrointestinal tract. From there, they are absorbed into the bloodstream and into cells, where amino acids and small fragments are re-purposed to form the body's own proteins and tissues. These proteins have a huge range of functions, such as nutrient, ion and mineral transporters, signal transduction, nervous system regulation, and natural immunity.

Gut Health and Autoimmunity

Digestive dysfunction

Dysfunction of some proteins may contribute to a number of conditions known as autoimmune disorders. There is a theory that as a consequence of poor gut health, autoimmune diseases may arise due to problems in the digestion of proteins.

Poor protein metabolism

Poor protein metabolism may occur due to digestive enzyme dysfunction. Thiol proteases are enzymes which play a role in the breakdown of proteins into amino acids. This may result in an immune reaction to the larger dietary peptide (a protein subunit or fragment) left to circulate in the digestive system. In addition, there is evidence that some types of protein may be more resistant to breakdown by another digestive enzyme, trpytase.

The intestinal epithelial barrier and 'Leaky Gut' Syndrome

The next steps in digestion should protect against the release of under-digested nutrients into the rest of the body. A main factor in this is the barrier between the intestine and the bloodstream, through which complete digestive products should be allowed to pass.
This is known as 'absorption'.

The site of most protein breakdown product absorption is the intestinal epithelial barrier. This is a layer of cells that have 'tight junctions' between them, which play an important role in absorbing molecules from the gut. This is known as intestinal permeability.

The passage of large molecules such as dietary protein fragments is controlled by a protein called zonulin (also known as pre-haptoglobulin).

Zonulin is similar in structure to a bacterial endotoxin known as ZOT, which is used by Vibro cholerae (the causative agent of cholera) to 'hijack' the tight junction in order to invade the 
tissues of an infected human.

If zonulin concentration or activity become abnormally elevated, it may affect intestinal permeability in a way that allows larger protein fragments through the epithelial barrier. If this occurs, these proteins may encounter the cells of the immune system.

Digestion and the immune system

The immune system is a highly complex system itself, but it has been theorised that it can misinterpret large peptides as antigens, or molecules that elicit an immune response. They attack the peptides by releasing inflammatory molecules, which may damage the surrounding tissue. Therefore, inappropriate peptide absorption may be associated with the increased risk of autoimmune activation, or an attack of immune cells on the body's own cells and tissues. Some research supports the theory that there may be a link between 'leaky gut syndrome' and the increased risk of immune-mediated damage and disease.

Irritable Bowel Disease. Barrier defects may exacerbate the autoimmune defects of inflammatory bowel disease (IBD), a condition in which either cytokines or interleukins (immune protein types) are over-expressed and attack the body's own tissues. Intestinal permeability improvement was associated with a significant reduction of colitis (a subtype of IBD) in an animal study.

Type 1 diabetes, multiple sclerosis, rheumatoid arthritis and coeliac diseases. Changes in intestinal permeability has been linked to other autoimmune diseases such as type 1 diabetes, multiple sclerosis, rheumatoid arthritis and coeliac disease.

Coeliac disease is an autoimmune reaction to common dietary proteins that make up gluten. One of these proteins, giladin, is also associated with the secretion of zonulin, thus possibly increasing the risk of 'leaky gut' even in those without the propensity to develop coeliac disease.

The 'tight junctions' between intestinal cells may also be disrupted by:

• Cancer treatments, including radiotherapy and chemotherapy. This may increase the risk of autoimmune disease development.
   
• The use of non-steroidal anti-inflammatory drugs (NSAIDs) may be associated with increased intestinal permeability.
   
• The risk of tight junction abnormalities may also have a genetic component.
   
• Advanced age may also be associated with the increased risk of 'leaky gut syndrome'.

Treatment strategies and future developments

There are a number of treatment options proposed and/or in development to correct intestinal permeability disorders, which may contribute to the management of the diseases as mentioned above. These include:

Exercise

Appropriate moderate exercise may manage the effects of inflammation caused by 'leaky gut'.

Exercise has demonstrated the ability to reduce immune protein counts in other autoimmune conditions such as systematic lupus erythromatosus. Some research indicates that exercise may reduce the risk of IBD development.

On the other hand, there is evidence that short-term exercise may exacerbate inflammation in patients with type 1 diabetes.

More extensive review of the research into exercise in chronic inflammatory diseases is inconclusive, due to the variability of training regimens, time-frames (i.e. single sessions or long-term exercise programmes) and exercise types used. This may indicate a need for the design of specialised exercise programmes, in order to optimise any positive effects of exercise on intestinal permeability disorders. However, this option treats the symptoms and consequences of tight junction abnormalities, not the cause.

Zonulin inhibition

Zonulin over-activity may play a role in intestinal permeability disruption, as outlined above. Therefore, drugs that inhibit zonulin release or block its receptor in the tight junction may have a positive impact in conditions where 'leaky gut syndrome' contributes to disease.

Larazotide acetate, a tight junction regulator, may be a promising candidate, and is the first anti-zonulin drug in development. It demonstrated some efficacy in inhibiting giladin- and ZOT-mediated tight junction changes in animal studies. However, it did not significantly inhibit the activity of zonulin in a double-blind trial of 86 coeliac patients randomised to either this drug or a placebo. Another trial with 184 coeliac patients randomised to three separate doses of larazotide or placebo, after a challenge with the same concentration of gluten, demonstrated a significant reduction in symptoms in the group receiving the lowest dose of the drug (1mg) only. However, these symptom scores were based on subjective patient reports, and empirical measures of biological coeliac disease markers did not differ between any of the groups. Therefore, much more testing and development of this drug is necessary before it is approved for intestinal permeability-associated illness.

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