Gut conditions from indigestion to ulcerative colitis are treated with the gamut of pharmaceutical drugs. But, Raymond J Playford asserts, the role natural therapies have to play is rapidly expanding.
Dyspepsia, colloquially referred to as indigestion, is a major healthcare problem. It accounts for approximately five per cent of all general practitioner visits in the UK and eight per cent in Italy.1 A 2002 study reported that the population prevalence of dyspepsia in China was 18.4 per cent.2 Drugs for dyspepsia make a major impact on UK National Health Service prescribing costs, with proton pump inhibitors leading the field, costing $455 million per year in the UK alone.
In the community, dyspepsia is even more of a problem, with up to 40 per cent of the general population suffering from dyspeptic symptoms, most dealing with it using over-the-counter medication. For the hospital physician, gastrointestinal complaints constitute a major part of the workload with one in six hospital admissions being due to gut problems and digestive problems contributing to one in ten deaths in the UK.
Most of the major causes of gastrointestinal complaints seen in hospitals comprise the following conditions: gastro-esophageal reflux, peptic ulceration, non-ulcer dyspepsia, constipation, irritable bowel syndrome and inflammatory bowel disease. A less common (affecting up to 0.5 to 1 per cent of the North American and European communities) condition is Celiac disease, which is due to a specific allergy to gluten in wheat and similar materials, causing major inflammation and injury to the small intestine. Although not usually associated with any major inflammatory response, many people also complain of more generalised 'food allergies' where ingestion of particular food substances induces gut symptoms such as nausea and bloating. For patients with this form of food allergy, conventional treatment falls far short of the range of alternative modalities, and usually consists of advice to avoid the triggering factor.
The vast majority of people with gut complaints do not have an underlying cancer but it is important to exclude this, particularly if there are symptoms, such as bleeding, unexplained weight loss, difficulty in swallowing or anaemia.
The gastrointestinal tract, particularly the stomach and small intestine, possesses the remarkable ability to remain intact despite being constantly bathed in acid and proteolytic enzymes that can digest virtually any form of food eaten, including the GI tract of other animals (e.g., haggis, a Scottish food comprised of sheep stomach). The gut therefore possesses powerful mucosal defence and repair mechanisms and when a superficial and limited mucosal injury does occur, such as following direct physical trauma or ingestion of noxious agents such as aspirin or alcohol, it is usually quickly healed within a few days.
Mucosal integrity is maintained when the damaging effects of aggressive factors, such as hydrochloric acid and proteolytic enzymes, are counter-balanced by mucosal defence mechanisms. These include a high rate of cellular turnover (second only to the haemopoietic 'bone marrow' system), an efficient mucosal blood flow, a continuous adherent mucus layer and the presence of regulatory peptides that can directly stimulate repair and also influence all of the other protective factors.
When the system breaks down, possibly due to a combination of increased aggressive factors in subjects with a predisposition to illness due to innate weakened defences, excessive inflammation or ulceration occurs. Therapeutic intervention, whether with medical therapy or other approaches, therefore aims to reduce the actions of the aggressive factors or strengthen the defence mechanisms (Table 1).
For many gastrointestinal conditions, current therapy (Table 2) is imperfect and there remains a great demand for novel approaches both in the pharmaceutical arena and in the potential 'natural' market. The potential of natural bioactive products in the prevention/ treatment of gastrointestinal problems is an area growing in value to consumers as well as upstream to manufacturers and nutritive ingredient suppliers.
The initial question is: What constitutes natural therapy? This is far from clear and I consider it more of a continuum (see "Where Does Natural Therapy End?", below). Space prohibits detailed discussion of all factors and therefore examples are taken from each category.
ESSENTIALLY UNMODIFIED: HONEY
Essentially Unmodified: Honey
It is likely that a major mechanism of relevance for the potential medical use of honey relates to its hyper-osmolarity. This results in anti-microbial activity and this mode of action has the advantage of not being influenced by the ever-increasing concern over multi-antibiotic resistance.
Although activity against the bacterium Helicobacter pylori, a major cause of stomach inflammation and ulceration, has been shown when the bacteria are grown in vitro,3 some clinical trials have not been as supportive of the clinical use of honey.4 Nevertheless, many patients anecdotally consider it of value for dyspeptic symptoms such as 'indigestion pain' and 'heartburn'.
One of its major potential clinical uses is as a topical covering of serious skin wounds and burns. Honey rapidly clears bacteria from colonised and infected wounds; is sometimes effective against antibiotic-resistant strains; does not stick to wound tissue, which prevents tearing of newly formed tissue in the wound site when dressings are changed; and is easily rinsed from the wound with water. Some forms of honey, particularly 'manuka honey,' are claimed to have specific anti-microbial activity in addition to its hyperosmolar effects, although this point remains controversial.5
Partly Purified: Colostrum
Colostrum is the milk produced for the first few days following birth. Bovine colostrum is a commercial by-product of the milk industry and is already available as a dietary supplement. The claims made for some colostrum preparations are wide and include anti-ageing, anti-inflammatory, anti-microbial benefits, and athletic enhancement. However, some of the claims made for these preparations are based on limited evidence with major extrapolation from cell culture systems to whole-body physiology.
Nevertheless, studies have confirmed the maintenance of biological growth factor activity in several of these products when studied both in cell culture and in vivo, including some limited clinical trials. For example, one form of colostrum has been shown to prevent the increase in small intestinal permeability caused by ingestion of the pain-killing drug indomethacin.6
In addition, our group recently showed in a four-week, randomised clinical trial that colostrum enema therapy was efficacious (compared to an albumin solution) in reducing inflammation and improving symptoms in patients suffering from ulcerative colitis.7 The identity of the factors responsible for such changes are currently unclear but may include epidermal growth factor, transforming growth factor alpha, and transforming growth factor beta. Cell culture studies suggest that more than one factor is probably involved.8
Isolated: Epidermal Growth Factor
EGF, a 53 amino acid peptide, is present in colostrum and also is produced by the salivary glands and duodenal glands of humans and other animals. It is a potent stimulant of growth and has been shown to be beneficial in several models of upper and lower gastrointestinal injury.9
There have been relatively few clinical trials of EGF, although these are currently ongoing. One notable example was of an individual case report of a child necrotizing enterocolitis, a severe ulcerative condition of the bowel, which has a high death rate. A seven-day infusion of EGF caused the histology of the small intestine to revert to an essentially normal appearance and the child subsequently recovered.10
Although EGF is a constituent of colostrum, the costs and difficulty of isolating pure factors from these natural sources means that most clinical trials will be using artificially produced (usually recombinant) forms of the peptide. Although there appears to be little biological difference between the natural and artificially produced peptide, there is the concern that artificially produced peptides cannot be considered as a 'natural' approach. Of note, recombinant EGF is approximately 10 times less expensive as purified human EGF.
Synthetically Produced: Zinc Carnosine
Carnosine is a di-peptide comprising beta-alanine and L-histidine. It is naturally present in long-living cells such as muscle and nerves where, amongst other actions, it probably plays a role as an antioxidant.
Zinc carnosine is an artificially produced derivative of carnosine where it is linked in a one-to-one ratio to provide a polymeric structure. While most digestive aids focus on suppressing or neutralising stomach acid, zinc carnosine supports the natural cytoprotective mechanisms of the stomach without interfering in the normal digestive process. Zinc carnosine has been extensively studied in cell culture and animal models and also as a potential anti-ulcer drug in clinical trials. Zinc carnosine possesses antioxidant effects,11 and has been shown to have beneficial effects in various animal models of gut injury such as water immersion stress and HCl-ethanol gastric damage models12 and trinitro benzene model of colitis. 13
Clinical trials for the treatment of gastric ulcer have also shown a beneficial effect above placebo,14 although, perhaps not surprisingly, it does not appear as efficacious in healing ulceration as proton pump inhibitor therapy used by most clinicians for severe gastric ulceration.
Artificially Modified: Immune-Enhanced Milk
Milk and colostrum contain both specific (immunoglobulin) and non-specific (e.g. lactoferrin) anti-microbial activity. There is currently interest in improving the specific anti-microbial activity of milk and colostrum by immunising the cows against a particular organism, such as rotavirus. Such approaches have been shown to be beneficial in treating neonatal gut infections.15
Recent advances in molecular biology have also allowed modification of animal milk to produce increased quantities of growth factors and also to qualitatively change the composition, including making the human equivalent of various peptides. This usually requires the production of transgenic sheep where the relevant peptide is linked to a genetic promoter causing expression within the milk.16 Although this is certainly of interest, this approach appears to be a long way from what most people consider natural therapy.
Pitfalls To Consider
Many natural products are marketed with extremely limited data regarding which of the various (sometimes incompletely identified) ingredients are responsible for any biological activity demonstrated. This is a potential major concern because quality control and production of reproducible product is clearly hampered under these circumstances. As an example, products reporting to contain peptide growth factors are often stored at room temperature for prolonged periods, whereas the recommendations for storage of purified isolated forms of the same growth factors may well be at -20(infinity)C or 4(infinity)C. This is because many peptides have a limited shelf life before partial degradation of the peptides occurs.
In a similar vein, quality control simply employing measurement of immuno-reactivity of proteins (such as antibodies or growth factors) is a very indirect way of determining active constituents, as the presence of immunoglobulins that no longer react to their antigens (targets) or growth factors that have lost their growth factor activity are likely to be of little value.
The gut possesses a remarkable ability to digest a huge variety of things, including many compounds that form part of medication. For example, we have previously shown that, in acidic human gastric juice, 75 per cent of the biological activity of EGF is digested within a few minutes of ingestion and that residual activity is rapidly lost once it reaches the small intestine. This is because several peptide factors have been shown to be rapidly digested by pancreatic enzymes unless preserved by the presence of other food proteins, such as casein or soy bean trypsin inhibitor.17 The maintenance of biological activity following ingestion is therefore an area that is often neglected in the nutraceutical arena. Simply demonstrating that a product (e.g., plant extract) has a biological action in vitro (e.g., adding it to fibroblast cells and showing it causes growth) gives virtually no information regarding whether it will possess any activity once swallowed.
Even if the relevant factors survive their transit through the bowel, if they are going to affect gut function they may well be required to interact with specific receptors. The distribution of these receptors is therefore clearly of importance. For example, the EGF receptor is only present on the side and bases of the cell lining the gastrointestinal tract.18 Any EGF present in intestinal juice will therefore not interact with its receptor unless the bowel is damaged. Alternatively, if the factor is meant to have a more generalised physiological effect, such as athletic enhancement, the relevant compounds will probably have to be absorbed, usually by the small intestine, and pass through the liver before reaching the general circulation. Metabolism by the liver may remove biological activity or can even alter the molecular structure of the active compounds, to produce toxic derivatives.
As discussed above, several natural products or derivates have undoubted biological activity, although the details of the active constituents may be incompletely defined. Currently, when marketed as a dietary supplement, regulatory control and safety issues are much less stringent than if the same product were marketed as a drug. This is a potential cause of concern because though clinicians are accustomed to making decisions on risk-benefit for patients with clinical disease, the major market for such products is in the prophylactic area. These products are therefore being used by people who are essentially well. Several countries now have concerns over this matter and are considering changes in their safety regulations. For example, the UK medicine control agency now requires reporting of adverse reactions of unlicensed herbal remedies. This has been caused, at least in part, by reports of some products, such as Chinese herbal remedies, being associated with serious conditions such as progressive liver or kidney disease.
Gastrointestinal disorders seen by the clinician are only the tip of the iceberg. Many people with symptoms are self-medicating with a combination of over-the-counter medications and natural alternatives. The potential market for new approaches is therefore high. Although what constitutes a natural therapy may be a matter of debate, this area shows immense promise as a field for further research. Areas that need to be addressed include quality control, safety and regulatory issues, if this promise is to be fulfilled.
Raymond Playford is professor of gastroenterology, Imperial College Faculty of Medicine, Hammersmith Hospital, in London. He has received funding for colostrum research from Scientific Hospital Supplies, research grants from the Medical Research Council for studies of epidermal growth factor, lecture fees from proton pump inhibitor companies including Wyeth, Astra, and Byk UK, as well as from Lonza US, which markets zinc carnosine.
Email: [email protected]
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