The diagnosis of ‘inflammatory bowel disease’, or IBD, is among medicine’s many umbrella terms. It hovers over a range of inflammatory conditions of the bowel, although two in particular – ulcerative colitis (UC) and Crohn’s disease – are the most common.
In the gut, some degree of inflammation is necessary and desirable. Inflammatory cells in the intestinal tract protect us from its normal contents, and this highly effective chronic inflammation is tightly controlled. IBD is presumed to develop when this control goes haywire, causing a massive overreaction of the gut immune system to the gut contents.
In this regard, it shares common ground with atopic disorders such as asthma, where the immune system of the respiratory tract overreacts to foreign bodies that would otherwise not register on its radar. Indeed, the link between these two disorders of the mucosal linings of the respiratory and gastrointestinal tracts is often overlooked. This lining contains a rich reservoir of microbes, both healthful and harmful, the dynamic balance of which must be maintained for optimal health.
In battling IBD, the first thing the cure-seekers looked for was a bacterial overgrowth in the gut that could trigger such an immense inflammatory response. Stool samples from patients with both Crohn’s and UC suggested an abundance of certain bacteria, such as Listeria and Yersinia. However, finding bacteria in stools is normal and doesn’t necessarily mean there’s a problem.
Until recently, we knew very little about the ecology of the gut, and what appears to be an abundance of some types of bacteria may actually be relative. For instance, if levels of beneficial bacteria in the gut decline, then normal levels of harmful bacteria would appear to be ‘high’.
This may be the reason that treating IBD with antibiotics – which kills both ‘good’ and ‘bad’ bacteria, while encouraging the overgrowth of resistant varieties of harmful ones – has had only modest success in reducing symptoms. There is certainly no evidence that antibiotics cure IBD. Likewise, anti-inflammatory drugs, including steroids, have only a middling track record in treating the chronic symptoms of IBD because they don’t address the root cause of the inflammation.
Ecology of the gut
The human digestive tract has a complex and delicate ecosystem that plays host to as many as 200-300 species of bacteria, viruses and parasites. This biodiversity helps to maintain our internal balance.
A baby is born with a sterile gut, so it is up to early life experiences to populate that gut with the correct ratio of beneficial to harmful bacteria (which some scientists say is a ratio of 85:15 per cent, respectively). Breastfeeding for six months or longer lays the foundations. Breastmilk contains beneficial flora, especially bifidobacteria, but can also contain a minor level of microbial contamination – just enough to begin ‘training’ the gut. Human milk also has a growth factor (completely lacking in synthetic formulas) that encourages the growth of bifidobacteria, which play an important role in preventing colonisation of the infant intestinal tract by non-indigenous or disease-causing species.
Mild childhood diseases – the same ones we so assiduously vaccinate against – are also important in training the immune system to respond appropriately to foreign bodies. For this reason, it comes as little surprise that evidence from small trials has turned up potential links between the MMR vaccine and Crohn’s – although this remains a highly controversial hypothesis.
Recently, measles virus fragments have been found in the intestines of children with ‘new-variant’ IBD (IBD plus developmental disorder). The virus was present in 75 of the 91 children with IBD vs 5 of the 70 non-IBD children (Mol Pathol, 2002; 55: 84-90).
While the foundations for a healthy gut are laid in early life, certain adult fads may not be helpful. In the last 20 years or so, the ‘natural’ healthcare industry has had a mission to clean out every possible pathogen from the digestive tract. Today’s consumers are confronted with a huge array of herbal detox, antiparasitic and antiworm formulas. With these, people are passing things in their stools they never even knew existed. And such is our horror of playing host to creepy-crawlies that few have ever asked if this preoccupation is a healthy one.
Many of the microorganisms that reside in our bodies do so without harm – they are part of our normal flora. It may even be that, in ridding ourselves of relatively harmless organisms, which may even have a relevant immunoregulatory role in our bodies, we have inadvertently derailed our immune processes to the extent that, in vulnerable individuals, IBD is the inevitable result.
What else upsets the balance?
Several aspects of modern life contribute to the disruption of gut immunity. Whereas at one time we may have eaten food grown in nutrient- and microbe-rich soils, today our soil and our food are highly depleted and sanitised. Similarly, animals that supply our meat and dairy products are routinely treated with antibiotics and antiparasitic medicines, which are passed on up the food chain to humans.
Diets with highly processed foods don’t help either as they lack the necessary building blocks for a healthy gut, such as fibre and amino acids. Worse, refrigeration – hailed as the saviour of modern food production – may also have something to answer for. Recently, scientists have put forward the hypothesis that the ‘cold chain’, which our food follows from farm to table, may encourage the growth of Listeria and Yersinia, both associated with Crohn’s (Lancet, 2003; 362: 2012-5). The theory is still speculative, but includes the intriguing possibility that refrigeration upsets the microbial balance of our food, killing off less harmful – even beneficial – bacteria, leaving the more harmful ones to thrive.
Certain common drugs can also alter gut ecology. Doctors who believe that IBD is purely bacterial in origin may prescribe antibiotics, but they can increase the risk of fungal infection (Mycopathologia, 2002; 156: 9-11), and new research shows that IBD can result from, or even mimic, fungal infections such as histoplasmosis. A large number of Crohn’s suffers, for example, have aflatoxin – a mycotoxin made by Aspergillus fungi – in their blood. Increasingly, baker’s yeast (used in bread and other bakery goods) has been implicated as a possible trigger for Crohn’s (Am J Gastroenterol, 1999; 94: 1711).
Ironically, most antibiotics are themselves mycotoxins derived from fungi, and some scientists hypothesise that Crohn’s is due to a mutated form of normal bacteria resulting from antibiotic overuse.
Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen are also believed to cause and worsen colitis, another form of IBD, by attacking the mucosal lining of the gut, increasing its permeability and contributing to colonic bleeding (Gut, 1995; 36: 55-9). NSAIDs such as ibuprofen, flufenamic acid, mefenamic acid and naproxen have been implicated in acute episodes and relapses of another form of IBD, proctocolitis (Postgrad Med J, 1986; 62: 773-6).
All in all, what is emerging is a picture of modern life as the unbalancing factor in immune health – a theory which has been dubbed the ‘hygiene hypothesis’.
The hygiene hypothesis
The idea theorises that the aggressive measures designed to improve modern sanitation have altered our immune responses. While primarily linked to atopic disorders, it may also be relevant to gut disorders.
IBD is rare in developing countries, where living conditions are more crowded and less sanitised, but is becoming more common in affluent Western industrialised countries. Modern advances in hygiene that have nearly wiped out the gut worms called helminths may hold a key to this increase.
Intestinal immunity consists mainly of two types of infection-fighting white blood cells called T cells. Th1 produces an inflammatory response, while Th2 neutralises it. It is thought that immune-system dysfunction is down to an imbalance in these cell responses. Allergies, for instance, are driven by Th2 dominance whereas autoimmune disorders, such as multiple sclerosis (MS) and IBD, are the result of a Th1 overreaction.
New evidence suggests that certain microbes play a key role in regulating Th1 and Th2 pathways. Experiments with mycobacteria, present in soil and untreated water, suggest that exposure can protect against autoimmune diseases such as lupus, rheumatoid arthritis and type 1 diabetes. Scientists believe that mycobacterial exposure promotes the production of the T regulatory cells that modify both Th1 and Th2 responses (Trend Immunol, 2001; 22: 354).
Other data suggest that parasitic worms – which have been with us for more than three million years – may have a similar effect. To survive, parasites release substances that alter gut immunity to avoid being eliminated by their host. By boosting Th2 production just enough to pull the immune system away from autoimmunity, they may also hold the key to healing IBD. It’s a theory that ties in nicely with the evidence that worm-free children in industrialised countries are more likely than those in other areas to develop autoimmune disorders.
New directions in treatment
Encouraged by data supporting the hygiene hypothesis, some investigators are now trying to prevent illness by artificially pumping up the Th1 system. British researchers are currently conducting trials of a Th1-inducing vaccine, made from a mycobacterium called SRL172, to counteract asthma. So far, the vaccine appears to damp down asthma symptoms. However, given the patchy success of vaccines in modern healthcare, others suggest that the effort may be better spent finding more ‘natural’ alternatives.
University of Iowa scientists may have hit on an obvious solution. Early studies in mice supported the idea that exposure to helminthic worms protected against IBD (FASEB J, 2000; 14: 1848-55).
More recent studies in humans have involved US researchers giving patients (who volunteered) a single drink laced with the microscopic eggs of the porcine whipworm Trichuris suis, a worm that doesn’t normally infect people.
These patients hadn’t been helped by standard treatments. Four of them suffered from Crohn’s disease and three had UC. After ingesting the eggs, all seven patients improved substantially, with six of them going into complete remission. The treatment was safe, with no noticeable adverse effects, and the patients’ improvements were maintained with doses every three weeks for more than 28 weeks (Am J Gastroenterol, 2003; 98: 2034-41).
Less wriggly, but every bit as primitive, is a potential IBD treatment derived from dirt. Just 1 g of soil – not much more than a small packet of low-calorie sweetener – can contain as many as 10,000 species of microorganisms. Among these microbes are several unique types of probiotics, which have now been refined into so-called ‘homoeostatic soil organisms’ (HSOs). These beneficial ‘transient’ and ‘resident’ bacteria are found naturally in healthy soil, although many of these varieties of soil bacteria are different from those that we ingest (say, in live yoghurt) or which normally reside in our intestinal tract. Ideally, we would take these bacteria in together with unpolluted food grown in rich, non-chemicalised soil.
But this, however, is a faint hope. Agricultural studies carried out as early as 1935 to 1940 – in fact, around the time that IBD first began to appear – noted that HSOs were completely missing in commercially used soils. When we sterilise our soil with pesticides and herbicides, we do to the soil what the overuse of medical antibiotics has done to the human gastrointestinal tract – we eliminate not only the harmful bacteria, but the beneficial ones as well.
While new products containing HSOs are slowly coming on the market, the original formulation used in Primal Defense (made by a US company called Garden of Life) contains, among other things, Lactobacillus acidophilus, L. bulgaricus, L. delbrueckii, L. casei, L. caucasicus, L. fermentii, L. plantarum, L. brevis, L. helveticus, L. leichmannii, L. lactis, Bacillus licheniformis, B. subtilis, Bifidobacterium bifidum and Saccharomyces boulardii.
Preliminary research has suggested that Primal Defense may have antifungal, antimicrobial and immunomodulating properties. Encouragingly, HSOs are now being used with some success in the treatment of inflammatory bowel conditions and autoimmune disorders (Prog Nutr, 2002; 4: 97-108, 109-15).
Other early trials have shown success when patients with ulcerative colitis have received faecal flora from healthy donors (J Clin Gastroenterol, 2003; 37: 42-7).
The possibility that worms and dirt may be therapeutic has not yet reached the stage where it translates into widespread clinical practice. And not surprisingly, many are likely to feel uncomfortable with the idea of deliberately ingesting parasites.
Nevertheless, the fact that this type of therapy has worked so well in experimental research throws up some interesting questions about modern notions of hygiene, both internal and external. Prior to 1930, dirt and worms were a fact of life; IBD was not. While such remedies may seem like a giant step backwards, they may actually represent forward motion for people whom conventional (and sanitised) science has failed to help.