Intestinal dysfunctions are now believed to be contributing factors to many chronic diseases such as allergies, autoimmune and inflammatory disorders, or degenerative diseases.
NORMAL FUNCTION OF THE GASTROINTESTINAL TRACT
The gastrointestinal tract is one of the largest interfaces between the human internal environment and the outside world. Its function is of course to digest and absorb the crucial nutrients provided by food. At the same time however, it must also provide an efficient barrier that will exclude undigested dietary molecules, bacterial compounds, environmental toxins, all molecules that are present in the food, but would pose a serious threat to health if allowed to pass through the intestinal mucosa and access the systemic circulation.
A number of factors can affect the delicate balance between transport of nutrients and exclusion of detrimental macromolecules, and lead to serious health problems.
INTESTINAL DYSBIOSISA frequent disorder of intestinal function is dysbiosis, i.e. the overgrowth of pathogenic bacteria in the intestine.The adult human intestinal tract is estimated to contain up to 10exp14 viable microorganisms (10 times more than the number of cells that form the body!). Over 50 different genera of bacteria are represented, accounting for more than 500 different species...Intestinal microflora represents an ecosystem of the highest complexity.
This microflora plays critical roles in the digestion and absorption of nutrients, in the synthesis of vitamins (B and K groups) and fatty acids, in the detoxification of ingested chemicals, but also in the regulation of the immune system.
Alterations in the composition of the gut microflora may have serious consequences for the host health. Factors that can affect the microflora include antibiotic use, stress, and diet.
»Antibiotic use is a common cause of major alterations. Dosage, length of administration, spectrum of activity will determine the impact on the microbial flora.
»Psychological stress can also affect the composition of the flora, including a significant decrease in beneficial bacteria (Lactobacilli and Bifidobacteria) and an increase in pathogenic E. coli. Stress may affect bacterial growth by significantly reducing the mucosal production of mucopolysaccharides and mucins, which are important for inhibiting the adherence of pathogenic organisms, and by decreasing the production of immunoglobulin A (IgA), which play a crucial role in their elimination. Neurochemicals produced upon psychological stress can also directly enhance the growth of pathogenic organisms: norepinephrine stimulates the growth of Y. Enterocolitica, P. Aeruginosa, and gram-negative bacteria such as E. coli.
»Another factor that may have an impact on the human intestinal flora is diet. Some diets promote the growth of beneficial microorganisms, while others promote harmful microfloral activities. For instance, diets rich in sulfur compounds (dairy products, eggs, certain vegetables, dried fruits...) promote the growth of sulfate-reducing bacteria. Globally it appears that populations consuming the typical Western diet have more anaerobic bacteria, less Enterococci, and fewer yeasts than populations consuming a vegetarian or high complex-carbohydrate diet.
INTESTINAL PERMEABILITY: LEAKY GUT SYNDROME
As discussed above, the healthy intestinal mucosa normally absorbs only small molecules that result from complete digestion : amino acids, simple sugars, fatty acids, vitamins, and minerals. Intestinal cells express specialized carrier proteins that transport nutrients through the intestinal wall and into the bloodstream. Bigger molecules will not be transported by these systems, and are normally kept within the gut due to the fact that the intestine mucosal cells are tightly packed together. Leaky Gut Syndrome (LGS) is a condition in which the ability of the intestinal wall to keep out large and undesirable molecules is reduced. Substances that are normally kept within the intestines are "leaking" across the intestinal wall. This happens when the spaces between the cells of the intestinal wall become enlarged ; macromolecules, antigens and toxins will then make their way to the bloodstream.
What causes Leaky Gut Syndrome
A large number of factors can lead to leaky gut :
»Dietary components: fermentation of certain dietary components (proteins, refined carbohydrates) leads to potentially harmful end-products : ammonia, amines, phenols, sulfides…These compounds reduce the life-span of mucosal cells. Food additives, alcohol, caffeine also irritate the gut wall.
»Gut dysbiosis: production of toxic compounds through fermentation also depends on the type of bacteria present in the bowel. In case of dysbiosis, overgrown pathogenic bacteria produce toxins and compounds that are very detrimental to intestinal cells. For instance, sulfate-reducing bacteria produce toxic hydrogen sulfide.
»Food allergies and intolerances: intolerance to certain food (lactose…) can lead to damaging gut inflammation.
»Chronic stress: in addition to favoring dysbiosis, stress reduces blood flow to the gut leaving it unable to repair itself. Stress also causes the cells of the intestine to contract which results in larger gaps between cells.Consequences of Leaky Gut
Altered permeability of the intestinal wall can have highly detrimental effects, including :
»Nutritional deficiencies: the carrier systems that normally transport the nutrients through the intestinal wall are less active in damaged or inflammed mucosal cells.
»Increased absorption of environmental toxins: the gut mucosa is normally an efficient barrier against environmental chemicals that are present in food (food additives, pesticides, PCBs…). When allowed to pass into the circulation, these toxins can cause damage to all organs, notably the liver and the brain. Multiple Chemical Sensitivities may develop as the nervous system becomes sensitized.
»Development of allergies and auto-immune reactions: undigested, large molecules pass into the bloodstream. The immune system recognises these molecules as foreign and raises antibodies against them. As a result, affected patients will develop allergies to many types of foods, which actually initiates a vicious cycle, since allergies will cause gut inflammation that leads to more intestinal permeability…In addition, some of the molecules that pass into the blood may share homologies with proteins that are normally present in the body. Antibodies against these molecules will therefore attack the bodies own cells, leading to auto-immune diseases.
»Chronic activation (inflammation) of the immune system. One bacterial compound that can easily make its way to the blood is lipopolysaccharide (LPS). Present in the bloodstream LPS will induce a strong pro-inflammatory response in monocytes and macrophages, involving recognition by a receptor (Toll-like receptor-4) and the subsequent secretion of cytokines such as IL-1, IL-6, TNF-alpha. Such chronic inflammatory condition is observed Chronic Fatigue Syndrome (CFS/ME). LPS also induces the NK-kB-mediated production of nitric oxide. Because NO is increased, NK function is inhibited and opportunistic infections such as mycoplasma infections are often observed. Herpesviruses, which tend to reactivate in a context of immune activation, will also be frequently detected. For more details see the Chronic Fatigue Syndrome section.
Intestinal permeability can ultimately lead to a large number of symptoms affecting every organ in the body, and has been linked with several distinct illnesses : as discussed above leaky gut is a likely contributor to CFS/ME ; it is probably also central to another poorly defined condition often associated with CFS/ME, Inflammatory Bowel Syndrome. Other diseases, many of them being allergic or auto-immune diseases, have also been linked with leaky gut : rheumatoid arthritis, asthma, multiple sclerosis, Addison’s disease, lupus…
IRRITABLE BOWEL SYNDROME (IBS)Among the pathologies that develop following intestinal dysbiosys and leaky gut, the most frequent is probably Irritable Bowel Syndrome (IBS). IBS is characterized by abdominal pain or discomfort along with signs of bowel dysfunction, most commonly diarrhea and/or constipation. Current figures suggest that 10-20% of the population may suffer from the disease.
IBS is believed to be the result of inappropriate and chronic activation of the mucosal immune system. The causes of this activation are not clear, the illness is most probably multifactorial.
Factors that may have a role in IBS include:
»Neurological Dysfunction (Brain-Gut Interaction)
Neurological Dysfunction and Brain-Gut Interaction
A major development in the study of IBS and other gastrointestinal diseases has been to realise the influence of the nervous system in these disorders. The gut has the highest concentration of nerve cells in the body, besides the brain. There is constant communication between the brain and the gut, and the neurotransmitter serotonin, produced by nerve cells, can exert a wide range of effects on the intestines, most notably controlling intestinal motility and intestinal secretions.
Recent studies suggest that IBS patients present increased levels of serotonin ; giving serotonin-like substances to test subjects seems to trigger IBS symptoms. Other studies have shown abnormalities in the way serotonin acts in IBS patients. These abnormalities in serotonin levels and function may directly cause abnormalities in gut function.
Stress has long been thought to play a major role in IBS. Due to the high concentration of nerve cells in the gut, any alteration of brain function due to stress can easily impact on gut function.
Chronic stress leads to chronic inhibition of intestinal function. As discussed above, stress can favor intestinal dysbiosis and leaky gut ; stress also causes the release of inflammatory chemicals in the gut, such as substance P, and can activate gut inflammation when experienced in conjunction with another factor such as an infection.
Food Sensitivities and Intolerances ; Celiac Disease
Eating certain food can exacerbate the symptoms of IBS. In a recent study, IBS patients were tested for IgG reactions to different foods (IgG indicate food sensitivities, rather than classic food allergies which involve IgE). Patients were then put on a diet that excluded foods to which they had tested positive ; these elimination diets resulted in a significant reduction of symptoms.
A particular case of food intolerance is Celiac Disease. A subset of IBS patients have been found to have mild/moderate Celiac Disease, which is an intolerance to gluten (immune reaction to gluten protein, that will cause damage to the intestine). People with Celiac Disease have to avoid gluten-containing foods such as wheat, rye, barley, oats.
As discussed above the consequences of dysbiosis include bowel discomfort, leaky gut, food allergies, gut inflammation, all of which are associated with IBS.
Research has actually shown that IBS patients have low numbers of beneficial bacteria (lactobacilli and bifidobacteria) and an abnormally high number of facultative organisms which ferment food residues to produce large amounts of gas and toxic waste products.
There seem to be genetic factors that predispose to the development of IBS: immediate relatives of an individual with IBS are 4 to 20 times more likely to develop the disease than the general population. The identification of an exact genetic mutation has been so far elusive however recent results suggest an implication of genes relevant to inflammation in general (cytokines), as well as genes coding for Toll-like receptors (notably TLR-4, that recognizes LPS).
Links Between IBS and CFS, Fibromyalgia
IBS is often diagnosed in people who have also been diagnosed with Chronic Fatigue Syndrome and two related conditions, fibromyalgia (FMS) and Gulf War Syndrome (GWS). Between 30-70% of CFS patients may have concurrent IBS.
This is not surprising since intestinal dysfunctions such as dysbiosis and leaky gut can contribute to both diseases. Evidence for intestinal dysbiosis is often seen in CFS.
Intestinal permeability, and the subsequent leakage of LPS into the blood, could explain the chronic immune activation observed in CFS patients. Permeability to environmental chemicals can lead to Multiple Chemical Sensitivities, a disorder frequently associated with CFS. Not all patients with IBS develop CFS, however. Other factors (infections, genetic background…) may determine the evolution of each disease.