Much evidence suggests that gastrointestinal tract problems are on the rise in the modern world with significant health consequences that extend well beyond the gut itself. For instance, autism is increasing, especially in male children, and researchers at MIT and elsewhere point to the GI-tract and disturbances caused by glyphosate and other chemicals used in industrial agriculture as among the causes. Food processing with its emulsifiers and storage techniques likewise may play a role in the upsurge in the prevalence of various inflammatory bowel conditions. Modern over-nutrition and other dietary habits, such as over-consumption of refined carbohydrates and under consumption of omega-3 fatty acids are yet other factors implicated. Researchers trying to uncover patterns underlying contemporary GI-tract issues have been attempting to fit the various known and suspected causes into manageable conceptual models. Recent work suggests that a three-part model involving gut bacteria, gut barrier function ("leaky gut") and inflammation may help with prevention and therapy.¹ The components of the model have emerged from studies of inflammatory bowel disease (IBD, including Crohn's Disease and ulcerative colitis), yet they clearly have application to more ordinary and quite common forms of bowel irritation and discomfort.

Irritable bowel syndrome (IBS) is a catch-all for common bowel conditions. It currently affects 10–20 percent of the adult population in developed countries. To be sure, the causes of IBS have not been definitively identified and can vary among individuals (food allergies, over-reactive immune system, stress, hormone imbalance, etc.). Symptoms include abdominal pain, flatulence, bloating, change in bowel habits, diarrhea, constipation (or a combination of both), and these often interfere with daily activities and affect the quality of life of the sufferers. Available medications exhibit only limited efficacy and fail to relieve all IBS symptoms over the long term.

Current science no longer views the gastrointestinal system as a simple digestive and disposal apparatus. It is estimated that sixty percent or more of all the macrophages, the first line immune cells of the body, line the GI-tract. Specialized cells in the gut constantly sample its contents in active surveillance for external threats. Microbes in the small and, especially, the large intestine perform a multitude of functions, including aspects of nutrition, such as synthesizing some vitamins and making minerals and other nutrients more available. The intestinal wall controls not only the passage of nutrients and the disposal of bodily wastes, but also regulates immune interaction with the contents of the intestines. GI-tract disturbances can involve any one of the major aspects of gut health or combinations of these. Hence, gut complaints can involve disturbed intestinal microbiome (dysbiosis), disrupted barrier function (leaky gut) and/or improper immune system activation (inflammation).

The Inhabitants of the Gastrointestinal Tract
The microbes present within the body collectively are termed the microbiota. The genomic content (the complete set of genes in the microbiota) is termed the microbiome. Both genetic and environmental factors shape the microbiome. Important early factors are natural birth versus cesarean section, breast-feeding versus formula feeding, and so forth. In adults, dietary habits are highly significant. Vegetarians and meat eaters differ in the make-up of the bacteria in the gut. The amounts and types of fiber in the diet, the amounts and types of carbohydrates and fats, under-nutrition and over-nutrition all matter. So do the level of hygiene and exposure to infections, antibiotics and other drugs.

The human gut consists of a series of micro-environments. Except for the stomach and the upper two thirds of the small intestine, there are differing bacteria and ratios of bacteria in each of these areas, starting with the mouth. In fact, the human gastrointestinal tract contains a large and diverse population of microorganisms — over 800 different bacterial species comprising nearly 100 trillion living organisms. The composition of this gut flora varies among individuals depending on diet, age, medication (antibiotics), stress, and physiological conditions. Not surprisingly, different probiotics perform different functions and offer different benefits. One big divide, of course, is between the two most important groups of probiotic bacteria, Lactobacilli, found mostly in the lower small intestine and upper large intestine, and Bifidobacteria, found mostly in the large intestine, i.e., the areas of lower pH.

For clarity's sake, keep in mind that scientists use a standard genus, species, strain taxonomy in describing bacteria. An example is the probiotic bacterium, Lactobacillus rhamnosus R0011. The genus is Lactobacillus, the species is rhamnosus and the strain is R0011. Dietary supplements properly list all three components of the name because strains even of the same species can exhibit divergent effects in the body.

Broadly speaking, the Lactobacilli act on sugars and starches to create lactic acid, among other things. For instance, L. acidophilus La-14 assists in breaking down lactose (milk sugar) and 15 other carbohydrates and this may improve digestion of dairy products by those individuals who are lactose intolerant. Clinical trials have shown that this strain may improve immune response and bowel regularity. It works especially well in conjunction with another bacteria strain, L. rhamnosus R0011. Interestingly, L. rhamnosus R0011 in conjunction with L. helveticus R0052 in humans enhances the eradication of H. pylori (a cause of stomach ulcers) in combination with conventional medical treatment.

Bifidobacteria, such as B. longum BB536, have been shown to colonize the intestine, stimulate immune response, and promote the growth of other beneficial bacteria. BB536 also decreased the incidence of influenza in seniors. Blood analysis showed significantly higher bactericidal activity of neutrophils and higher NK cell activity at the fifth week of administration compared to pre-administration. There has also been evidence reported that suggests BB536 can help modulate allergies and possess antiallergenic effects. Other bifidobacteria provide their own ranges of benefits.

Increases in certain bacteria and decreases in others— both in absolute numbers and the varieties present—are observed in disturbed gut function. Typically, the more severe the dysfunction, the greater the divergences from normal microbiota. It is unclear to what extent these specific changes are the driving forces for inflammatory and related immune processes and to what extent they reflect the condition, although feedback is highly likely. The finding that certain strains of probiotics reduce excessive inflammation by means of modulation of immune and other responses via the gut is one of the major advances in the knowledge of probiotics in recent years.

Inasmuch as different probiotic species and different strains of the same species often provide different and distinct benefits and also often interact to lead to yet other results, there are good reasons for supplementing with more than one strain and/or species. Similarly, different probiotics may be more to be desired at certain ages or under particular conditions. No single strain can easily fulfill all these requirements. A mixture of species, therefore, is usually most suitable for supplementation.

Mucosal Barrier Function & The Leaky Gut Syndrome
The mucosal barrier of the gut performs many functions, one of which is to separate the contents of the gut from immediate contact with the gut wall and direct access to the body's immune system. Ideally, the contents of the intestines are sampled routinely by specialized cells located in Peyer's patches along the far end of small intestine. Allopathic medicine does not recognize leaky gut syndrome as a distinct condition, yet in IBD it has been demonstrated that the contents of the intestine do, in fact, have direct access to the surface of the intestinal wall and perhaps beyond. Mucus barrier changes may be as much the result of unwanted bacteria (dysbiosis) as a cause. It is possible for substances even to leak into the bloodstream due to defects in the tight junctions that normally characterized the
intestinal wall. Leaky gut can be described as intestinal permeability or intestinal hyperpermeability.

There is little doubt but that leaky gut syndrome involves chronic inflammation. However, controversy arises as to whether this inflammation is a cause or a consequence. Likewise, is the inflammation local or does it prime further inflammation throughout the body leading to or aggravating a host of other conditions, such as allergies?

In IBD, toxemia, meaning the passage of toxins into the blood, is well documented, as are immune system irregularities. The extent of leaky gut in less active and less severe bowel conditions is debated hotly. Nevertheless, indications of intestinal barrier dysfunction and dysbiosis, such as inappropriate immune activation, abdominal pain, flatulence, etc., strongly suggest that leaky gut is, in fact, an aspect of IBS and other less well defined GI-tract issues.

As noted already, available medications have only limited efficacy and fail to relieve IBS symptoms over the long term. Fortunately, there are a number of natural supplements that are documented to help prevent and/or relieve symptoms associated with IBS. For instance, fiber can help with the toxemia issues as well as promote normal intestinal flora. Research has shown that soluble fiber, such as psyllium, can be fermented in the gut and the metabolites may decrease transit time and pressure. Some fibers can increase water retention, thereby increasing the stool mass and, again, reducing transit time. Fiber supplementation in IBS patients promotes significant improvements in constipation and general IBS symptoms.

Similarly, clinical studies have shown the benefits of Lactobacillus and Bifidobacteria species in the treatment of IBS or IBS-like symptoms. This is probably due to their abilities to reduce inflammation, visceral hypersensitivity, and stress responses. Studies have shown that some strains are effective in treating bloating and flatulence while others relieve gastrointestinal pain and irregularity. It has also been reported that effects can vary among individuals. Thus, one may want to try different strains and dosages or a blend of multiple strains and monitor the response.

Another useful supplement is the amino acid L-glutamine to support the health of the cells that make up the enterocytes in the gastrointestinal tract. It not only directly nourishes the mucosal lining of the intestine, but also helps repair it when it is damaged by hypersensitivity, physical stress, or an overreactive immune system. Lglutamine can stimulate the bowel to re-absorb the water from the stool, reducing the number and frequency of bowel movements.

Then there are the everuseful omega-3 fatty acids. Omega-3 fatty acids can replace omega-6 fatty acids in the cell membrane and prevent their harmful effects by reducing the secretion of unwanted prostaglandins and proinflammatory molecules. They also reduce production of platelet aggregators and vasoconstrictors while increasing the secretion of vasodilators and platelet aggregation inhibitors.

Other supplements that have shown the ability to promote improvements in tight junctions include curcumin, boswellia, bile acid supplements and butyric acid supplements.

Immune Function
Both the microbiota and the barrier function aspects of GI-tract health at various points tie into immune function. Therefore, it would seem to be clear that the overall regulation of the immune system necessarily plays a role in the control of immune-related inflammation in the gut. Diet is one of the most significant components involved in what should be a homeostatic system.

Omega-6 fatty acids account for the majority of polyunsaturated fatty acids found in Western diets. Omega-6 fatty acids can stimulate production of harmful prostaglandins and leukotrienes, as well as platelet aggregators and vasoconstrictors. Omega-3 fatty acids, on the other hand, compete with omega-6 fatty acids by replacing omega-6 fatty acids in the cell membranes and provide beneficial effects such as:

1. a reduction in harmful prostaglandin E2 (PGE2) metabolite production,
2. a decrease in thromboxane A2, a strong platelet aggregator and vasoconstrictor,
3. suppressed formation of leukotriene B4, a proinflammatory molecule that is also responsible for leukocyte chemotaxis and adherence, and
4. maintained or increased production of beneficial prostaglandins such as PGI2 and PGI3, protective vasodilators, and inhibitors of platelet aggregation.

In autoimmune diseases, such as inflammatory bowel disease, Crohn's disease, and ulcerative colitis, the major contributors to disease development are thought to be proinflammatory mediators that include omega-6 fatty acid, arachidonic acid metabolites, harmful prostaglandins, leukotrienes, and pro-inflammatory cytokines. It has been reported that people who are affected by these diseases have elevated levels of leukotriene B4 and other arachidonic acid metabolites. Interestingly, in clinical studies, omega-3 fatty acid or fish oil supplementation significantly decreased the production of leukotriene B4 and overall leukotrienes in these patients. Omega-3 fatty acid supplementation was also able to induce dramatic improvements in tissue histology, the rate of disease relapse, clinical activity, and steroid-sparing effect after treatment, although responses to supplementation varied among individuals reflecting that there are underlying differences as well as common factors in these diseases.

In all cases, the goal should be to normalize immune function. Scientists understand that the immune system can be overactive as well as underactive and that balance is the key. On the one hand, the immune systems needs vigilante macrophages, natural killer cells and other "soldiers" to be on alert to attack invading organisms before these can take hold in the body. For instance, the cold virus is most successfully combatted if the immune system can react and eliminate it before it has had a chance to multiply. On the other hand, rheumatoid arthritis and other autoimmune diseases in which the body attacks itself afflict millions of Americans. Immune overactivity causes unpleasant side effects, such as allergies and inflammation, and can lead to immune exhaustion and collapse. The answer, therefore, is to balance the body's immune system so that it is neither overactive nor underactive.

Much of this balance is maintained by subsets of helper T cells (Th). There is a ratio between the Th1 subset that is involved mainly in inflammation and the activation of white cells (phagocytes, NK cells, etc.) and the Th2 subset that activates specific B cells. The Th1 and Th2 cells may cross-inhibit function, which means that the more active the one set is, the less active the other set is. Most Americans initially have too much Th1 function and too little Th2. This is one reason that chronic inflammation is so very common in the US. However, the body cannot allow chronic high levels of inflammation, and therefore the immune system begins to shut down as a result. Stimulating more Th1 activity—leading to more inflammation—will never be more than a short term fix if inflammation is not controlled because the body will again attempt to turn off Th1 function in order to reduce the level of inflammation. Hence, there is a common pattern in which chronic immune activation aggravates allergies, IBS, even weight gain, yet at the same time a reduction in immune surveillance allows the development of cancer in later life.

Balancing the immune system is a bit harder than simply stimulating it. Fortunately, there are a few supplements that do this and more. One of the most extensively tested of these supplements is called Moducare®. Developed by Patrick Bouic, Ph.D., head of Immunology at the University of Stellenbosch in South Africa, Moducare® consists of a proprietary blend of phytonutrients called sterols and sterolins. The sterol family of compounds includes fatty substances such as betasitosterol found in saw palmetto. Sterolins are sterols with a glucose (sugar) molecule attached, something that greatly improves absorption into the body. Taken together, sterols and sterolins are more active than when supplemented as single pure substances.

A number of other immune regulators are available. Chamomile extracts (German chamomile) are useful as anti-inflammatories and calm some forms of allergies. Chamomile is particularly interesting because of its calming and immune-regulating effects complement its antioxidant benefits. Another significant immunomodulator is the flower pollen extract sold under names such as Cernitin™. Items already mentioned include turmeric extracts and boswellia extracts, to which can be added quercetin and a number of herbal extracts available as dietary supplements. None of these will be sufficient in the long run, however, without changes in the diet to improve the balance between omega-6 and omega-3 fatty acids or the inclusion of more fiber and consumption of more vegetables and whole fruit.

Some Conclusions
As noted at the outset, GI-tract disturbances can involve any one of the major aspects of gut health or combinations of these. Hence, gut complaints can involve disturbed intestinal microbiome (dysbiosis), disrupted barrier function (leaky gut) and/or improper immune system activation (inflammation). There are strong feedback loops linking these aspects of gut health and therefore solutions to gut issues typically are most successful if all three are addressed together. This means appropriate changes in diet, adoption of probiotic supplementation (either as supplements or via dietary sources), nutrition aimed specifically at improving the health of the cells lining the GI-tract and adopting strategies to reduce inflammation and balance the immune system.

References:

1. Vindigni SM, Zisman TL, Suskind DL, Damman CJ. The intestinal microbiome, barrier function, and immune system in inflammatory bowel disease: a tripartite pathophysiological circuit with implications for new therapeutic directions. Therap Adv Gastroenterol. 2016 Jul;9(4):606 –25.