A Practical Clinical Guide to Understanding
Dysbiosis and Irritable Bowel Syndrome (IBS)
by Len Saputo, M.D.
The human cell is analogous to a complex industrial plant in that it cannot operate properly without adequate raw materials, with malfunctioning metabolic machinery, or in the presence of too many toxic interfering compounds. Indeed, it is critical that our cells receive perfect nutrition, but this benefit cannot be realized if the nutrition consumed is not delivered to the cellular level.
The gastrointestinal tract has three primary physiological functions: digestion of food, absorption of nutrients into the body, and keeping toxins out of the body. Failure of any of these functions will lead to defective energy production, increased energy needs, and wasting of the body’s reserves that serve as a buffer against the development of disease.
That nutrition is important in maintaining good health has been known for thousands of years. However, the role of the gastrointestinal tract as the site of origin and/or exacerbation of many diseases is a relatively new concept. Elie Metchnikoff, about 100 years ago, conceived the notion that the development of many illnesses originated from a “toxic bowel.” In his eagerness to cure, he went a little overboard and began to recommend a colectomy as treatment for many of his patients. Needless to say, this had very limited success, and his cure as well as his concept rapidly fell into disrepute. Nonetheless, Metchnikoff’s concept stands as a major contribution in medical history.
Over the past 30 years there has been a renewed interest in the metabolic consequences that can result from disordered intestinal ecology (dysbiosis) and from increased intestinal permeability (leaky gut syndrome). These two concepts have revolutionized the way that we can look at the normal function and malfunction of the gastrointestinal tract, as well as the interconnectedness of these concepts to many disease states.
We will discover, as we learn about dysbiosis and leaky gut syndrome, that they can exist separately or simultaneously, and that each can cause the development of the other as well. Additionally, they are particularly important because of their widespread presence in so many clinical situations. We will learn that the clinical management of dysbiosis and leaky gut syndrome is critically important in controlling the manifestations of many underlying disease processes, as well as in the potential prevention of diseases prior to the onset of clinical symptoms.
Nature, when finally understood, will reveal its remarkable balance and infinite wisdom. This incredible perfection is exemplified par excellence in the complex ecological balance that exists between the microflora in the human gastrointestinal tract and its human host. When the host and the microflora co exist in harmony, a healthy state of symbiosis results. When they live in dys symbiosis, or for short, in “dysbiosis,” this disordered ecology often results in mal-homeostasis, and ultimately in clinical disease. (1)
The gastrointestinal flora has been equated to an organ system within itself. There are more than 500 different bacterial species, 99% of which are anaerobic, that collectively comprise more metabolic activity than any organ system in the human body. (2)
A wide variety of important functions are normally provided by the microflora when the ecology is undisturbed and healthy. These normal functions include the metabolism of hormones, carcinogens, and xenobiotics, the synthesis of vitamins such as vitamin K, B5, B6 and biotin, the synthesis of short chain fatty acids (SCFA’s) such as butyrate, the crowding out of pathogenic flora, as well as the stimulation of the secretory immunoglobulin A antibody (SIgA) and intramural antibody systems. (3-5)
The presence of abnormal microflora in the gastrointestinal tract can result in a) deactivation of digestive enzymes that can lead to maldigestion and malnutrition, b) consumption of vitamin B12 and certain amino acids (6), c) saturation of the essential omega 3 and 6 fatty acids, d) disruption of the intestinal lining that can cause the leaky gut syndrome (7), e) sensitization against translocated bacteria and their fragments that can lead to leaky gut syndrome and to autoimmune diseases (8, 9), f) development of yeast overgrowth syndromes (10), g) development of irritable bowel syndrome and inflammatory bowel disease such as C. difficile enterocolitis (11), h) and the deconjugation of bile acids and estrogens that might potentially induce bowel or breast cancer.(12)
The causes of dysbiosis (see table 1) are far more prevalent than generally appreciated by most medical practitioners. Basically, any situation that can alter the physical, chemical, or physiological integrity of the gastrointestinal tract can result in changes in the make up of the microflora. The microflora by itself, however, is rarely the instigator of dysbiosis. What happens that enables certain of these organisms to overgrow, and thereby upset the balanced ecological environment that previously existed? What makes an organism that is normally commensal, pathogenic?
There are two factors that determine the pathogenicity of an organism. First, the virulence of the organism, or its ability to overgrow and then to produce toxins that are injurious to the human host, is an obvious factor. The second factor, host resistance, is one that modern medicine half heartedly acknowledges but generally does not adequately address. In fact, what is widely believed is that the organism that is invading the tissues is the primary underlying problem, and that eradicating it is the solution. It is interesting that all organisms inhabiting the intestinal tract (including friendly bacteria such as acidophilus), under the right circumstances can cause sepsis and death (13). Yet, at other times, i.e. when patients are immunocompromised, as in the case of AIDS or cancer, modern medicine does pay attention to the fact that host defenses are weakened. In these situations, rather than focusing on increasing host defenses, the goal seems to be being more aggressive at killing all organisms that might be potential pathogens. Indeed, it is looked at as a war between man and germs.
It should be becoming clear that the presence of dysbiosis is, at the very least, a signal that there is something abnormal going on in the gastrointestinal tract, and that it should be investigated. There are at least 9 pathways that can lead to dysbiosis. They include:
TABLE I (14):1. Dietary
2. Inflammatory conditions
7. Xenobiotic exposures
8. Immune dysfunction
9. Miscellaneous conditions
It should not be a surprise that what we eat can affect which organisms will have a growth advantage in our intestinal tracts. The microflora has to eat too, and each bacterial species has specific nutritional needs that, if met, will allow it to enjoy accelerated growth. The normal, friendly bacteria that inhabit the gut survive on high fiber diets (15). If we consume adequate amounts of fiber, these bacteria will have the nutrition they need to flourish.
Diets that are high in fat and meat and low in fiber lead to what is termed “putrefactive dysbiosis.” In this situation, a potentially pathogenic bacterium called bacteroides tends to proliferate and, because it produces urease, results in the overproduction of ammonia. In this setting, the pH of the stool becomes more alkaline, SCFA production of butyrate falls, and enzymes capable of deconjugating bile acids and estrogen are generated. The consequences of these biochemical changes lead to nutritional shortages for colon and, to a lesser extent, small intestinal mucosal cells, as well as in increased levels of bile acids (increasing risks for colon cancer) and of estrogen (possibly increasing the risks for breast cancer).
Inflammatory conditions of the intestinal tract such as Crohn’s disease, and a variety of infectious agents (bacterial, viral, fungal, parasitic) can cause mechanical disruption of the intestinal lining, and subsequent loss of normal defense mechanisms that prevent the growth of many bacterial strains. Wide varieties of opportunistic microorganisms can then take advantage of this change in environment and create an ecological shift of the microflora. The metabolic products of many of this new microflora are toxic to the bowel, and cause further pathological changes; thereby creating a vicious cycle that may be self-perpetuating.
Failure to digest food because of insufficient gastric acid, lactase, or other digestive enzymes, allows more nutrients to reach the lower small intestine and colon, where the microflora can then overgrow (16-18). This bacterial overgrowth can lead to the overproduction of enzymes (proteases) that are able to degrade enzymes produced by the intestinal lining and the pancreas, and can result in maldigestion. This type of dysbiosis has been called “fermentation excess dysbiosis.”
Stress can have profound effects on the psycho neuro endocrine immune systems of the gastrointestinal tract that can lead to lowered host defenses (19-21). In addition, the completeness of the digestive process is related to the time it takes food to pass through the intestinal tract (transit time), and this can be substantially altered by the neuroendocrine effects of stress. These factors enable opportunistic microorganisms to shift the ecological balance of the intestinal tract.
The use and abuse of antibiotic therapy may be the single most frequent cause of significant dysbiosis in clinical practice today. In every instance when antibiotics are used, there are profound changes in the consistency of the microflora in the gastrointestinal tract, and possibly in every other location of the body where there is a microflora (i.e. mouth, vagina, lung, skin, and conjunctiva). If host defenses are adequate, and the resulting ecological balance not too deeply disturbed, the normal microflora may be able to re establish it’s original health promoting symbiotic relationship.
However, in the situation where there is repeated or prolonged antibiotic treatment, especially in the presence of inadequate host defenses, a state of severe and sustained dysbiosis may develop, which can then result in clinical disease. This condition, wherein the bowel microflora has been substantially reduced, has been termed "deficiency dysbiosis." Another mechanism allowing deficiency dysbiosis to develop is the inadequate consumption of fiber, the major source of nutrition of the normal, health promoting, and intestinal flora. One of the most dreaded iatrogenic diseases that too often develops in this situation, is clostridium difficile enterocolitis, a potentially life threatening “complication” of antibiotic usage.
It is ironic that conventional medical treatment of this condition is to use additional antibiotic therapy aimed at stopping the clostridium difficile overgrowth. While this approach may be successful at times, it demonstrates the typical, “us against the germs” attitude of modern medicine. This approach focuses on killing the micro organisms that are invading the body, without regard for the primary underlying process that relates to the ecology of the microflora or its human host’s defense mechanisms.
I have treated a number of cases of this kind of deficiency dysbiosis, where perplexed physicians have witnessed multiple recurrences of enterocolitis despite multiple courses of progressively more aggressive antibiotic therapy. A more rational approach is to give a very short pulse of antibiotic therapy for a few days, and then simultaneously replace the friendly bacteria and the fiber that they require for sustenance, stimulate the growth and development of the immune system of the intestinal tract, and provide nutritional support that allows the gastrointestinal mucosal surface to repair itself. To the surprise of most physicians with whom I have worked, this approach has worked within a few days in every case I have managed so far.
Our environmental exposures are increasing at an alarming rate in this age of widespread synthetic chemical production. Many of these toxic substances find their way into the intestinal tract through food, water and a variety of products that get into our mouths (i.e. toothpastes, mouth washes, dental amalgams etc.). These substances cause both damage to the cells of the intestinal tract, thereby lowering host resistance, and to the microflora itself. Both of these factors can create an environment that favors changes in the ecological balance of the intestinal tract and sets the stage for the development of dysbiosis. A wide variety of pharmaceutical drugs, such as steroids, birth control pills, NSAIDs, some chemotherapeutical agents, antacids, and H2 blockers etc. etc., can have profound effects on the balance of the gut microflora (22).
One of the best-kept secrets in health care is that the gastrointestinal tract is the largest immune organ in the human body. When you think about this, however, it should not really come as much of a surprise. The intestinal lining has a huge surface area that separates the outer external world from the internal milieu of the body. Where is there a better strategic location for the body's defense system than at the site of entry of potential dangerous organisms or chemicals? It doesn't require a rocket scientist to envision that if this large, strategically placed immune system isn’t working up to par, that the lowered defenses that ensue may not be sufficient to keep the ecology of the intestinal tract in balance.
Our immune systems can malfunction in at least three ways. First, it can be weakened so that it cannot mount up an adequate response (immunosuppression) to fight off usual stresses as is seen in stress, cancer and AIDS. Second, it can overreact in a way where it hyper-responsive to normal stimuli, as occurs in asthma, migraine, or food allergies. This can result in not only using up the immune reserves of the body, but may cause immune reactions that create tissue injury. Third, it can set the stage for autoimmune reactions, wherein antibodies are made against our own tissues such as occurs in rheumatoid arthritis or lupus. Regardless of the mechanism of immune malfunction, the end result is the same, abnormal host defense mechanisms that can lead to the development of dysbiosis.
The diagnosis of dysbiosis centers around three approaches: a careful history and physical examination, a comprehensive diagnostic stool analysis (CDSA), and possibly, breath testing. It is also important to keep in mind that dysbiosis is not a disease per se. As a matter of fact, dysbiosis is usually found in patients that are totally asymptomatic. Nonetheless, the presence of disordered intestinal ecology is clearly an abnormal situation, and may be an important finding that serves as a warning that the onset of clinical disease is imminent. Certainly, the presence of dysbiosis warrants a full laboratory evaluation of gastrointestinal function that includes at least an assessment of intestinal permeability and a liver detoxification profile (see the next section on leaky gut syndrome). Because of the fact that the 9 pathways that can lead to dysbiosis relate to almost everyone, it is the opinion of the author that a CDSA is a very reasonable and cost effective screening test that should be done on nearly every patient.
The degree of difficulty in treating dysbiosis depends on host defenses and nutritional status, as well as the severity of the disordered ecology. In situations where there is a severe underlying disease such as AIDS, cancer, or malnutrition, the dysbiosis may be impossible to fully correct and may be only partially improved. In the management of dysbiosis it is important to treat the underlying cause whenever possible. This requires accessing each of the 9 pathways as possible factors that may be causing the dysbiosis, and then finding ways to eliminate them. The general approaches that are important in managing dysbiosis are aimed at restoring the normal microflora, providing optimal nutrition for the intestinal mucosa, reducing toxic environmental exposures, and restoring the intestinal immune system’s SIgA antibody production.
The microorganisms normally inhabiting the healthy gastrointestinal tract have been identified, and consist mainly of several species of bifidobacter, acidophilus, and E. coli. These organisms can be cultured, put into capsule form, and ingested into the intestinal tract, where they can re establish a healthy ecological balance. These bacteria are termed “probiotics,” meaning supporting the microflora, in contrast to antibiotics, which kill the microflora. To this mixture of probiotics is often added a “prebiotic,” which consists of the fiber that the microflora must have as nutritional support to sustain its continued growth.
As we have already discussed, the state of health of the intestinal mucosal cells is important in maintaining host resistance, and host resistance is a powerful determinant that controls which microflora can survive. It is easy to understand that nutritional support for the intestinal mucosal cells is necessary to maintain effective host defense mechanisms. It is just as easy to appreciate the importance of avoiding toxic exposures that could interfere with cellular metabolism. Generally, I have recommended that patients consume organic food, juice whenever possible, and use a variety of vitamins (A, B's, E, and C, often to bowel tolerance), minerals, nutrients (especially L glutamine and phosphatidyl choline), essential fatty acids, gammaoryzanol, bioflavonoids like quercetin, and antioxidants (coenzyme Q 10, lipoic acid, glutathione, ginkgo biloba). (23-32)
Host immunity is another factor that is important in regulating the consistency of the microflora. Secretory IgA levels in the intestinal lumen are frequently either suppressed or exaggerated in dysbiosis. In hyperimmune states, as in certain parasitic infections, or in allergically mediated diseases, as with food allergies or autoimmune states, levels of SIgA can be increased. Treatment of this condition is accomplished by correcting the underlying condition. In situations, where the SIgA is depressed, it can often be stimulated through the use of saccharomyces boulardii or licorice root extract. (33)
We must remember that we are not just treating the gut, but a human being. This always requires looking at the whole person and addressing issues related to body, mind, and spirit, and remembering that these factors are inextricably interwoven. Additional issues, such as adequate rest, exercise, stress reduction, and meaningful purpose in life, must all be considered when developing a healing strategy for every patient.
The interrelationship of dysbiosis and leaky gut and the fundamental importance in intestinal permeability will be presented in Part II of this series on the function of the gastrointestinal tract in health and disease.
1. Galland, Leo and Barrie, Stephen, “Intestinal dysbiosis and the causes of disease.” J. Advancement Medicine, 1993, 6:67-82.
2. Borriello, S P (1990) Gastrointestinal Microflora. In: Caprilli R, and Torsoli, A (Eds) Coloproctology. Basic knowledge for clinical practice. International University Press, Roma, 950106.
3. Grubb, R, Midtvedt, T, et al. “The regulatory and protective role of the normal microflora.” Proceedings of the 5th Bengt E. Gustafsson Symposium (Stockholm, Sweden) June 1-4, 1988.
4. Hill, M J. “Microbial metabolism in the digestive tract.” CRC Press, Inc.
5. Latella, G and Caprilli, R, “Metabolism of large bowel mucosa in health and disease.” Int J Colorect Dis (1991)6:127-32.
6. Giannela, R A, Broitman, S A, Zamcheck, N. “Production of vitamin B12 analogues in patients with small bowel bacterial overgrowth.” Gastroenterology, 1972:62(2):255-60.
7. Dreyer, H P, Seifert, J, Sass, W. “Mucosal Permeation of Macromolecules and Particles,” in Intestinal Absorption and Secretion. E Skadhauge and K Heintez, Eds. 1983; MTP Press; Hing Ham; 505-13.
8. Wells, C L, Jechorek, R P, et al. Arch Surg 1991;126:247-52.
9. Husby, S, Jensenius, J C, et al. Scand J Immunol 1885;22:83-92.
10. Helstrom, P, Balish, E. Infect and Immun 1979;23(3):764-74.
11. Collins, S M, “Irritable Bowel Syndrome Could Be an Inflammatory Disorder,” European Journal of Gastroenterology and Hepatology. 1994;6(6):478-82.
12. Goldin, Barry R. “The metabolism of the intestinal microflora and its relationship to dietary fat, colon and breast cancer.” Dietary Fat and Cancer, 1986, Alan R. Liss, Inc pages 655-85.
13. Haenel, J H, Bendig, J. “Progress in Food and Nutrition Science,” 1975;1(1):21- 64.
14. Rowland, I R, “Factors affecting metabolic activity of the intestinal microflora.” Drug Metabolism Reviews, 19(3 & 4)1988:243-61.
15. Delzenne, N, Gibson, G R, Roberfroid, M. “The Biochemistry of Oligofructose, a Nondigestible Fiber: An Approach to Calculate Its caloric Value,” Nutrition Reviews. 1993;51(5):137-46.
16. Lichtman, S N, et al. “Hepatic injury associated with small bowel bacterial overgrowth in rats is prevented by metronidazole and tetracycline.” Gastroenterology, 1991; 100(2):513-9.
17. Kirsch, M. “Bacterial Overgrowth.” Am J Gastroenterol., 1990; 85:231-37.
18. Stockbrugger, R S, and Armbrecht, U. “Bacterial overgrowth in the upper Gastrointestinal tract and possible consequences: report of a workshop in Brussels, Belgium, Feb 9-10, 1990. Microb. Ecol. Health Dis., 4:1-7.
19. Whitehead, W E. “The Disturbed Psyche and Irritable Gut,” European Journal of Gastroenterology and Hepatology. 1994;6:483-88.
20. Guthrie, E, and Creed, F. “The Difficult Patient: Treating the Mind and the Gut,” European Journal of Gastroenterology and Hepatology. 1994;6:489-94.
21. Mayer, E A. “The Sensitive and Reactive Gut,” European Journal of Gastroenterology and Hepatology. 1994;6(6):470-77.
22. Bjarnason, I, et al. “Importance of local versus systemic effects of non-steroidal anti-inflammatory drugs in increasing small intestinal permeability in man.” Gut, 1991;32(3)275-7.
23. Surawicz, C M, et al. “Treatment of recurrent Clostridium difficile colitis with vancomycin and Saccharomyces boulardii.” Am J Gastroenterol, 1989. 84(10)1285-7.
24. Surawicz, C M, et al. “Prevention of antibiotic-associated diarrhea by Saccharomyces boulardii: a prospective study. Gastroenterology, 1989. 96(4):981-8.
25. Klimberg, V S, et al. “Oral glutamine accelerates healing of the small intestine and improves outcome after whole abdominal radiation.” Arch Surg, 1990; 125(8):1040-5.
26. Souba, W, “The gut: A key; metabolic organ following surgical stress: Benefits of glutamine supplementation. Contem Surg, 1989; 35(5A):5-13.
27. Souba, W, “Glutamine: a key substrate for the splanchnic bed.” Ann Rev Nutr, 1991;11:285-308.
28. Van der Hulst, R, et al. “Glutamine and the preservation of gut integrity.” Lancet, 1993, 341(8857)1363-5.
29. Hagen, T M, et al. “Fate of dietary glutathione: disposition in the gastrointestinal tract. Am J Physiol, 1990;259:G530-35.
30. Cody, V, et al., ed. “Plant Flavonoids in Biology and Medicine II. Biochemical, Cellular, and Medicinal Properties. Progress in Clinical and Biological Research, Vol 280, 1988, Alan R. Liss, Inc.: New York. 481.
31. Fukush, T, “Studies on edible rice bran oils.” Part 3. Antioxidant effects of oryzanol. Rep Hokaido Inst Pub Health, 1966. 16:111.
32. Yagi, K, and Ohishi, N. “Action of ferulic acid and its derivatives as anti- oxidants.” J Nutr Sci Vitaminol, 1979. 205:127-35.
33. Buts, Jean-Paul, et al. Stimulation of Secretory IgA and Secretory Component of Immunoglobulins in Small Intestine of Rats Treated with S. Boulardii.” Dig Dis and Sci, vol 15, No. 2(Feb 1990):251-56.