Majid Ali, M.D.

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Editor, The Journal of Integrative Medicine
Formerly, Associate Professor of Pathology (adj.), College of Physicians
and Surgeons of Columbia University, NY
Formerly, President of Staff and Chief Pathologist, Holy Name Hospital, Teaneck, NJ
Fellow, Royal College of Surgeons of England - Diplomate,
American Board of Anatomic and Clinical Pathology
Diplomate, American Boards of Environmental Medicine
Past President Capital University of Integrative Medicine

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Adapted from Majid Ali, M.D.'s book, The Canary and Chronic Fatigue

Chronic Fatigue and Battered Bowel Ecology

The bowel ecosystem is always injured in chronic states, and its restoration is the second core thrust of my management philosophy for chronic fatiguers — the first core thrust being a global strategy for reducing oxidative stress.

THE GUT IS A MISUNDERSTOOD ORGAN
In drug medicine, when the symptoms are directly related to the gut, the treatment strategy consists of symptom suppression with drugs. When the symptoms are not directly related to the gut, any suggestion of a possible role of a damaged bowel ecosystem in the cause of symptoms is unceremoniously dismissed.

In my view, the most remarkable phenomenon in the entire field of human biology is this: A vast number of clinical problems that are seemingly unrelated to the bowel spontaneously resolve when the focus of clinical management turns to all the issues in bowel ecology. How often do symptoms of persistent debilitating fatigue in young men and women clear up when an altered state of bowel ecology is restored to normal? How often do troublesome mood swings subside when therapies focus on the bowel? How often does arthralgia (pain and stiffness in joints with or without joint swelling) resolve when all the bowel issues are addressed? How often do we successfully prevent chronic headache; anxiety; palpitations; incapacitating PMS; recurrent attacks of vaginitis; asthma and skin lesions by correcting the abnormalities in the internal environment of the bowel? The answers to these questions will vary widely among physicians.

Physicians who regularly neglect the bowel (and those who never understood the issues of bowel ecology in the first place) will dismiss these questions with scorn. None of this has been proven with double-blind cross-over studies, they will strenuously protest. Other physicians who have learned to respect the bowel — as the ancients did — and care for their patients with a sharp focus on bowel issues will readily and unequivocally validate my personal (and fairly extensive) clinical experience.

LIFE IN THE BOWEL ECOSYSTEM
The bowel ecosystem teems with life. Shrouded in metabolic mists, it is as rich in biologic diversity and as broad in biochemical interrelationships as any other ecosystem on this planet Earth. The ancients seemed to have an intuitive sense about it. Death begins in the bowel, they pronounced in more than one way. Leeuwenhoek studied fecal bacteria during his invention of the microscope in 1719, and, thus, was the first man to study life in the bowel ecosystem with modern scientific methods. Metchnikoff, the Russian biologist, who single- handedly developed the concept of the cellular arm of the immune system, became intensely interested in the aging process in his later years when he moved to Paris where he served as the head of the Pasteur Institute. He studied the longevity of Bulgarians and provided strong evidence that certain bowel microbes played important roles in preserving health and promoting longevity among them. He named the microbe he thought was most prominent in this field as Lactobacillus bulgaricus. Metchnikoff's work opened the floodgates of basic research on the bowel flora.

WINDOWS ON THE WORLD
A cell looks at the world around it through its cell membrane. It is this membrane that separates the cell's internal order from external order. Although molecular host defense mechanisms of both immune and nonimmune types have progressed from simple single-cell forms to multicellular forms to highly developed complex organisms such as humans, the fundamental pattern of host defenses has remained the same: The cell membrane or its counterparts carry the primary responsibility for preserving the biologic integrity of the organisms. For the professional reader, I discuss at length the energy and biochemical events which occur at the cell membrane in health and disease in my monograph, The Agony and the Death of a Cell, published in the 1991 syllabus of the American Academy of Environmental Medicine.

For humans, the gut mucosa is the true counterpart of the cell membrane of unicellular organisms. From a phylogenetic perspective, the gut mucosa would be expected to be the primary host defense organ. This indeed is the case when one looks at health and disease from a holistic perspective.

In a biologic sense, man's gut lining is his window to the world around him. What do we ever get through our skin but a little vitamin D when we get a chance to bask in the sunshine? What do we get through our lungs? All our ancestors ever received through their lungs was oxygen. Now we receive — unwillingly and under severe protest — a heavy load of environmental pollutants. Everything else that enters our biologic systems enters through the gut lining. It is important to recognize that the mucosal linings of the mouth, esophagus and stomach essentially are extensions of the gut lining. The states of health and absence of health are expressions of the dynamics of foods within the gut ecosystem — the effects on foods of the digestive-absorptive processes as well as the various life forms in the gut.

HUMAN MOLECULAR DEFENSES EXIST AS PLANTS IN THE SOIL OF THE BOWEL CONTENTS
The ancients seemed to have known this intuitively. We seem to have taken a very circuitous route to grasp this most fundamental of all aspects of the immune system. I remember that the hakim (folk-doctor) in my village always prescribed laxatives for a headache. He prescribed remedies that seemed to work on the bowel for problems of the skin, joints, liver and other organs. Of course, I, then a medical school student, found it very amusing. It never occurred to me then why these folk-doctors would prescribe year after year remedies that couldn't work. More important, from my present perspective, I never wondered why people accepted those remedies year after year if they afforded no relief. I was into the science of medicine then. I wasn't into finding out what worked and what didn't. Nor did I ever doubt the science of my professors who doled out prescriptions for drugs by the dozens for sheer symptom suppression. That was then. And that was poor Pakistan. Now I question the science of an average American family practitioner when he prescribes drugs for chronic bowel symptoms. How scientific is his use of antacids for symptoms of burning or pain in the pit of the stomach? How scientific is his use of antispasmodic drugs for abdominal cramps? How scientific is his use of antidiarrheal drugs for diarrhea? How scientific is his use of steroids for inflammatory bowel disorders? Steroids suppress the immune system. How scientific is it to further suppress the immune system for problems caused by an errant immune system in the first place? How scientific is the use of anti-inflammatory agents, anxiolytic drugs, antidepressants, antispastic agents, antihistamines, and, of course, broad-spectrum antibiotics for treating various types of bowel disorders that we — by our own admission — do not understand the causes of?

THE BOWEL PERPLEXES A PATHOLOGIST
How many different things can the bowel do? It cramps. It obstructs. It turns and twists. It ulcerates. It bleeds. How does the bowel know when to cramp and when to obstruct or bleed? And when to turn and twist?

For many years I have studied a host of clinical syndromes in which the symptom- complexes can be related to events occurring in the bowel. As a hospital pathologist, I have had the opportunity to examine more than 11,000 bowel biopsies during the last 25 years. Every time I peered at a bit of bowel through a microscope and saw inflammation — colitis in common jargon — I wondered where and how it might have started. We pathologists know quite a bit about how a damaged bowel looks, but we know little, if anything, about the initial energetic-molecular events that set the stage for tissue damage. What is the cause of ulcerative colitis? Pathologists will tell you it is not known. What is the cause of Crohn's colitis? The answer: unknown. What is the cause of irritable bowel syndrome and spastic colitis? Unknown. What is the cause of microscopic colitis and collagenous colitis? The answer is the same.

Why is it that we do not know the cause of any of these types of colitis? The reason is we search for answers in the damaged structure after the fact rather than in the events preceding the damage. None of these "diseases" can be understood except with ecologic thinking.

During the early 1980s, my research colleague, Dr. Madhava Ramanarayanan, and I introduced the micro-elisa assay for allergen-specific IgE antibodies. This research interest and several subsequent studies gave me important insights into immune and nonimmune events that inflict tissue injury. It also raised serious questions about many of the prevailing concepts regarding the role of food and mold allergy in the causation of numerous bowel disorders. As a clinician, I have cared for a fairly large number of patients with autoimmune and immunodeficiency syndromes. These microscopic, immune, molecular, and clinical observations — as disparate as they appeared in the usual clinical setting — began to take coherent and integrated forms before me. I began to recognize that events taking place in the bowel were clearly related to many clinical syndromes that seemed to have nothing to do with the bowel according to the prevailing concepts of pathogenesis of disease. The single most important insight into the workings of the human immune and nonimmune defense systems for me has been this: The integrity of human molecular defenses cannot be preserved except through preservation of the gut ecology. My clinical work with chronic fatigue states allowed me to test and validate this fundamental concept with therapies founded on my view of injured bowel ecosystems.

LAPs AND TAPs: THE GOOD AND BAD GUYS OF THE BOWEL
LAPs and TAPs are my abbreviations for lactic acid-producing and toxic agents- producing microbes in the bowel. LAPs preserve the normal bowel ecosystem, TAPs disrupt it.

In the chapters (from The Canary and Chronic Fatigue) , What Is Chronic Fatigue? and Where Does It All Begin?, I discuss many elements that increase oxidative stress on energy and detoxification enzymes. It turns out that almost all these elements also suppress LAPs and — both directly by inhibiting LAPs and indirectly by other mechanisms — promote the growth of TAPs. This subject is of enormous significance in the normal aging process as well as in the accelerated aging process associated with chronic fatigue states.

LAPs confer many important host defenses upon the bowel discussed later in this section. TAPs are equally versatile in their functions and produce a very large number of noxious substances in the bowel. Among these are ammonia; phenols; tryptophan metabolites; vaso-constrictive amines such as histamine, tyramine, agmatine and cadaverine; certain steroid metabolites; and many toxins — most notably mycotoxins derived from fungi (yeast). This area has received rather limited investigative attention, and it is almost certain that future research will uncover a host of as yet undetected bacterial and fungal toxins and metabolic villains. Finally, the bowel flora both produce and potentiate some carcinogenic substances.

Not unexpectedly, LAPs-TAPs dynamics are profoundly influenced by food choices. American and British individuals show overgrowth of some TAPs such as bacteroides and some types of clostridia as compared with Japanese, Indians and Ugandans (Lancet 1:95-100; 1971). It appears likely that these differences are due to an abundance of fats and beef in the former populations' diet.

BACTERIA: THE MASTER CHEMISTS
Bacteria are living beings capable of executing an enormous number of biochemical reactions. Farmers used bacteria and fungi to turn compost into fertilizer long before biologists understood the metabolism of these single-celled bodies. A partial list of such reactions brought about by the normal bowel flora includes production of ammonia, conversion of amino acids into amines and phenols, inactivation of digestive enzymes such as trypsin and chymotrypsin and other enzymes located on the surface of cells lining the gut, deconjugation of hormones such as estrogen and bile acids, denaturation of bile steroids, breakdown of food flavonoids, hydrogenation of polyunsaturated fatty acids in food, utilization of certain amino acids such as B12, conversion of some compounds into carcinogens, and many other enzymatic reactions.

I list below the three genera of LAPs and several genera of TAPs that most frequently populate the bowel ecosystem.

About 30 species of LAP microbes have been identified. Some important members of these three groups (L, Lactobacillus; B, Bifidobacterium; S, Streptococcus) include the following:

Most byproducts of modern technology threaten LAP microbes. In addition, alcohol, nicotine, various pharmacologic agents, and highly processed and "preserved" foods have a negative impact on lactic-acid producers.

Normal fecal flora in man includes the following: Bacteroidaceae (Bacteroides and Fusobacteria), Eubacteria, Lactobacilli, Bifidobacteria, Veillonellae, Acidaminococci, Megasphaerae, Peptococcaceae (Ruminococci, Peptococci and Peptostreptococci), Clostridia (C. perfrigens and other species), Enterobacteriaceae, aerobic Lactobacilli, Streptococci, Staphylococci, and yeast and fungi (often used interchangeably).

LAPs: THE GUARDIAN ANGELS OF HUMAN CANARIES
The LAPs angels look after human canaries in many ways.

First and foremost, LAPs keep TAPs out. It appears that this essential role is played through different mechanisms that include simple physical crowding out of the potential pathogens as well as production of antimicrobial substances. L. acidophilus produces acidophilin, acidolin and bacterlocin; L. plantartium produces lactolin; L. bulgaricus produces bulgarican; and L. brevis secretes lactobacillin.

Second, they produce many life span molecules. Notable among them are members of the vitamin B complex, especially folic acid and biotin and vitamin K. Lactobacillic acid is an important fatty acid that is produced by some lactic-acid producers and is then converted into essential fatty acids. Another notable molecule in this context is tryptophan — this is likely to be one of the mechanisms by which yogurt has been reported to be beneficial in cases of chronic anxiety and other conditions.

Third, they play a pivotal role in digestion. Lactose intolerance is a very common clinical problem. It is often not fully appreciated that a major portion of lactose ingested in dairy products is actually broken down to simpler sugars by lactase enzymes produced by lactic acid producers. Lactic acid and lactase producers also play important roles in protein digestion. This is one of the primary reasons protein intolerance is so common among individuals with altered states of bowel ecology.

Fourth, LAPs actively break down some toxins produced during metabolism such as ammonia, free phenols and polypeptides.

Fifth, LAPs normalize bowel transit time and are effective in controlling infant and adult diarrhea.

Sixth, the antiviral and antifungal roles played by LAPs, having long been empirically suspected by nutritionists and holistic physicians, have recently been documented with research studies.

Seventh, the cholesterol-lowering effects of fermented milk have been attributed, among other mechanisms, to orotic acid, which facilitates fat metabolism in the liver.

Eighth, some LAP microbes suppress tumor cells in rats. This factor is not of direct relevance to human canaries — at least not yet, though in time accelerated oxidative damage is likely to increase the incidence of cancer in chronic fatigue states.

BOWEL ECOTOXICITY

What is bowel ecotoxicity? How may it be detected? The answers to those questions can be both simple and complex. As for the former, ecotoxicity exists when endogenous and exogenous toxins in the bowel exceed its ability to ability to rid itself of those molecular species. Ecotoxicity exists when the characteristics of health described in an earlier chapter are not present, month after month, year after year. As for the latter, below I provide an incomplete answer. (Complete answer to those questions may indeed not be forthcoming for decades.)

Until the dawn of the pesticide and xenobiotics age, the human bowel flora was, in a broad sense, in equilibrium with that of the soil. As I child I recall pulling carrots from my 'personal' vegetable patch, barely washing them, and eating them with relish. I also recall the crunch of some sand between my then-strong teeth. That era, of course, is long gone. The soil all over the globe has been now diffusely and unrelentingly chemicalized. Today if a child were to eat vegetables smeared with dirt, she will not be exposed to the soil flora that I was then. Children today can be expected to take variable doses of pesticides, herbicides, and xenobiotics with their vegetables and fruits.

After the reunification of Germany, pediatricians from 'clean' Munich in West Germany and 'polluted' Leipzig from East Germany conducted a collaborative study to determine how much higher the incidence of asthma in the East German town was notorious for its industrial air pollution. I would have predicted they would see more asthma in children raised on the clean but highly chemicalized soil of Munich than in Leipzig, with its polluted air but far less chemicalized soil. That, indeed, was the case when the results of that study were published.31

Not unexpectedly, LAPs-TAPs dynamics are profoundly influenced not only by the soil composition but also by food choices. American and British individuals show overgrowth of some TAPs, such as bacteroides and some types of clostridia, with much higher frequency than is seen in Japanese, Indians and Ugandans. It appears likely that these differences are due to excess use of antibiotics and an abundance of fats in the former populations' diet.

A very revealing look into the presence and degree of bowel ecotoxicity is provided by data concerning 24-hour urinary excretion of mycotoxins, bacterial toxins, and related molecular species produced largely in the bowel. Table 2 shows data for 100 patients with chronic energy deficit disorders.

Absence of the Guardian Angels of Human Canaries

Perhaps the best way to gain some sense of the dynamics of bowel ecotoxicity is to examine how healthful bowel flora in bygone years helped preserve health. Consider how the LAP angels promote healthful aging:

First and foremost, LAPs keep TAPs under check. It appears that this essential role is played through different mechanisms that include simple physical crowding out of the potential pathogens as well as production of antimicrobial substances. L. acidophilus produces acidophilin, acidolin and bacterlocin; L. plantartum produces lactolin; L. bulgaricus produces bulgarican; and L. brevis secretes lactobacillin.

Second, LAPs produce many lifespan molecules. Notable among them are members of the vitamin B complex, especially folic acid and biotin, and vitamin K. Lactobacillic acid is an important fatty acid that is produced by some lactic-acid producers and is then converted into essential fatty acids. Another notable molecule in this context is tryptophan—this is likely to be one of the mechanisms by which yogurt has been reported to be beneficial in cases of fibromyalgia, chronic fatigue, and related conditions.

Third, LAPs play a pivotal role in digestion. Lactose intolerance is a very common clinical problem. It is often not fully appreciated that a major portion of lactose ingested in dairy products is actually broken down to simpler sugars by lactase enzymes produced by lactic acid producers. Lactic acid and lactase producers also play important roles in protein digestion. This is one of the primary reasons protein intolerance is so common among individuals with altered states of bowel ecology.

Fourth, LAPs actively break down some toxins produced during metabolism such as ammonia, free phenols and polypeptides.

Fifth, LAPs normalize bowel transit time and are effective in controlling infant and adult diarrhea.

Sixth, the antiviral and antifungal roles played by LAPs, having long been empirically suspected by nutritionists and holistic physicians, have recently been documented with research studies.

Seventh, the cholesterol-lowering effects of fermented milk have been attributed, among other mechanisms, to orotic acid, which facilitates fat metabolism in the liver.

Eighth, some LAP microbes suppress tumor cells in rats. This factor is not of direct relevance to human canaries — at least not yet, though in time oxidosis and dysoxygenosis is likely to increase the threat of cancer in persons with OD (oxidative-dysoxygenative) states.

It is noteworthy that all eight elements mentioned above increase, directly or indirectly, the fury of oxidosis, acidosis, and dyxoxygenosis.

RESTORATION OF BOWEL ECOLOGY
Disruptions of bowel ecology can be arrested and reversed only with a gardener's sense of tending to the soil, nurturing the plants, and respect for the sunshine. That, of course, is the theme of this chapter. The sun-related factors — chronic anger, hostility, conflict, and a sense of being a victim — both slow down the bowel transit time and significantly reduce perfusion in different parts of the alimentary tract. Those anatomically-mediated responses, of course, form the core of the so-called stress response. I discuss this subject at length in What Do Lions Know About Stress and Healing Miracles and the Bite of the Gray Dog .
The Seed-Feed-and-Occasionally-Weed Approach to Restoration of Bowel Ecology

In 1994, in The Canary and Chronic Fatigue, I described my seed-feed- and-occasionally-feed approach to addressing the chronic ecologic issues of the alimentary tract. Below, I reproduce some text from that volume:

Seeding is the repopulation of the gut with microflora that have been destroyed by indiscriminate use of antibiotics or crowded out by the unrestrained proliferation of yeast and bacterial organisms such as the Proteus and Pseudomonas species.

The "guardian angel bacteria" for bowel ecology belong to the Bifidobacterium and Lactobacillus species. Some other species also play protective roles. In health, these organisms provide the necessary counterbalance to the growth of yeast and pathogenic bacterial organisms. Beyond this, these organisms produce several molecules that play critical roles in our molecular defense systems.

Feeding is the use of some growth factors that the normal bowel flora require to flourish. These include biotin, pantetheine, Vitamin B12 and others. We clinicians have used Vitamin B12 for decades with good clinical results (to the great chagrin of those "academicians" who considered it quackery because they couldn't understand how this vitamin could ever help anybody except those with pernicious anemia). One of the principal mechanisms by which vitamin B12 exerts its myriad beneficial effects is by serving as a "growth hormone" for health-preserving bowel flora. Of course, this vitamin has several other essential roles. It plays a role in the citric acid cycle (the main molecular pathway for energy generation where it facilitates the conversion of methylmalonyl-CoA to succinyl-CoA) and is essential for cell maturation. Further, Vitamin B12 benefits many patients with neuropsychiatric disorders unassociated with anemia or macrocytosis.

Occasional weeding is the use of several natural substances that are known to suppress the overgrowth of pathogenic bacteria, viruses and yeasts. During initial treatment, I frequently use oral nystatin or fluoconazole (Diflucan) for short periods of two to three weeks, partly for diagnostic and partly for therapeutic reasons (how a person with one of the ABE states responds to these agents is useful in assessing the degree of damage to bowel ecology). Extensive clinical experience has convinced me that long-term clinical results are far superior when the use of drugs is kept to a minimum.

Simple-minded efforts to "get rid of the yeast" with nystatin and "yeast- free diets" usually yield poor long-term results. Cold hands are associated with "cold bowel." Cold hands and cold bowel are the result of oxidatively-damaged thyroid enzymes (underactive thyroid gland), oxidatively-damaged autonomic nerve cells and fibers (dysautonomia) or an oxidatively-overdriven adrenalin gland (the relentless chatter of the cortical monkey). None of these problems can be effectively managed with yeast-free diets and Nystatin. Of course, there are other essential issues of nutrition, environment, food and mold allergy, and fitness. In the management of battered bowel ecosystems, it is essential to consider the biologic individuality of the patient. It is necessary to adopt an integrated, long-term approach that addresses all relevant issues of bowel flora and parasites, bowel transit time, bowel ischemic patterns, IgE-mediated disorders related to candida and other yeast antigens, malabsorptive dysfunctions, and secondary systemic consequences.

Physicians who are not familiar with natural therapies for managing chronic bowel and gastric disorders are in for a pleasant surprise. A very large number of effective natural agents are available to them. Extensive clinical experience has convinced me that for nonlife-threatening, chronic disorders, natural therapies are far superior to the huge array of drugs that are foisted upon us.

Following are important consideration in integrative management of chronic gastric and bowel disorders:

First, all patients should be offered standard drug therapies for acute disorders when any question exists about impending clinical crises or risk of serious complications.

Second, all patients managed with natural agents should be prepared for slow and sustained recovery over weeks and months. It is my practice not to wean my patients off drugs prescribed by other physicians. Rather, my clinical strategy is to go for gentle restoration of bowel and gastric ecologies. The patients sense clinical improvement within several days or some weeks. It is at this time that they ask me if they should begin to reduce the dose of drugs they are taking, and I am only too happy to provide guidance on how to do so gradually.

Third, all patients are required to attend a full-day workshop in which I give detailed information about the devastating impact of internal and external environments on our biology. In addition, nutrition and exercise classes are given by the nursing staff at the institute.

Fourth, all patients must be managed with an overarching philosophy of holistic molecular relatedness in human biology. I repeat this essential point several times at the risk of offending the reader because it is the very essence of the new medicine that the problems of the 21st century call for.

Fifth, and this is of critical importance for the general reader, a self-help approach to health requires guidance from a knowledgeable professional. Safety first. This is the first principle of molecular medicine as it must be for all other types of medicine.