EXCERPTED FROM POWER HEALING (RANDOM HOUSE, 1998)
BY LEO GALLAND, M.D.

In keeping with its immense surface area and intense exposure to foreign antigens, the intestinal tract is the largest organ of immune surveillance and response in the human body (Targan et al., 1987). It should not be surprising that events occurring in its lumen or on the mucosal surface have systemic effects on immune function and disease resistance. This chapter examines the contribution made by luminal organisms commonly encountered in humans: bacteria, protozoa and yeasts. Particular attention win be given to data concerning a role for Giardia lamblia infestation and Candida albicans colonization in the pathogenesis of chronic fatigue and immune dysfunction.

BACTERIAL MICROFLORA

Over 500 species of bacteria live in the healthy human alimentary canal; in the average adult they weigh about one kilogram. The normal colonic microflora ferment soluble fibre to yield short-chain fatty acids which supply 5-10% of human energy requirements (McNeil, 1984). Endogenous flora synthesize at least seven essential nutrients, supplementing dietary intake: folic acid, biotin, pantothenic acid, riboflavin, pyridoxine, cobalamin and vitamin K (Mackowiak, 1982). They participate in the metabolism of drugs, hormones and carcinogens, including digoxin (Lindenbaum et al., 1981), sulphasalazine, and estrogens (Gorbach, 1982). By demethylating methylmercury, gut flora protect mice from mercury toxicity (Rowland et al., 1984). They prevent potential pathogens from establishing infection by numerous mechanisms, which include: production of short-chain fatty acids and bacteriocin, induction of a low oxidation-reduction potential, competition for nutrients, deconjugation of the bile acids (which renders them bacteriostatic), blockade of adherence receptors and degradation of bacterial toxins (Savage, 1980).

Germ-free animals have mild to moderate defects in immune function when compared to control animals. These include lower levels of natural antibodies, hyporesponsive macrophages and neutrophiles, defective production of colony-stimulating factors, leukopenia, lymphoid hypoplasia, subnormal interferon levels and weak delayed hypersensitivity (DHS) responses. They are more susceptible to infection with intracellular parasites such as Listeria, Mycobacterium and Nocardia, but are not more susceptible to viral infection (Mackowiak, 1982). Adverse effects of endogenous bacteria have also been described, indicating the complexity of the host-saprophyte relationship. In diseases where host immune response is the primary cause of pathology, such as lymphocytic choriomeningitis, germ-free animals fare better than control animals (Mackowiak, 1982).

The immunologic effects of normal gut flora are in part due to antigenic stimulation and in part to the bacterial origin of specific immune activators, such as endotoxin lipopolysaccharicle (LPS) and muramyl dipeptides Worrison and Ryan, 1979; Mackowiak, 1982; Stokes, 1984). An important role for these substances in normal immune regulation has not been established, however (Mayrhofer, 1984).

The gut flora of healthy individuals is very stable (Sears et al., 1950,19-%); this stability may in part be due to interbacterial inhibition (Sprunt and Redman, 1968). Alteration in the level of normal flora by antibiotics has long been known to allow secondary infection by pathogenic bacteria and yeasts (Keefer, 1951; Seelig, 1966).

Occasional publications describe abnormal fecal flora in patients with atopic eczema. Kuvaeva et al. (1984) studied 60 infants in Moscow with IgE mediated food allergy and eczema. They reported a decrease in anaerobic bacteria and lactic acid-producing aerobes and an increase of Enterobacteriaceae. Severity of eczema was directly proportional to severity of dysbiosis. No control data are given. Ionescu et al. (1986) studied fecal flora in children and adults with atopic eczema. Compared with healthy controls, there was a marked reduction in Lactobacillus, Bifidobacterium and Enteroccoccus species in the great majority of cases. This was associated with increased concentrations of Candida species, Proteus, Klebsiella, and Staphylococcus allreus, and appearance of atypical coliforms and Clostridium innocutan. The high frequency of hypoalbumenernia, indicanuria and steatorrhea in the eczema group suggested small bowel bacterial overgrowth with secondary malabsorption. In neither of these studies is it possible to determine whether abnormal bowel flora caused allergy or whether food-allergic disease destabilized gut flora.

Immunologic reactions to normal or abnormal components of the bacterial gut flora are implicated in the etiology of some inflammatory disorders. Reactive arthritis may occur after intestinal infection with Salmonella typhimurium, Yersinia enterocolitica serotype 3, Shigella flexneri, Campylobacter jejuni and Clostridium difficile (Inman, 1988). Because arthritogenic potential is strain-specific and because 60-80% of patients with reactive arthritis carry the HLA-B27 gene, it is likely that genetically determined antigenic crossreactivity plays a role (Yu et al., 1989).

Ankylosing spondylitis (AS) occurs almost exclusively in HLA-B27positive individuals. An increased rate of intestinal colonization with Klebsiella pneumoniae has been described in this condition, according to some but not all studies (Kinsella, 1988). Immunologic cross-reactivity has been shown for HLA-B27 antigen expressed on the host cell membrane and antigens present in K. pneumoniae, S. flexneri and Y. enterocolitica, suggesting molecular mimicry in the pathogenesis of this disease (Yu, 1988). Workers in Australia have demonstrated bacteria with cross-reactive antigenic determinants in bowel flora of B27-positive AS patients; these bacteria are almost never found in B27-positive controls without AS (McGuignan et al., 1986).

Endotoxemia has been described in patients with psoriasis (Rosenberg and Belew, 1982a) and cystic acne (Juhlin and Michaelson, 1984). Activation of the alternative complement pathway (APC) by gut-derived endotoxin may play a role in the pathogenesis of these disorders. Exposure of macrophages to endotoxin causes release of cytokines, such as interleukin-1 (Il-1) and tumor necrosis factor (TNF). These peptides have powerful effects on the immunologic and metabolic response to infection. Whether gutderived endotoxins influence cytokine production in vivo is unknown.

GIARDIA LAMBLIA

Although it was first described by van Leuwenhoek in 1681, it is only in the past 25 years that G. lamblia has been acknowledged as an important pathogen (Gillon, 1984). Giardiasis is the commonest cause of parasitic disease in the United States (Myer and Jarroll, 1980) with an overall prevalence estimated at 7.4%, which is about the same as its average worldwide prevalence (Mahmoud and Warren, 1975). Prevalence in Great Britain varies from 2% to 10% (Felman and Nikitas, 1985). At least 27% of Giardia infections identified at the University of Edinburgh Medical School had been acquired within the UK and a diagnosis of giardiasis had not been suspected in two-thirds of cases (Gibb, 1989).

Reports based on stool screening may underestimate the prevalence of giardiasis. Comparison of stool examination with duodenal aspiration has consistently shown that stool examination fails to identify infected patients even at the height of acute infection. Single stool specimens have a sensitivity of zero (Rosenthal and Liebman, 1980) to 50% (Kamath and Murugasu, 1974). Collecting multiple specimens over several days increases the sensitivity to 85-90% (Gillon, 1984).

To overcome the limitations of stool analysis we developed a diagnostic technique by which rectal mucus obtained at anoscopy is stained with a monoclonal antibody to Giardia cysts and examined by epifluorescence microscopy (Galland and Bueno, 1989). We recently conducted a two-year retrospective study of 218 patients who presented to our medical clinic with a chief complaint of chronic fatigue (Galland et al., 1990). G. lamblia infection was identified by rectal swab in 61 patients. The symptoms of patients with and without giardiasis, are shown in Table 1.

All patients with giardiasis and 86% of patients without giardiasis complained of digestive symptoms, but these were generally mild. The most interesting difference between the two groups lies in the positive association between giardiasis and symptoms such as myalgia, muscle weakness, flu-like feelings, sweats and adenopathy. In fact, 61% of fatigued patients with giardiasis had been diagnosed elsewhere as suffering from chronic fatigue syndrome (CFS) or ME, compared to only 19% of fatigued patients without giardiasis. Cure of giardiasis resulted in clearing of fatigue and related 'viral' symptoms (myalgia, sweats, flu-like feelings) in 70% of cases, some palliation of fatigue in 18%, and was of no benefit in 12%. This study shows that giardiasis can present with fatigue as the major manifestation, accompanied by minor gastrointestinal complaints and sometimes by myalgia and other symptoms suggestive of ME. It indicates that G. lamblia infection may be a common cause of CFS, at least in the United States. It is noteworthy that tricyclic antidepressants, a standard treatment for CFS, suppress the growth of Giardia in vitro (Weinbach et al., 1985).

The mechanism by which G. lamblia causes disease is not known. Experiments with human volunteers demonstrate that the ability of Giardia to produce infection and to cause diarrhea depends upon the strain of G. lamblia used (Nash et al., 1987), the inoculum dose (Rentdorff, 1954; Rentdorff and Holt, 1954), and previous exposure to the organism (Nash et al., 1987). Heterogeneity of Giardia isolates from humans in the same city occurs and has been proposed as one mechanism for variability of clinical response to infection (Korman et al., 1986).