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D
r. Galland's Integrated Medicine
 

The Effect of Intestinal Microbes on Systemic Immunity

© Leo Galland MD, FACN

The following is one in an ongoing series of columns entitled Dr. Galland's Integrated Medicine by Leo Galland MD, FACN . View all columns in series

The ease with which G. muris infections are established in mice varies with the genetic background of the host (Belosevic et al., 1984). Acute murine giardiasis suppresses the response of splenic and mesenteric lymphocytes to sheep erythrocytes; susceptible mice express a greater degree of immunosuppression than do resistant mice (Belosevic et al., 1985a). Acute giardiasis in rodents is associated with increased intestinal production of prostaglandins E and F (Ganguly et al., 1984b) and cyclic AMP (Ganguly et al., 1984a), probably a result of macrophage activation (Kanwar et al., 1987). Just as production of PGE by host macrophages may contribute to diarrhea, activation of a population of suppressor macrophages in mesenteric lymph nodes contributes to immunosuppression in acute giardiasis (Belosevic et al., 1985b). Disaccharidase deficiency, a frequent complication of giardiasis, may also be immunologically mediated. Sensitized gerbils develop a depression of disaccharidase activity when exposed to Giardia antigens; live organisms are not required (denHollander et al., 1988).

In chronic infection, the immune response to the host also appears to be a critical determinant of outcome (denHollander et al., 1988). Chronic giardiasis in humans has been associated with deficiency of secretary IgA (Vinayak et al., 1987) and with impaired macrophage cytotoxicity (Smith et al., 1982). In animals infected with G. muris, both T helper/inducer lymphocytes and mast cells are critical for clearance of the parasite (Heyworth et al., 1987; denHollander et al., 1988), whereas cytotoxic T cells and natural killer cells are not (Heyworth et al., 1986). It is noteworthy that athymic mice with chronic giardiasis do not develop mucosal damage (Roberts-Thompson and Mitchell, 1978). Gillon et al. (1982) have proposed that the release of enteropathic lymphokines by intraepithelial T cells is the cause of the intestinal injury in chronic giardiasis. In humans, the severity of malabsorption observed with chronic giardiasis is more closely related to the presence of intraepithelial lymphocytes and the antibody titer to Giardia cyst antigen than to the estimated parasite burden (Solomons, 1982).

In rodents and humans, therefore, acute Giardia infection elicits a protective response from mast cells and T helper lymphocytes (responsible for stimulating sIGA secretion) which is essential for clearance of parasites. A macrophage response occurs as well; this is both protective (Smith et al., 1982) and immunosuppressive (Belosevic et al., 1985b), depending perhaps on the activity of different macrophage populations. Chronic giardiasis is a disease of immune dysregulation in which effector lymphocytes mediate tissue damage. Defective control of macrophage-lymphocyte communication in Giardia infection is likely, and appears to be genetically determined. Defective macrophage-lymphocyte communication is also a feature of human atopic disease (Galland, 1986) and the relationship between human giardiasis and allergy is therefore of interest.

Immunologic hypersensitivity to G. lamblia has been reported; the result may be asthma (Fossati, 1971; Lopez-Brea et al., 1979), urticaria (Harris and Mitchell, 1949; Wilhelm, 1958; Webster, 1958; Dellamonica et al., 1976; Weisman, 1979; Kennou, 1980; Farthing et al., 1983), arthritis (Goobar, 1977; Farthing et al., 1983; Woo and Panayi, 1984; Shaw and Stevens, 1987; Galland, 1989) and uveitis (Carroll et al., 1961). Hypersensitivity reactions may occur in the absence of digestive complaints (Wilhelm, 1957; Kennou, 1980; Galland, 1989). In none of these cases was the mechanism of hypersensitivity known; eosinophilia. was a feature in only two cases (Kennou, 1980; Farthing et al., 1983). A high frequency of pre-existing atopic disease occurs in patients with chronic giardiasis (Chester et al., 1985; Galland et al., 1990) and may be a factor in susceptibility to infection. We have observed that when several members of a family are infected with Giardia, symptoms tend to be more prominent among those with allergy. We suspect that the immune dysregulation which underlies atopy allows the immunologic response to Giardia infection to favor chronic disease.

Two other features of chronic giardiasis are relevant to an understanding of CFS: the effect of G. lamblia infection on nutritional status and its interaction with other organisms, specifically viruses, bacteria and fungi.

G. lamblia can cause intestinal protein loss without producing diarrhea (Sherman and Lieberman, 1980). Specific micronutrient deficiencies have also been described in chronic giardiasis. Low levels of carotene and folate (Brasitus, 1983) and abnormal vitamin A and folic acid absorption curves (Solomons, 1982) occur in a large minority of patients with chronic symptoms. Serum vitamin B12 may be low (Cowan and Campbell, 1973), and abnormal Schilling tests occur in a substantial number of patients (Solomons, 1982). Direct competition between parasite and host for vitamin B,2, as suggested by Cowan and Campbell (1973), seems unlikely, as Giardia selectively damages the duodenum and upper jejunum, and cobalamin is absorbed in the distal ileum. Bacterial overgrowth of the small bowel has been described in giardiasis (Yardley et al., 1965; Tandon et al., 1977; Tompkins et fil., 1978; Rogers, 1979) and is associated with severity of malabsorption (Tompkins et al., 1978; Tandon et al., 1977). Solomons (1982) has proposed bacterial overgrowth as a possible cause of abnormal Schilling tests in giardiasis. Bacteroides fragilis produces a substance which binds the B12-intrinsic factor complex (Mackowiak, 1982) and may cause malabsorption.

Colonization of the jejunum with Candida albicans was reported in 30% of patients with giardiasis and was absent in controls (Naik et al., 1978). The implications of intestinal candidiasis for CFS are described later in this chapter. Some strains of G. lamblia contain double-stranded RNA viruses (denHollander et al., 1988). The role of Giardia as a vector for viral infection requires further study.

AMOEBAE

Entamoeba histolytica infects 10% of the world's population (Walsh, 1986a,b). Cysts can be found in stool samples of 2% to over 40% of individuals, depending on the area and level of hygiene and sanitation (Guerrant, 1986). Amoebic antibodies, indicative of past or present invasive infection, were found in 1% of general hospital patients, 2% of random serum specimens, and 4% of healthy military recruits in the United States (Walsh, 1986b). Amoebic infection is found in about one-third of homosexual men attending clinics for sexually transmitted diseases in the United States (Petri and Ravdin, 1986). Over 90% of individuals infected with Entamoeba histolytica are asymptomatic.

The clinical response to amoebic infection is better understood than the clinical response to Giardia infection. Pathogenic strains of Entamoeba histolytica are able to evade lysis by both classical and alternative pathways of complement (Reed et al., 1986). Intestinal bacteria, E. coli in particular, are necessary for this complement resistance and for amoebic virulence (Wittner and Rosenbaum, 1970). It is suggested that ingested bacteria lower the redox potential and allow the amoebae to escape destruction by oxidative enzymes (Gitler and Mirelman, 1986). Whereas amoebae of low virulence are killed by granulocytes, highly virulent amoebae resist phagocytosis and instead kill the attacking leukocytes (Guerrant et al., 1981; Chadee et al., 1985). Mirelman (Mirelman, 1987; Mirelman et al., 1986) has reported that one can reversibly change the zvmodeme patterns of Entamoeba histolytica isolates from non-pathogenic to invasive by culturing amoebae with the gut flora of patients who have either invasive disease or no symptoms. His work, which is controversial, suggests that pathogenicity may actually be determined by the bacterial milieu.

The immunologic effects of amoebic infection have been the focus of a recent trans-Atlantic controversy. Workers in London observed that Entamoeba histolytica infestation of HIV-infected homosexual men involved only non-pathogenic amoebic zymodemes; amoebic antibodies were absent and there was no association with diarrhea or increased morbiditv (AllasonJones et al., 1986). Several North American groups, on the other 6nd, have found that AIDS patients with diarrhea are often infected with 'nonpathogenic' amoebae. Treatment with metronidazole or paromomyci Produces relief of diarrhea in parallel with the disappearance of these amoebae from feces (Rolsten et al., 1986; Sullam et al., 1986; Pearce and Abrams, 1987). Several researchers in the United States have advanced the notion that infection with E. histolytica and other parasites may promote the development of AIDS in HIV-infected individuals (Pearce, 1983; Pearce and Abrams, 1984, 1986; Archer and Glinsman, 1985; Krogstad, 1986; Petri and Ravdin, 1986; Croxson et al., 1988). Entamoeba histolytica contains a soluble lectin which is mitogenic for T lymphocytes (Chen et al., 1985; Petri and Ravdin, 1986). T helper cell activation by this lectin may induce HIV replication in vivo. A soluble Entamoeba histolytica protein, although not mitogenic itself, induced HIV replication in tissue culture of lymphocytes obtained from three out of seven men with chronic HIV infection (Croxson et al., 1988).

Synergism between intestinal parasites and lymphotrophic retroviruses has also been advanced as an explanation for the pathogenesis of Burkitt's lymphoma (Burkitt, 1983) and adult T cell leukemia/lymphoma (Tajima. et al., 1981). It seems likely that the clinical importance of amoebic infection is related as much to the characteristics of the host as of the parasite.

Chronic Entamoeba histolytica infection of humans has been associated with autoimmune phenomena, including the appearance of antibodies to colonic epithelial cells (Salem et al., 1973) and development of symmetrical polyarthritis very similar to rheumatoid arthritis (RA) (Zinneman, 1950; Rappaport et al., 1951; Kasliwal, 1970). Singh et al. (1985) measured amoebic antibody levels in 41 Indian patients with a primary diagnosis of RA, 35 age- and sex-matched healthy volunteers, 162 hospital inpatients and 26 patients with other arthritides. Amoebic antibodies were elevated in 39% of RA patients and 0-11% of the various control groups. Only two patients with RA had experienced recent diarrheal disease. These authors suggest that an excessive and prolonged antibody response to Entamoeba histolytica or other enteric organisms may contribute to joint inflammation in RA.

Galland (1989) described a patient with rheumatoid-like arthritis and antinuclear antibodies whose arthritis went into rapid and complete remission upon treatment of G. lamblia infection with metronidazole. Relapse occurred when the patient acquired Entamoeba histolytica during a trip to Egypt; remission occurred slowly following treatment of amoebiasis. Diarrhea, polyarthritis and circulating antinuclear antibodies developed in a United States serviceman heavily infested with Endolimax nana, allegedly a non-pathogen (Burnstein and Liakos, 1983). Metronidazole rapidly reversed all abnormalities. The reported cases of amoebic arthritis may represent a variant of parasitic rheumatism, an inflammatory polyarthropathy produced by circulating antigen-antibody complexes (Bocanegra, 1988). The presence of autoantibodies, however, is not characteristic of parasitic rheumatism, and suggests other mechanisms of immune dysfunction: either a pre-existing disease is exacerbated by intercurrent amoebic infection or amoebic infection itself provokes autoirnmunity, perhaps mediated by the action of immune response genes (Singh et al., 1985).

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About The Author
Leo Galland, M.D. has received international recognition as a leader in the field of Nutritional Medicine for the past 20 years. A board-certified internist, Dr. Galland is a Fellow of the American College of Physicians and the American College of Nutrition, an Honorary Professor of the International College of Nutrition, and the author of more than 30......more
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