Brief report
Increased serum IgA and IgM against LPS of enterobacteria in chronic fatigue syndrome (CFS): Indication for the involvement of gram-negative enterobacteria in the etiology of CFS and for the presence of an increased gut–intestinal permeability

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Abstract

There is now evidence that chronic fatigue syndrome (CFS) is accompanied by immune disorders and by increased oxidative stress.

The present study has been designed in order to examine the serum concentrations of IgA and IgM to LPS of gram-negative enterobacteria, i.e. Hafnia alvei; Pseudomonas aeruginosa, Morganella morganii, Proteus mirabilis, Pseudomonas putida, Citrobacter koseri, and Klebsiella pneumoniae in CFS patients, patients with partial CFS and normal controls.

We found that the prevalences and median values for serum IgA against the LPS of enterobacteria are significantly greater in patients with CFS than in normal volunteers and patients with partial CFS. Serum IgA levels were significantly correlated to the severity of illness, as measured by the FibroFatigue scale and to symptoms, such as irritable bowel, muscular tension, fatigue, concentration difficulties, and failing memory.

The results show that enterobacteria are involved in the etiology of CFS and that an increased gut–intestinal permeability has caused an immune response to the LPS of gram-negative enterobacteria. It is suggested that all patients with CFS should be checked by means of the IgA panel used in the present study and accordingly should be treated for increased gut permeability.

Introduction

There is now some evidence that chronic fatigue syndrome (CFS) is accompanied by immune disorders and by increased oxidative stress. Immune activation is suggested by an increased expression of T lymphocyte activation markers, such as CD26 and CD38 and alterations in cytokine production. Poor cellular immunity is suggested by lowered natural killer cell cytotoxity, decreased mitogen-induced lymphocyte responses and defects in early T cell activation. Inflammatory reactions are indicated by decreased serum zinc levels and increased serum concentrations of the alpha2 globulin fraction (review: Maes et al., 2005, Maes et al., 2006).

Increased oxidative stress in CFS is suggested by increased levels of isoprostanes and oxidized low density lipoproteins (Kennedy et al., 2005), higher LDL thiobarbituric acid reactive substances (TBARS) and decreased anti-oxidative defences, such as lower serum zinc and dehydroepiandrosterone-sulphate (Vecchiet et al., 2003, Maes et al., 2005, Maes et al., 2006).

The occurrence of CFS may not only be triggered by viral and bacterial infections, stressful life events and physical stress, type III–IV allergies for food and heavy metals, but also by an increased permeability of the gut barrier (Maes, 2005).

The present study has been carried out in order to examine whether CFS is accompanied by an increased permeability of the gut barrier whereby an immune response is mounted to endotoxins secreted by gram-negative enterobacteria.

Section snippets

Subjects

Forty subjects participated in the present study, 11 unrelated controls (staff or their family members), and 29 patients admitted to the M-Care4U Outpatient Clinics, Belgium. We made the diagnosis of CFS by means of the Centers for Disease Control and Prevention (CDC) criteria (Fukuda et al., 1994). Patients with chronic fatigue but not fulfilling all diagnostic CFS criteria were classified as suffering from partial CFS. The severity of CFS was measured by means of the FibroFatigue scale, i.e.

Methods

Fasting blood was sampled during the morning hours for the determination of the IgM and IgA against the LPS of 7 different enterobacteria (see Table 1). The analyses were performed by means of an indirect ELISA method according to the methods outlined by the manufacturer (Gemacbio, The Ultimate Biopharmaceuticals, France) and described previously (Geffard et al., 2002). Each serum sample was measured in duplicate and tested simultaneously with three standard solutions. The optical densities

Statistics

Relationships between variables were assessed by means of Pearson's product moment correlation coefficients, canonical correlation analysis and Spearman's rank order correlations. Group mean differences were examined by means of analysis of variance (ANOVA) or covariance (ANCOVA) and by means of linear discriminant analysis. Post-hoc contrasts between multiple group means were ascertained by means of the Dunn test. The independence of classification systems was ascertained by means of analysis

Results

Table 1 shows that there were no significant differences in age or in sex distribution between the study groups. At the p = 0.01 level, no significant relationships were found between age or gender and the serum IgM and IgA levels. Patients with CFS had significantly greater scores on the FibroFatigue scale than patients with partial CFS (50.9 ± 5.5 versus 32.6 ±5.3, F = 84.7, df = 1 / 24, p < 10 5).

Table 1 shows that the serum IgM levels against LPS of Proteus mirabilis were significantly greater in

Discussion

The findings of the present study show that CFS is accompanied by increased serum levels of IgA and, to a lesser extent, IgM against the LPS of gram-negative enterobacteria.

Increments in serum IgM levels can be seen in mucosal immunity and immune activation, e.g. in the B1 lymphocytes. The latter are a significant source of natural serum IgM, thereby serving as a first line of defence against systemic bacterial and viral infections (Thurnheer et al., 2003). B1 cells can migrate to the

Acknowledgments

The research reported was supported by a NARSAD Distinguished researcher award to M.Maes and by M-CARE4U and CRC-MH, Antwerp, Belgium. The secretarial assistance of Indra Corten is greatly appreciated.

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