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Abstract We have previously discovered a panel of anti-microbial antibodies from patients with Crohn’s disease (CD) and Sjogren’s syndrome (Sjo). We have also demonstrated the increase of these anti-microbial antibodies in other autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis in a small number of cases. The seroprevalence of these antibodies in the normal healthy population is unknown. We set to survey the normal population for these anti-microbial antibodies. We collected 288 blood samples from the donor units of the leukocyte-reduced red blood cells from the American Red Cross, and examined the presence of the anti-microbial antibodies in these blood samples using direct ELISA assays established in our laboratory using the recombinant microbial protein antigens. Our results showed that the prevalence of RPOB antibody in the normal blood donor population is 2.4% (7 positive of 288 samples). The prevalence of EF-G antibody is 4.2% (12 positive of 288 samples), ATP5a 5.2% (15 positive), Hsp65 2.8% (8 positive), EF-Tu 5.6% (16 positive), and NMPC 4.2% (12 positive). Meanwhile, in 109 patients with Crohn’s disease and 28 patients with Sjogren’s syndrome, these anti-bacterial antibodies are significantly increased (p<0.001). These results indicate that the specific anti-microbial antibodies within the normal general population are uncommon, but frequent in chronic disease states. The presence of increased anti-microbial antibodies in the blood of patients but not in normal controls can serve as biomarkers for chronic diseases such as Crohn’s disease and Sjogren’s, and their presence indicates abnormal B-cell/plasma cell function in response to the commensal/pathogenic microbes. Since the antigens were derived from the common microbes present on the surface of the normal population, the antimicrobial antibodies in patients with diseases but not in the normal population suggest a deficient clearance of the microbes from the circulation by the innate immunity system in chronic diseases. These results also raise questions of bacterial vaccination using whole bacterial extracts as these anti-bacterial antibodies appear pathogenic rather than protective, offering fresh thinking in designing bacterial vaccines as preventive or therapeutic measures in chronic diseases such as Crohn’s disease and Sjogren’s Disease.