Azathioprine, Mercaptopurine, and 5-Aminosalicylic Acid Affect the Growth of IBD-Associated Campylobacter Species and Other Enteric Microbes

Abstract

<i>Campylobacter concisus</i> is a bacterium that is associated with inflammatory bowel disease (IBD). Immunosuppressive drugs including azathioprine (AZA) and mercaptopurine (MP), and anti-inflammatory drug such as 5-aminosalicylic acid (5-ASA) are commonly used to treat patients with IBD. This study aimed to examine the effects of AZA, MP, and 5-ASA on the growth of IBD-associated bacterial species and to identify bacterial enzymes involved in immunosuppressive drug metabolism. A total of 15 bacterial strains of five species including 11 <i>C. concisus</i> strains, <i>Bacteroides fragilis, Bacteroides vulgatus, Enterococcus faecalis</i>, and <i>Escherichia coli</i> were examined. The impact of AZA, MP, and 5-ASA on the growth of these bacterial species was examined quantitatively using a plate counting method. The presence of enzymes involved in AZA and MP metabolism in these bacterial species was identified using bioinformatics tools. AZA and MP significantly inhibited the growth of all 11 <i>C. concisus</i> strains. <i>C. concisus</i> strains were more sensitive to AZA than MP. 5-ASA showed inhibitory effects to some <i>C. concisus</i> strains, while it promoted the growth of other <i>C. concisus</i> strains. AZA and MP also significantly inhibited the growth of <i>B. fragilis</i> and <i>B. vulgatus</i>. The growth of <i>E. coli</i> was significantly inhibited by 200 μg/ml of AZA as well as 100 and 200 μg/ml of 5-ASA. Bacterial enzymes related to AZA and MP metabolism were found, which varied in different bacterial species. In conclusion, AZA and MP have inhibitory effects to IBD-associated <i>C. concisus</i> and other enteric microbes, suggesting an additional therapeutic mechanism of these drugs in the treatment of IBD. The strain dependent differential impact of 5-ASA on the growth of <i>C. concisus</i> may also have clinical implication given that in some cases 5-ASA medications were found to cause exacerbations of colitis.