Polymicrobial Associations in Inflammatory Bowel Disease

University Of Nebraska Lincoln, Lincoln NE

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Abstract

DESCRIPTION (provided by applicant): Ulcerative colitis (UC) is a chronic idiopathic inflammatory bowel disease (IBD) affecting approximately 1 million Americans. Host inflammatory and immune defense directed against unknown component(s) associated with the gut surface are generally accepted as the underlying cause, however, the initiating triggering mechanism(s) for defense activation in IBD/UC is still unknown. Colonic spirochetosis (CS), a form of IBD that also affects humans, is a common and spontaneous cause of colonic damage and inflammation in macaques kept in National Primate Research Centers (NPRC) throughout the US. Thus, macaques are an ideal model for detailed analysis of the mechanisms involved in CS and relationship to IBD/UC. In macaques as in humans, CS is characterized by massive epithelial attachment of spirochete microbes identified as Brachyspira aalborgi and B. pilosicoli alone or together with spiral flagellated microbes. Comparative 16S rRNA gene sequence analysis of PCR-amplified products from DNA extracted from the colons of both macaques and humans with CS revealed specific phylotypes of enterohepatic Helicobacter species with morphologies similar to the flagellated microbes seen in CS. The Central Hypothesis of this application is that specific polymicrobial associations involving certain enterohepatic Helicobacter and Brachyspira species adherent onto the colonic epithelium of macaques can elicit serological correlates of IBD. Therefore, the purpose of this application is to determine the identity and relative prevalence of epithelium-adherent Brachyspira and Helicobacter species present in CS, and correlation with serum antibodies to several serological correlates of IBD. To accomplish this, we will perform retrospective and prospective analyses of control colons from macaques without epithelium-adherent microbes, and colons obtained from macaques with CS using pathological, immunohistological, molecular genotypic and bacteriological methods and correlation with the presence and titer of antibodies to bacterial flagellins and non-specific serological correlates of human IBD. It is anticipated that by the end of this project we will know the relative prevalence of infection by individual or combinations of Brachyspira and Helicobacter species in CS and their association with serological correlates of IBD. Once the relevant microbes associated with CS have been cultured and identified, and serological correlates of IBD have been determined, hypothesis-driven research aimed at understanding the mechanism(s) and implication(s) of these associations in the context of human IBD/UC will be possible. This is the first step towards characterizing a unique and potentially important polymicrobial association that could impact the development of diagnostic methods, and implementation of more effective preventative and therapeutic intervention strategies for IBD.