Comparative Genomics Of Adherent And InvasiveEscherichia coli Associated With Intestinal Inflammation Reveals Patho-adaptive Determinants Of Virulence Kenenth W. Simpson, College of Cornell University, Ithaca NY Intestinal bacteria are implicated increasingly as a pivotal factor in the development of Crohn’s disease (CD) but the specific components of the complex polymicrobial environment driving the inflammatory response are unresolved. Using contemporary culture-independent methodologies we have discovered that the mucosal flora of people with Crohn’s ileitis, Boxer dogs with granulomatous colitis, and mice with Toxoplasma and NSAID induced ileitis are selectively enriched in E. coli. Culture based characterization of E. coli from the inflamed mucosa of people, dogs and mice indicates they belong to a putative new pathogroup, Adherent and Invasive E. coli (AIEC), originally isolated from CD ileitis in France. Our findings raise the possibility that AIEC strains share common pathoadaptive determinants of virulence that promote intestinal inflammation across species.
We used comparative genomics to identify genes of AIEC strains that could provide novel insights into how these bacteria might elicit intestinal inflammation in a Crohn’s susceptible individual. We sequenced and assembled the genomes of 8 AIEC strains (4 CD, 3 ileitis and 1 colitis ; 1 murine ileitis, 1 murine fecal isolate ; 2 granulomatous colitis of Boxer dogs) and one non-AIEC strain from CD ileum. Total genome sizes were 4.7 - 5.2 Mb. The sequences were compared with publicly available genome sequences of E. coli and Shigella. E. fegusonii was used as an out group.
Phylogenies based on the non-recombinant portion of the genome, involving over 600 loci, strongly supported the independent evolutionary history of AIEC strains, including AIEC from the same host and with the majority of AIEC closely related to different strains of extraintestinal pathogenic E. coli (ExPEC) e.g. UPEC and APEC. Based on gene content, AIEC as an overall pathotype did not cluster as a single group, rather AIEC strains from different species intermingled in several distinct clusters with ExPEC. Genomic comparisons across biochemical categories revealed that AIEC were overrepresented in siderophores, heme uptake, iron uptake, and biosynthesis of natural products compared to non-pathogenic strains. Compared to other E. coli pathogens AIEC were overrepresented in intracellular survival and replication, proinflamatory effects, and types II and IV secretory proteins, and lacking type III.