Abstract
Escherichia coli is a facultative anaerobic symbiont found widely among mammalian gastrointestinal tracts. Several human studies have reported increased commensal E. coli abundance in the intestine during inflammation; however, host immunological responses toward commensal E. coli during inflammation are not well-defined. Here, we show that colonization of gnotobiotic mice with different genotypes of commensal E. coli isolated from healthy conventional microbiota mice and representing distinct populations of E. coli elicited strain-specific disease phenotypes and immunopathological changes following treatment with the inflammatory stimulus, dextran sulfate sodium (DSS). Production of the inflammatory cytokines GM-CSF, IL-6, and IFN-γ was a hallmark of the severe inflammation induced by E. coli strains of Sequence Type 129 (ST129) and ST375 following DSS administration. In contrast, colonization with E. coli strains ST150 and ST468 caused mild intestinal inflammation and triggered only low levels of pro-inflammatory cytokines, a response indistinguishable from that of E. coli-free control mice treated with DSS. The disease development observed with ST129 and ST375 colonization was not directly associated with their abundance in the GI tract as their levels did not change throughout DSS treatment, and no major differences in bacterial burden in the gut were observed among the strains tested. Data mining and in vivo neutralization identified IL-6 as a key cytokine responsible for the observed differential disease severity. Collectively, our results show that the capacity to exacerbate acute intestinal inflammation is a strain-specific trait that can potentially be overcome by blocking the pro-inflammatory immune responses that mediate intestinal tissue damage.
Highlights
The mammalian gut harbors a wide variety of bacteria that coexist in a mutually beneficial state with their host [1]
Lesions from mice colonized with either E. coli Sequence Type 129 (ST129) or ST375 and treated with dextran sulfate sodium (DSS) were characterized by extensive epithelial ulceration, submucosal and mucosal edema, neutrophilic, and monocytic cell infiltration, gland hyperplasia and stromal collapse (Figure 1C)
Consistent with macroscopic observations, mice receiving either DSS only or E. coli strains only developed minimal microscopic lesions (Figures 1B,C). These results demonstrate that commensal E. coli populations have strain-specific, disease-causing potentials during intestinal inflammation
Summary
The mammalian gut harbors a wide variety of bacteria (i.e., the gastrointestinal microbiota) that coexist in a mutually beneficial state with their host [1]. The host provides the niches and nutrients essential for microbial propagation and population survival Disruption of this homeostatic relationship, which occurs during enteric infection or inflammation, can result in robust and potentially pathogenic immune responses that are thought to drive disease pathogenesis [5]. Even among lineages not known to be primarily pathogenic, phenotypes can range from the capacity to protect against invading enteric pathogens to exacerbation of inflammation induced by a variety of stimuli [11] With respect to the former, the gut isolate E. coli EM0 strain and even the JM105 cloning host strain can each protect against Salmonella Typhimurium infection in germ-free mice [13]. These contrasting traits of protection versus pathobiont have not been systematically studied across the population structure of E. coli
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