The Gut Commensal Bacteroides thetaiotaomicron Exacerbates Enteric Infection through Modification of the Metabolic Landscape

Abstract

SUMMARY The enteric pathogen enterohemorrhagic Escherichia coli (EHEC) causes severe diarrhea but the influence of the gut microbiota on EHEC infection is largely unknown. A predominant member of the microbiota, Bacteroides thetaiotaomicron (Bt), is resident at EHEC attachment sites. We show that Bt enhances EHEC virulence gene expression through the transcription factor, Cra, which is functionally sensitive to sugar concentrations. This enhanced virulence accompanies increased formation of attaching and effacing (AE) lesions requisite for EHEC colonization. Infection with Citrobacter rodentium, a natural mouse pathogen homologous to EHEC, in Bt-reconstituted mice results in increased gut permeability along with exacerbated host pathology and mortality compared to mice deplete of microflora. Bt modifies the metabolite environment at infection sites, increasing metabolites involved in gluconeogenesis, with stark increases in succinate, which can be sensed by Cra. Our findings suggest that microbiota composition affects disease outcome and may explain links between microbiota composition and disease susceptibility.

Coculture of Escherichia coli O157:H7 with a Nonpathogenic E. coli Strain Increases Toxin Production and Virulence in a Germfree Mouse Model

“…A further exploration of the interactions between E. coli O157:H7 and the plethora of bacterial species present in the gut is needed to appreciate how the gut microbiome affects the virulence of this foodborne pathogen. It was also shown previously that fecal Bacteroides thetaiotaomicron alters Stx2 expression (40)(41)(42), although two studies (40,42) report decreases while one (41) report shows Hematoxylin-and eosin-stained renal sections from mice infected with either C600 or PA2 and PA2 plus C600. The mice were scored as described in Materials and Methods.…”

Bacterial Chat: Intestinal Metabolites and Signals in Host-Microbiota-Pathogen Interactions

“…Fucose is sensed by EHEC via the histidine sensor kinase FusK to modulate LEE gene expression and sugar metabolism (28,117). Hence, EHEC exploits B. thetaiotaomicron to promote the expression of its virulence repertoire (28,118).…”

When pathogenic bacteria meet the intestinal microbiota

“…For example, the intestinal microbiota can also produce metabolites that might unexpectedly enhance pathogen virulence expression and colonization in the gut [57][58][59][60][61] ( figure 3a). Bacteroidetes thetaiotaomicron, found to lead to a competitive exclusion of C. rodentium through the consumption of similar carbohydrates [14], can also cleave sialic acid moieties from mucin and produce high levels of succinate that can lead to an enhanced colonization by C. difficile [58,59].…”

“…Bacteroidetes thetaiotaomicron, found to lead to a competitive exclusion of C. rodentium through the consumption of similar carbohydrates [14], can also cleave sialic acid moieties from mucin and produce high levels of succinate that can lead to an enhanced colonization by C. difficile [58,59]. The production of fucose or succinate from the host mucin by commensal bacteria can also modulate the expression of the virulence factor ler, a master regulator of the locus of enterocyte effacement (LEE) genes in EHEC [60,62], thus contributing to EHEC virulence. Other examples of pathogens that utilize the intestinal microbiota to facilitate their own infection include C. difficile whose spores require by-products from the microbiota, such as bile salts, to germinate [63] and S. Typhimurium that utilizes di-hydrogen generated by the microbiota for its luminal growth [64].…”