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Inflammation-induced acid tolerance genes gadAB in luminal commensal Escherichia coli attenuate experimental colitis.

ABSTRACT: Dysregulated immune responses to commensal intestinal bacteria, including Escherichia coli, contribute to the development of inflammatory bowel diseases (IBDs) and experimental colitis. Reciprocally, E. coli responds to chronic intestinal inflammation by upregulating expression of stress response genes, including gadA and gadB. GadAB encode glutamate decarboxylase and protect E. coli from the toxic effects of low pH and fermentation acids, factors present in the intestinal lumen in patients with active IBDs. We hypothesized that E. coli upregulates gadAB during inflammation to enhance its survival and virulence. Using real-time PCR, we determined gadAB expression in luminal E. coli from ex-germfree wild-type (WT) and interleukin-10 (IL-10) knockout (KO) (IL-10(-/-)) mice selectively colonized with a commensal E. coli isolate (NC101) that causes colitis in KO mice in isolation or in combination with 7 other commensal intestinal bacterial strains. E. coli survival and host inflammatory responses were measured in WT and KO mice colonized with NC101 or a mutant lacking the gadAB genes (NC101?gadAB). The susceptibility of NC101 and NC101?gadAB to killing by host antimicrobial peptides and their translocation across intestinal epithelial cells were evaluated using bacterial killing assays and transwell experiments, respectively. We show that expression of gadAB in luminal E. coli increases proportionately with intestinal inflammation in KO mice and enhances the susceptibility of NC101 to killing by the host antimicrobial peptide cryptdin-4 but decreases bacterial transmigration across intestinal epithelial cells, colonic inflammation, and mucosal immune responses. Chronic intestinal inflammation upregulates acid tolerance pathways in commensal E. coli isolates, which, contrary to our original hypothesis, limits their survival and colitogenic potential. Further investigation of microbial adaptation to immune-mediated inflammation may provide novel insights into the pathogenesis and treatment of IBDs.

SUBMITTER: Tchaptchet S

PROVIDER: S-EPMC3811779 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Inflammation-induced acid tolerance genes gadAB in luminal commensal Escherichia coli attenuate experimental colitis.

Tchaptchet Sandrine S Fan Ting-Jia TJ Goeser Laura L Schoenborn Alexi A Gulati Ajay S AS Sartor R Balfour RB Hansen Jonathan J JJ

Infection and immunity 20130722 10

Dysregulated immune responses to commensal intestinal bacteria, including Escherichia coli, contribute to the development of inflammatory bowel diseases (IBDs) and experimental colitis. Reciprocally, E. coli responds to chronic intestinal inflammation by upregulating expression of stress response genes, including gadA and gadB. GadAB encode glutamate decarboxylase and protect E. coli from the toxic effects of low pH and fermentation acids, factors present in the intestinal lumen in patients with ...[more]

PMID: 23876805

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Project description:BackgroundAntimicrobials are often used to prevent and treat diarrhea induced by enteroaggregative Escherichia coli (EAEC) in young ruminants. However, drug overuse or misuse accelerates the spread of multidrug-resistant extended-spectrum β-lactamase (ESBL)-producing E. coli. Thus, supplementary foods as alternatives to antibiotics are needed to prevent colibacillus diarrhea in neonatal dairy calves. Ursodeoxycholic acid (UDCA), a therapeutic bile acid, helps alleviate colitis. However, how UDCA helps alleviate ESBL-EAEC-induced clinical symptoms and colitis remains unclear.ResultsWe investigated the microbial profiles and metabolites of healthy and diarrheic neonatal calves to determine microbial and metabolite biomarkers in early-life development. Both the gut microbiota communities and their associated metabolites differed between healthy and diarrheic calves. Commensal Butyricicoccus, Faecalibacterium, Ruminococcus, Collinsella, and Coriobacterium were key microbial markers that distinguished healthy and diarrheic gut microbiomes. Random forest machine-learning algorithm and Spearman correlation results indicated that enriched UDCA, short-chain fatty acids (SCFAs), and other prebiotics were strongly positively correlated with these five bacterial genera. We explored the effect of ursodiol on bacterial growth, cell adherence, and lipopolysaccharide-treated Caco-2 cells. Adding ursodiol induced direct antibacterial effects, suppressed proinflammatory effects, and reduced cell integrity damage. Oral ursodiol delivery to neonatal mice exhibited significant antibacterial effects and helped maintain colonic barrier integrity in mouse models of peritonitis sepsis and oral infection. UDCA supplementation attenuated colitis and recovered colonic SCFA production. To validate this, we performed fecal microbiota transplantations to inoculate ESBL-EAEC-infected neonatal mice. Microbiotas from UDCA-treated neonatal mice ameliorated colitis and hindgut commensal bacterial damage compared with that of the microbiotas from the control and placebo mice, as evidenced by colonization of abundant bacteria, including Oscillospiraceae, Ruminococcaceae, Lachnospiraceae, and Clostridia_UCG-014, and upregulated SCFA production.ConclusionsThis study provided the first evidence that UDCA could confer diarrhea resistance in ESBL-EAEC-infected newborn dairy calves. UDCA blocked bacterial growth and invasion both in vitro and in vivo, alleviated commensal bacterial dysbiosis during ESBL-EAEC infection in neonatal mouse models of sepsis and colitis via the TGR5-NF-κB axis, and upregulated SCFA production in the hindgut digesta. Our findings provide insight into the UDCA-mediated remission of ESBL-EAEC infections and the potential role of UDCA as an antibiotic alternative. Video abstract.

Dataset Information

Inflammation-induced acid tolerance genes gadAB in luminal commensal Escherichia coli attenuate experimental colitis.

Publications

Inflammation-induced acid tolerance genes gadAB in luminal commensal Escherichia coli attenuate experimental colitis.

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