title: Shift towards pro-inflammatory intestinal bacteria aggravates acute murine colitis via Toll-like receptors 2 and 4.
abstract: BACKGROUND
  Gut bacteria trigger colitis in animal models and are suspected to aggravate inflammatory bowel diseases. We have recently reported that Escherichia coli accumulates in murine ileitis and exacerbates small intestinal inflammation via Toll-like receptor (TLR) signaling.
  
  
  RESULTS
  Because knowledge on shifts in the intestinal microflora during colitis is limited, we performed a global survey of the colon flora of C57BL/10 wild-type (wt), TLR2(-/-), TLR4(-/-), and TLR2/4(-/-) mice treated for seven days with 3.5% dextrane-sulfate-sodium (DSS). As compared to wt animals, TLR2(-/-), TLR4(-/-), and TLR2/4(-/-) mice displayed reduced macroscopic signs of acute colitis and the amelioration of inflammation was associated with reduced IFN-gamma levels in mesenteric lymph nodes, lower amounts of neutrophils, and less FOXP3-positive T-cells in the colon in situ. During acute colitis E. coli increased in wt and TLR-deficient mice (P<0.05), but the final numbers reached were significantly lower in TLR2(-/-), TLR4(-/-) and TLR2/4(-/-) animals, as compared to wt controls (P<0.01). Concentrations of Bacteroides/ Prevotella spp., and enterococci did not increase during colitis, but their numbers were significantly reduced in the colon of DSS-treated TLR2/4(-/-) animals (P<0.01). Numbers of lactobacilli and clostridia remained unaffected by colitis, irrespective of the TLR-genotype of mice. Culture-independent molecular analyses confirmed the microflora shifts towards enterobacteria during colitis and showed that the gut flora composition was similar in both, healthy wt and TLR-deficient animals.
  
  
  CONCLUSIONS
  DSS-induced colitis is characterized by a shift in the intestinal microflora towards pro-inflammatory Gram-negative bacteria. Bacterial products exacerbate acute inflammation via TLR2- and TLR4-signaling and direct the recruitment of neutrophils and regulatory T-cells to intestinal sites. E. coli may serve as a biomarker for colitis severity and DSS-induced barrier damage seems to be a valuable model to further identify bacterial factors involved in maintaining intestinal homeostasis and to test therapeutic interventions based upon anti-TLR strategies.
authors.affiliation: Institut für Mikrobiologie und Hygiene, Charité - Universitätsmedizin Berlin, Charité Campus Mitte, Berlin, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Heimesaat
authors.forename: André
authors.initials: A
authors.lastname: Fischer
authors.forename: Britta
authors.initials: B
authors.lastname: Siegmund
authors.forename: Andreas
authors.initials: A
authors.lastname: Kupz
authors.forename: Julia
authors.initials: J
authors.lastname: Niebergall
authors.forename: David
authors.initials: D
authors.lastname: Fuchs
authors.forename: Hannah-Katharina
authors.initials: HK
authors.lastname: Jahn
authors.forename: Marina
authors.initials: M
authors.lastname: Freudenberg
authors.forename: Christoph
authors.initials: C
authors.lastname: Loddenkemper
authors.forename: Arvind
authors.initials: A
authors.lastname: Batra
authors.forename: Hans-Anton
authors.initials: HA
authors.lastname: Lehr
authors.forename: Oliver
authors.initials: O
authors.lastname: Liesenfeld
authors.forename: Michael
authors.initials: M
authors.lastname: Blaut
authors.forename: Ulf B
authors.initials: UB
authors.lastname: Göbel
authors.forename: Ralf R
authors.initials: RR
authors.lastname: Schumann
authors.forename: Stefan
authors.initials: S
authors.lastname: Bereswill
mesh_terms: D000208:Acute Disease; D000818:Animals; D001424:Bacterial Infections / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D003092:Colitis / Q000382:microbiology* / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D003106:Colon / Q000276:immunology / Q000382:microbiology*; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000235:genetics / Q000382:microbiology* / Q000517:prevention & control; D015212:Inflammatory Bowel Diseases / Q000150:complications / Q000235:genetics / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000502:physiology; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000502:physiology*
chemical_list: C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4