title: VSL#3 resets insulin signaling and protects against NASH and atherosclerosis in a model of genetic dyslipidemia and intestinal inflammation.
abstract: BACKGROUND
  Signals generated by the inflammed intestine are thought to contribute to metabolic derangement. The intestinal microbiota contributes to instructing the immune system beyond the intestinal wall and its modulation is a potential target for treating systemic disorders.
  
  
  OBJECTIVE
  To investigate the pathogenetic role of low grade intestinal inflammation in the development of steatohepatitis and atherosclerosis in a model of genetic dyslipidemia and to test the therapeutic potential of a probiotics intervention in protecting against development of these disorders.
  
  
  RESULTS
  ApoE(-/-) mice were randomized to receive vehicle or VSL#3, a mixture of eight probiotics, at the dose of 20×10(9) colony-forming units/kg/day for three months alone or in combination with 0.2% of dextran sulfate sodium (DSS) in drinking water. Administering DSS to ApoE(-/-) mice failed to induce signs and symptoms of colitis but increased intestinal permeability to dextran FITC and, while had no effect on serum lipids, increased the blood levels of markers of liver injury and insulin resistance. DSS administration associated with low level inflammation of intestinal and mesenteric adipose tissues, caused liver histopathology features of steatohepatitis and severe atherosclerotic lesions in the aorta. These changes were prevented by VSL#3 intervention. Specifically, VSL#3 reversed insulin resistance, prevented development of histologic features of mesenteric adipose tissue inflammation, steatohepatitis and reduced the extent of aortic plaques. Conditioned media obtained from cultured probiotics caused the direct transactivation of peroxisome proliferator-activated receptor-γ, Farnesoid-X-receptors and vitamin D receptor.
  
  
  CONCLUSIONS
  Low grade intestinal inflammation drives a transition from steatosis to steatohepatitis and worsens the severity of atherosclerosis in a genetic model of dyslipidemia. VSL#3 intervention modulates the expression of nuclear receptors, corrects for insulin resistance in liver and adipose tissues and protects against development of steatohepatitis and atherosclerosis.
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale, University of Perugia, Facoltà di Medicina e Chirurgia, Perugia, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mencarelli
authors.forename: Sabrina
authors.initials: S
authors.lastname: Cipriani
authors.forename: Barbara
authors.initials: B
authors.lastname: Renga
authors.forename: Angela
authors.initials: A
authors.lastname: Bruno
authors.forename: Claudio
authors.initials: C
authors.lastname: D'Amore
authors.forename: Eleonora
authors.initials: E
authors.lastname: Distrutti
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000517:prevention & control*; D050171:Dyslipidemias / Q000178:diet therapy*; D005234:Fatty Liver / Q000517:prevention & control*; D007249:Inflammation / Q000178:diet therapy*; D007333:Insulin Resistance / Q000502:physiology; D007422:Intestines / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019936:Probiotics / Q000627:therapeutic use*; D015398:Signal Transduction
chemical_list: D001057:Apolipoproteins E