title: Selective intestinal decontamination with norfloxacin enhances a regulatory T cell-mediated inflammatory control mechanism in cirrhosis.
abstract: Norfloxacin exerts immunomodulatory effects in cirrhosis beyond its bactericidal activity. We aimed at identifying the role of regulatory T (Treg) cells in the norfloxacin mechanism that compensates the inflammatory environment in cirrhosis.
  
  
  
  Consecutively admitted patients with cirrhosis and ascitic fluid (AF) with: spontaneous bacterial peritonitis (SBP), non-infected AF, and norfloxacin as secondary SBP prophylaxis (SID group). Tregs were defined by flow-cytometry as CD4+CD25+FoxP3+cells. Dendritic cells (DCs) were purified for co-stimulatory signalling evaluation and norfloxacin and IL-10 levels were measured in serum. Wildtype and recombination activating gene 1 (Rag1)-deficient mice with CCl4-induced cirrhosis were used for adoptive-transfer experiments using naïve CD4+T cells and Tregs.
  
  
  
  Eighty-four patients were included. Treg percentage was significantly increased in SID patients compared with SBP or non-infected AF patients. A positive correlation was observed between Tregs and serum norfloxacin and IL-10 levels. DCs from SID patients showed a significantly decreased expression of CD80 and CD86 compared with SBP and non-infected AF patients and correlated with norfloxacin levels. Modulation of co-stimulatory signalling by norfloxacin was not detected in Rag1-deficient mice and Rag1-deficient mice reconstituted with naïve T-cells. However, reconstitution with naïve T-cells and Tregs was associated with significantly downregulated CD80 and CD86 expression in the presence of norfloxacin. Norfloxacin immunomodulatory effect on IL-2 and IFN-gamma reduction and on the increase of IL-10 was significantly achieved only when the Tregs were restored in Rag1-deficient mice.
  
  
  
  These results provide a plausible mechanism for the immunomodulatory effects of norfloxacin in cirrhosis beyond its bactericidal effect.
authors.affiliation: CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.|Departamento Medicina Clínica, Universidad Miguel Hernández, San Juan de Alicante, Spain.
authors.forename: Oriol
authors.initials: O
authors.lastname: Juanola
authors.affiliation: CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Gómez-Hurtado
authors.affiliation: CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.|Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL-Fundación FISABIO), Alicante, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Zapater
authors.affiliation: CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Moratalla
authors.affiliation: Departamento Medicina Clínica, Universidad Miguel Hernández, San Juan de Alicante, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Caparrós
authors.affiliation: Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL-Fundación FISABIO), Alicante, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Piñero
authors.affiliation: CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.|Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL-Fundación FISABIO), Alicante, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: González-Navajas
authors.affiliation: CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Giménez
authors.affiliation: Digestive Disease Institute, Cleveland Clinic, Abu Dhabi, United Arab Emirates.
authors.forename: José
authors.initials: J
authors.lastname: Such
authors.affiliation: CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.|Departamento Medicina Clínica, Universidad Miguel Hernández, San Juan de Alicante, Spain.|Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL-Fundación FISABIO), Alicante, Spain.
authors.forename: Rubén
authors.initials: R
authors.lastname: Francés
mesh_terms: D019264:Adoptive Transfer; D000368:Aged; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D001424:Bacterial Infections / Q000188:drug therapy*; D018988:Bacterial Translocation / Q000187:drug effects*; D003713:Dendritic Cells / Q000187:drug effects; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000097:blood; D007376:Interleukin-2 / Q000097:blood; D008103:Liver Cirrhosis / Q000150:complications* / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009643:Norfloxacin / Q000627:therapeutic use*; D010538:Peritonitis / Q000188:drug therapy* / Q000382:microbiology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*
chemical_list: D000900:Anti-Bacterial Agents; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D051858:Forkhead Transcription Factors; C508609:IL10 protein, human; C508594:IL2 protein, human; D007376:Interleukin-2; D016753:Interleukin-10; D009643:Norfloxacin
keywords: bacterial translocation; cirrhosis; norfloxacin; regulatory T cells