Selective intestinal decontamination with norfloxacin enhances a regulatory T cell-mediated inflammatory control mechanism in cirrhosis

• Published in: Liver international 2016-12, Vol.36 (12), p.1811-1820
• Main Authors: Juanola, Oriol, Gómez-Hurtado, Isabel, Zapater, Pedro, Moratalla, Alba, Caparrós, Esther, Piñero, Paula, González-Navajas, José M., Giménez, Paula, Such, José, Francés, Rubén
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Aged; Animals; Anti-Bacterial Agents - therapeutic use; B7-1 Antigen - metabolism; B7-2 Antigen - metabolism; Bacterial Infections - drug therapy; bacterial translocation; Bacterial Translocation - drug effects; cirrhosis; Dendritic Cells - drug effects; Female; Forkhead Transcription Factors - metabolism; Humans; Interleukin-10 - blood; Interleukin-2 - blood; Liver Cirrhosis - complications; Liver Cirrhosis - microbiology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; norfloxacin; Norfloxacin - therapeutic use; Peritonitis - drug therapy; Peritonitis - microbiology; regulatory T cells; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology
• ISSN: 1478-3223; 1478-3231
• DOI: 10.1111/liv.13172

Background & Aims 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. Patients & Methods 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. Results 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. Conclusions These results provide a plausible mechanism for the immunomodulatory effects of norfloxacin in cirrhosis beyond its bactericidal effect.