Isabel Gómez-Hurtado1, Alba Moratalla1, Ángela Moya-Pérez2, Gloria Peiró3, Pedro Zapater4, José M González-Navajas1, Paula Giménez5, José Such6, Yolanda Sanz2, Rubén Francés7. 1. CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Unidad Hepática, Hospital General Universitario de Alicante, Alicante, Spain. 2. Ecología Microbiana y Nutrición, Instituto de Agroquímica y Tecnología de Alimentos, Consejo Superior de Investigaciones Científicas (IATA-CSIC), Valencia, Spain. 3. Servicio de Anatomía Patológica, Hospital General Universitario de Alicante, Alicante, Spain. 4. CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Unidad de Farmacología Clínica, Hospital General Universitario de Alicante, Alicante, Spain. 5. CIBERehd, Instituto de Salud Carlos III, Madrid, Spain. 6. CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Departamento de Medicina Clínica, Facultad de Medicina, Universidad Miguel Hernández, San Juan de Alicante, Spain. 7. CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Unidad Hepática, Hospital General Universitario de Alicante, Alicante, Spain; Departamento de Medicina Clínica, Facultad de Medicina, Universidad Miguel Hernández, San Juan de Alicante, Spain. Electronic address: frances_rub@gva.es.
Abstract
BACKGROUND & AIMS: Bacterial endotoxin is present in patients with advanced cirrhosis and can induce an immunogenic response without an overt infection. Norfloxacin is a gram-negative bactericidal drug able to maintain low endotoxin levels and stimulate IL-10 production. We aimed at investigating the role of IL-10 in decreasing endotoxin absorption in cirrhotic mice treated with norfloxacin. METHODS: Cirrhosis was induced by carbon tetrachloride or bile duct ligation in wild type and IL10-deficient mice with or without norfloxacin prior to an intragastrical administration of E. coli, K. pneumonia or E. faecalis. Spontaneous and induced bacterial translocation, free endotoxin and cytokine levels were evaluated in mesenteric lymph nodes. Intestinal permeability was followed by fluorimetry and barrier integrity markers were measured in disrupted intestinal samples. The inflammatory-modulating mechanism was characterized in purified intestinal mononuclear cells. RESULTS: Norfloxacin reduced spontaneous and induced MLN positive-cultures in wild type and IL-10-deficient animals. However, reduction of free endotoxin levels was associated with norfloxacin in wild type but not in IL-10-deficient mice. Wild type but not IL-10-deficient mice treated with norfloxacin significantly normalized intestinal permeability and improved gut barrier integrity markers. The toll-like receptor 4-mediated pro-inflammatory milieu was modulated by norfloxacin in a concentration-dependent manner in cultured intestinal mononuclear cells of wild type mice but not of IL-10-deficient mice. The restoration of IL-10 levels in IL-10-deficient animals reactivated the norfloxacin effect on inflammatory-modulation, gut barrier permeability, and luminal endotoxin absorption. CONCLUSION: Norfloxacin not only reduces gram-negative intestinal flora but also participates in an IL-10-driven modulation of gut barrier permeability, thus reducing luminal free endotoxin absorption in experimental cirrhosis.
BACKGROUND & AIMS: Bacterial endotoxin is present in patients with advanced cirrhosis and can induce an immunogenic response without an overt infection. Norfloxacin is a gram-negative bactericidal drug able to maintain low endotoxin levels and stimulate IL-10 production. We aimed at investigating the role of IL-10 in decreasing endotoxin absorption in cirrhotic mice treated with norfloxacin. METHODS:Cirrhosis was induced by carbon tetrachloride or bile duct ligation in wild type and IL10-deficient mice with or without norfloxacin prior to an intragastrical administration of E. coli, K. pneumonia or E. faecalis. Spontaneous and induced bacterial translocation, free endotoxin and cytokine levels were evaluated in mesenteric lymph nodes. Intestinal permeability was followed by fluorimetry and barrier integrity markers were measured in disrupted intestinal samples. The inflammatory-modulating mechanism was characterized in purified intestinal mononuclear cells. RESULTS:Norfloxacin reduced spontaneous and induced MLN positive-cultures in wild type and IL-10-deficient animals. However, reduction of free endotoxin levels was associated with norfloxacin in wild type but not in IL-10-deficient mice. Wild type but not IL-10-deficient mice treated with norfloxacin significantly normalized intestinal permeability and improved gut barrier integrity markers. The toll-like receptor 4-mediated pro-inflammatory milieu was modulated by norfloxacin in a concentration-dependent manner in cultured intestinal mononuclear cells of wild type mice but not of IL-10-deficient mice. The restoration of IL-10 levels in IL-10-deficient animals reactivated the norfloxacin effect on inflammatory-modulation, gut barrier permeability, and luminal endotoxin absorption. CONCLUSION:Norfloxacin not only reduces gram-negative intestinal flora but also participates in an IL-10-driven modulation of gut barrier permeability, thus reducing luminal free endotoxin absorption in experimental cirrhosis.
Authors: Georgios I Tsiaoussis; Stelios F Assimakopoulos; Athanassios C Tsamandas; Christos K Triantos; Konstantinos C Thomopoulos Journal: World J Hepatol Date: 2015-08-18
Authors: Piero Portincasa; Leonilde Bonfrate; Mohamad Khalil; Maria De Angelis; Francesco Maria Calabrese; Mauro D'Amato; David Q-H Wang; Agostino Di Ciaula Journal: Biomedicines Date: 2021-12-31
Authors: Agostino Di Ciaula; Jacek Baj; Gabriella Garruti; Giuseppe Celano; Maria De Angelis; Helen H Wang; Domenica Maria Di Palo; Leonilde Bonfrate; David Q-H Wang; Piero Portincasa Journal: J Clin Med Date: 2020-08-14 Impact factor: 4.241