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New findings about an ‘old’ drug: Immunomodulatory effects of norfloxacin in cirrhosis

2014; Elsevier BV; Volume: 61; Issue: 4 Linguagem: Inglês

10.1016/j.jhep.2014.06.028

1600-0641

Thierry Gustot,

Organ Transplantation Techniques and Outcomes

Role of interleukin 10 in norfloxacin prevention of luminal free endotoxin translocation in mice with cirrhosisJournal of HepatologyVol. 61Issue 4PreviewThe process by which bacteria exit the intestinal lumen, access the mesenteric lymph nodes (MLN) and colonize other organs is known as bacterial translocation (BT) [1], and is considered as the key spontaneous bacterial peritonitis (SBP)-leading mechanism in patients with advanced cirrhosis. However, not only viable bacteria but also their products translocate and induce a similar inflammatory response to that developed against SBP in the absence of an overt infection [2]. The presence of these enteric bacterial products such as DNA and lipopolysaccharide (LPS) in the bloodstream represents a threat that may compromise patients’ clinical outcome, as reported in studies revealing the association between their presence and a marked hemodynamic derangement [3,4], and others identifying LPS-binding protein and bacterial-DNA as independent predictors of severe bacterial infections [5] and mortality [6], respectively. Full-Text PDF An interesting study by Gomez-Hurtado et al. in this month’s issue of the Journal of Hepatology highlights new effects of norfloxacin on gut-associated lymphatic tissue (GALT) and translocation of bacterial products in murine models of cirrhosis [[1]Gomez-Hurtado I. Moratalla A. Moya-Perez A. Piero G. Zapater P. Gonzalez-Navajas J.M. et al.Role of interleukin 10 in norfloxacin prevention of luminal free endotoxin translocation in mice with cirrhosis.J Hepatol. 2014; 61: 799-808Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar]. Norfloxacin, launched in 1980, was the first commercially available fluoroquinolone. The beneficial role of norfloxacin in cirrhosis has been clearly demonstrated in several studies. Oral norfloxacin administration (400 mg/day) improves the circulatory derangement observed in cirrhotic patients, which is characterized by high cardiac output and low systemic vascular resistance [2Rasaratnam B. Kaye D. Jennings G. Dudley F. Chin-Dusting J. The effect of selective intestinal decontamination on the hyperdynamic circulatory state in cirrhosis. A randomized trial.Ann Intern Med. 2003; 139: 186-193Crossref PubMed Scopus (192) Google Scholar, 3Albillos A. de la Hera A. Gonzalez M. Moya J.L. Calleja J.L. Monserrat J. et al.Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement.Hepatology. 2003; 37: 208-217Crossref PubMed Scopus (364) Google Scholar]. Norfloxacin decreases the recurrence of spontaneous bacterial peritonitis (SBP) from ∼70% to 20% after a first episode (secondary prophylaxis) [[4]Ginès P. Rimola A. Planas R. Vargas V. Marco F. Almela M. et al.Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial.Hepatology. 1990; 12: 716-724Crossref PubMed Scopus (525) Google Scholar]. Norfloxacin in patients with low protein ascitic levels (<1.5 g/dl) and advanced cirrhosis (Child-Pugh score ⩾9 points with serum bilirubin level ⩾3 mg/dl or impaired renal function (serum creatinine level ⩾1.2 mg/dl, blood urea nitrogen level ⩾25 mg/dl, or serum sodium level ⩽130 mEq/L)) without prior SBP episode reduces the probability of SBP (primary prophylaxis) and hepatorenal syndrome (HRS) and improves 3-month survival [[5]Fernández J. Navasa M. Planas R. Montoliu S. Monfort D. Soriano G. et al.Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis.Gastroenterology. 2007; 133: 818-824Abstract Full Text Full Text PDF PubMed Scopus (543) Google Scholar]. The justification for norfloxacin administration in cirrhosis is based on its antibiotic effects on gut microbiota. Indeed, cirrhosis is associated with a pro-inflammatory process characterized by increased circulating cytokines (tumour necrosis factor (TNF)-α and interleukin (IL)-6) and a primed state of peripheral blood mononuclear cells [6Khoruts A. Stanke L. McClain C.J. Logan G. Allen J.I. Circulating tumor necrosis factor, interleukin-1 and interleukin-6 concentrations in chronic alcoholic patients.Hepatology. 1991; 13: 267-276Crossref PubMed Scopus (507) Google Scholar, 7Devière J. Content J. Denys C. Vandenbussche P. Schandene L. Wybran J. et al.Excessive in vitro bacterial lipopolysaccharide-induced production of monokines in cirrhosis.Hepatology. 1990; 11: 628-634Crossref PubMed Scopus (176) Google Scholar]. Bacterial translocation (BT) seems to be the main trigger of this systemic inflammation. Viable bacteria have been frequently isolated from mesenteric lymph nodes, and bacterial products, such as lipopolysaccharides (LPS) and bacterial DNA, have been detected in the blood of patients with decompensated cirrhosis [8Cicera I. Bauer T.M. Navasa M. Vila J. Grande L. Taura P. et al.Bacterial translocation of enteric organisms in patients with cirrhosis.J Hepatol. 2001; 34: 32-37Abstract Full Text PDF PubMed Google Scholar, 9Guarner C. Soriano G. Tomas A. Buldena O. Novella M.T. Balanzo J. et al.Increased serum nitrite and nitrate levels in patients with cirrhosis: relationship to endotoxemia.Hepatology. 1993; 18: 1139-1143Crossref PubMed Scopus (476) Google Scholar, 10Such J. Frances R. Munoz C. Zapater P. Casellas J.A. Cifuentes A. et al.Detection and identification of bacterial DNA in patients with cirrhosis and culture-negative nonneutrocytic ascites.Hepatology. 2002; 36: 135-141Crossref PubMed Scopus (238) Google Scholar]. Increased BT is permitted by increased intestinal permeability which is partially due to alterations in tight junction (TJ) proteins that are present in the advanced stages of cirrhosis [[11]Assimakopoulos S.F. Uncovering the molecular events associated with increased intestinal permeability in liver cirrhosis: the pivotal role of enterocyte tight junctions and future perspectives.J Hepatol. 2013; 59: 1144-1146Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar]. Intestinal bacterial overgrowth and dysbiosis (qualitative changes in the microbiome) observed in cirrhosis also contribute to BT [12Pande C. Kumar A. Sarin S.K. Small-intestinal bacterial overgrowth in cirrhosis is related to the severity of liver disease.Aliment Pharmacol Ther. 2009; 29: 1273-1281Crossref PubMed Scopus (117) Google Scholar, 13Bajaj J.S. Heuman D.M. Hylemon P.B. Sanyal A.J. White M.B. Monteith P. et al.Altered profile of human gut microbiome is associated with cirrhosis and its complications.J Hepatol. 2014; 60: 940-947Abstract Full Text Full Text PDF PubMed Scopus (636) Google Scholar]. On the other hand, gut inflammation observed in cirrhosis and intestinal macrophages producing nitric oxide and IL-6 might disrupt the intestinal barrier and contribute to bacterial translocation, creating a vicious cycle [[14]Du Plessis J. Vanheel H. Janssen C.E. Roos L. Slavik T. Stivaktas P.I. et al.Activated intestinal macrophages in patients with cirrhosis release NO and IL-6 that may disrupt intestinal barrier function.J Hepatol. 2013; 58: 1125-1132Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar]. Several years ago, Albillos et al. demonstrated that administration of norfloxacin in order to achieve selective intestinal gut decontamination reduces plasma levels of TNF-α, IL-6, and other surrogate markers of BT (LPS-binding protein and soluble CD14) in cirrhotic patients with ascites [[3]Albillos A. de la Hera A. Gonzalez M. Moya J.L. Calleja J.L. Monserrat J. et al.Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement.Hepatology. 2003; 37: 208-217Crossref PubMed Scopus (364) Google Scholar]. Prolonged antibiotic administration leads to the rapid emergence of resistant bacteria. Epidemiological studies have clearly demonstrated that long-term norfloxacin administration increases the risk of infections caused by quinolone-resistant, trimethoprim-sulfamethoxazole-resistant and extended-spectrum β-lactamase (ESBL)-producing strains in cirrhosis [15Fernández J. Navasa M. Gomez J. Colmenero J. Vila J. Arroyo V. et al.Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis.Hepatology. 2002; 35: 140-148Crossref PubMed Scopus (763) Google Scholar, 16Fernández J. Acevedo J. Castro M. Garcia O. de Lope C.R. Roca D. et al.Prevalence and risk factors of infections by multiresistant bacteria in cirrhosis: a prospective study.Hepatology. 2012; 55: 1551-1561Crossref PubMed Scopus (425) Google Scholar]. This has a major impact on the natural outcome of cirrhosis because infections with multi-resistant bacteria are associated with higher mortality rates than those with susceptible bacteria. Despite high rates of quinolone-resistant bacteria reported in Spain during the same period of a primary prophylaxis trial, norfloxacin maintained its efficacy in SBP and HRS prevention suggesting a potential non-antibiotic effect [[5]Fernández J. Navasa M. Planas R. Montoliu S. Monfort D. Soriano G. et al.Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis.Gastroenterology. 2007; 133: 818-824Abstract Full Text Full Text PDF PubMed Scopus (543) Google Scholar]. Norfloxacin exerts anti-bacterial effects by inhibiting bacterial DNA gyrase and topoisomerase IV [[17]Hooper D.C. Wolfson J.S. Mechanisms of quinolone action and bacterial killing.in: Hooper D.C. Wolfson J.S. Quinolone antibacterial agents. 2nd ed. American Society for Microbiology, Washington DC1993: 53-75Google Scholar]. Besides their anti-bacterial effects, quinolones have immunomodulatory activities (inhibitory effects on cytokines, chemokines, and other components of the immune system) through incompletely understood mechanisms [[18]Dalhoff A. Immunomodulatory activities of fluoroquinolones.Infection. 2005; 33: 55-70Crossref PubMed Scopus (142) Google Scholar]. These mechanisms include effects on intracellular cyclic AMP and phosphodiesterases, several transcription factors such as NFκB, AP1, and NFAT, and topoisomerase II. In cirrhotic patients receiving oral norfloxacin, these effects are suggested by a study demonstrating an inverse correlation between serum norfloxacin and pro-inflammatory cytokine (TNF-α, IL-12, and interferon (IFN)-γ) concentrations [[19]Zapater P. Cano R. Llanos L. Ruiz-Alcaraz A.J. Pascual S. Barquero C. et al.Norfloxacin modulates the inflammatory response and directly affects neutrophils in patients with decompensated cirrhosis.Gastroenterology. 2009; 137: 1669-1679Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar]. Moreover, norfloxacin-induced down-regulation of inflammation seems to be due to an induction of IL-10 and heme oxygenase (HO)-1 [[20]Gomez-Hurtado I. Zapater P. Bellot P. Pascual S. Perez-Mateo M. Such J. et al.Interleukin-10-mediated heme oxygenase 1-induced underlying mechanism in inflammatory down-regulation by norfloxacin in cirrhosis.Hepatology. 2011; 53: 935-944Crossref PubMed Scopus (31) Google Scholar]. In the current issue of the Journal of Hepatology, Gomez-Hurtado et al. reinforce the concept that IL-10 is involved in the beneficial effects of norfloxacin in cirrhosis through the use of IL-10-deficient mice [[1]Gomez-Hurtado I. Moratalla A. Moya-Perez A. Piero G. Zapater P. Gonzalez-Navajas J.M. et al.Role of interleukin 10 in norfloxacin prevention of luminal free endotoxin translocation in mice with cirrhosis.J Hepatol. 2014; 61: 799-808Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar]. In murine models of cirrhosis (CCl4 and bile duct ligation models), the administration of norfloxacin was associated with a reduction of serum and mesenteric lymph node (MLN) LPS concentrations, gut permeability to LPS, and increased expression of TJ proteins (TJP-1 and occludin) responsible for gut barrier integrity. In IL-10-deficient mice, the effects of norfloxacin were not observed and supplementation of IL-10 to these mice restored norfloxacin action, elegantly supporting an IL-10-dependent mechanism. In in vitro experiments, norfloxacin directly inhibited LPS-induced TNF-α production by intestinal mononuclear cells through an IL-10-dependent pathway. On the other hand, norfloxacin reduced spontaneous and induced BT in wild-type and IL-10-deficient mice. Taken together, these data suggest that norfloxacin exerts its effects through a reduction of bacterial overgrowth resulting in decreased passage of viable bacteria from the gut lumen to MLNs and through IL-10-mediated inhibition of intestinal inflammation, resulting in improvement of gut barrier integrity and reduction of bacterial product translocation. These findings highlight two important points. First, in clinical practice, we challenge daily the utility of norfloxacin prophylaxis in cirrhotic patients carrying quinolone-resistant bacteria or in patients who had a previous SBP episode on norfloxacin. At this time, we have no evidence that norfloxacin is ineffective in these specific cases and the non-antibiotic effects of quinolone treatment could be useful for these patients. Secondly, studying the mechanism of action of quinolones on the immune system and gut barrier could open areas of research aimed at the design of new non-antibiotic therapeutic options. Non-antibiotic strategies are clearly needed to limit the emergence of multi-resistant bacteria in a population susceptible to infections. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.