Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Efficacy of rifaximin on circulating endotoxins and cytokines in patients with nonalcoholic fatty liver disease Venkatanarayana Gangarapu a , Ali Tüzün Ince a , Birol Baysal a , Yusuf Kayar a , Ulkan Kılıç b , Özlem Gök b , Ömer Uysal c and Hakan Şenturk a Objective Recent studies have suggested that endotoxin-induced cytokines play an important role in nonalcoholic fatty liver disease (NAFLD). Rifaximin is a nonabsorbable antibiotic that might act on Gram-negative bacteria, thereby inhibiting endotoxin proinflammatory cytokine production in patients with NAFLD. Our aim was to investigate the efficacy of rifaximin on NAFLD. Methods Forty-two patients with biopsy-proven NAFLD [15 steatosis, 27 nonalcoholic steatohepatitis (NASH)] were included in this prospective, open-label, observational cohort study. BMI and serum aspartate aminotransferase, alanine aminotransferase (ALT), gamma glutamyl transferase, lipid profile, ferritin, C-reactive protein, glucose, insulin, homeostatic model assessment as well as endotoxin, serum Toll-like receptor 4 (TlR4), interleukin-1α (IL-1α), IL-6, IL-10, IL-12, and tumor necrosis factor-α (TNF-α) levels were measured before and after a 28-day administration of rifaximin (1200 mg/daily). Results were analyzed using nonparametric Wilcoxon signed-rank tests. Results A mild reduction in the mean BMI (32.3 ± 6.9 vs. 31.9 ± 6.8, P = 0.02) and a significant reduction in the endotoxin (0.9 ± 0.34 vs. 0.8 ± 0.13, P = 0.03) and IL-10 (4.08 ± 0.9 vs. 3.73 ± 0.7, P = 0.006) levels in the NASH group were noted. A significant reduction was observed in serum aspartate aminotransferase (50.4 ± 39 vs. 33 ± 14, P = 0.01), ALT (72 ± 48 vs. 45.2 ± 26.3, P = 0.0001), gamma glutamyl transferase (52 ± 33 vs. 41.2 ± 21.1, P = 0.02), LDL (137 ± 34 vs. 127 ± 27.5, P = 0.03), and ferritin (142 ± 214 vs. 89.3 ± 123, P = 0.0001) in the NASH group, but only in ALT (50.4 ± 26 vs. 35.5 ± 23.25, P = 0.01), and ferritin (73.6 ± 83 vs. 55 ± 76, P = 0.004) levels decreased significantly in the steatosis group. Treatment with rifaximin did not exert a significant effect on serum levels of TLR-4, IL-1, IL-6, IL-12, or TNF-α in either group. Conclusion In NAFLD and especially in NASH, short-term administration of rifaximin appears to be safe and effective. Eur J Gastroenterol Hepatol 27:840–845 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Introduction Nonalcoholic fatty liver disease (NAFLD) is a frequent liver disease, and 20% of patients with NAFLD develop chronic inflammation and fibrosis, which can progress to nonalco- holic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma [1–5]. The pathogenesis of NAFLD involves multiple hits, including lipotoxicity, oxidative stress, gut- originated endotoxins, and innate immune responses through Toll-like receptors (TLRs) that mediate inflammation [6]. Currently, NAFLD is managed primarily by a healthy diet and lifestyle modifications, which are difficult to sustain in the long term, and no specific treatment has been proven to be effective for NASH. A controversial new mechanism has been proposed recently for the pathogenesis of fatty liver: gut microbiota (GM) was proposed as an environmental factor that might play a causal role in the regulation of body weight and energy homeostasis [7–9]. The gut microbiome comprises 100 trillion bacteria. The dominating phyla are Firmicutes and Bacteroidetes (which comprise 90% of the GM) [10]. In obese individuals and patients with NASH, the ratio shifts in favor of a relatively higher abundance of Firmicutes compared with Bacteroidetes [11,12]. In addi- tion, a higher production of fermented colonic end pro- ducts, such as butyrate, acetate, and propionate, have been found in fecal samples of obese individuals [13], and similarly, higher fecal acetate concentrations in patients with NASH [14]. Altered GM composition and increased intestinal permeability enable a higher translocation of endotoxins [also known as lipopolysaccharides (LPS)] into the portal circulation. This leads to activation of CD14 and TLR-4, which induce an inflammatory response [15]. Several studies have suggested that LPS-induced cytokines play an important role in steatohepatitis [16]. Whereas T-helper 1 (Th1) cells produce proinflammatory cytokines interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-12 (IL-12), T-helper 2 (Th2) cells produce anti-inflammatory Departments of a Gastroenterology, b Medical Biology, Faculty of Medicine, Istanbul Medipol University and c Department of Biostatistics, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey Correspondence to Hakan Şentürk, MD, Gastroenterology Clinic of Bezmialem Vakif University, Vatan Caddesi, Adnan Menderes Bulvarı, Fatih 34093, Istanbul, Turkey Tel: + 90 532 3128340; fax: + 90 212 5332326; e-mail: drhakansenturk@yahoo.com Received 3 February 2015 Accepted 25 February 2015 European Journal of Gastroenterology & Hepatology 2015, 27:840–845 Keywords: endotoxins, gut microbiota, lipopolysaccharides, nonalcoholic fatty liver disease, rifaximin ’ Original article 0954-691X Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MEG.0000000000000348 840