Rifaximin in nonalcoholic fatty liver disease: hit multiple targets with a single shot Ahmed Abdel-Razik a , Nasser Mousa a , Walaa Shabana a , Mohamed Refaey g , Rasha Elzehery b , Rania Elhelaly b , Khaled Zalata c , Mostafa Abdelsalam d , Ahmed A. Eldeeb d , Mahmoud Awad e , Ayman Elgamal h , Ahmed Attia i , Niveen El-Wakeel f and Waleed Eldars f Background/Aims The pathogenesis of nonalcoholic fatty liver disease (NAFLD) may include increased insulin resistance, upregulation of proinflammatory cytokines, lipopolysaccharide, and BMI. Rifaximin is a minimally absorbable antibiotic that might act against a broad spectrum of gut bacteria. This study aimed to investigate the effects of rifaximin on NAFLD. Patients and methods Fifty participants with biopsy-proven nonalcoholic steatohepatitis (NASH) were registered in this multicentric, double-blind, randomized, placebo-controlled study. BMI, alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase, lipid profile, serum endotoxin, homeostatic model assessment, toll-like receptor-4, interleukin-10 (IL-10), IL-6, tumor necrosis factor-α, and cytokeratin-18 (CK-18) levels were evaluated at baseline and at 1, 3, and 6 months of rifaximin therapy (1100 mg/day). Results Patients were randomized into two groups (rifaximin group; n = 25 and placebo group; n = 25). After 6 months of rifaximin therapy, patients with NASH showed a significant reduction in homeostatic model assessment, alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase, endotoxin, toll-like receptor-4, IL-6, tumor necrosis factor-α, CK-18, and NAFLD-liver fat score (all P < 0.05), but no changes in the lipid profile; moreover, there was a mild nonstatistically significant reduction of BMI. However, in the placebo group, there was no significant difference in these variables at baseline and after therapy. Conclusion Rifaximin therapy appears to be effective and safe in modifying NASH through reduction of serum endotoxin and improvement of insulin resistance, proinflammatory cytokines, CK-18, and NAFLD-liver fat score. Eur J Gastroenterol Hepatol 00:000–000 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. Introduction Nonalcoholic fatty liver disease (NAFLD) has become the most widespread nonviral hepatic disease, with an esti- mated prevalence of 6–30% in the general population, affecting more than one billion individuals, in part owing to the increasing prevalence of obesity and related meta- bolic risk factors [1,2]. In the USA, chronic liver disease related to NAFLD is the third leading etiology for liver transplantation [3]. In NAFLD, steatosis can progress to nonalcoholic steatohepatitis (NASH) with fibrosis. Moreover, these advanced pathological characteristics in fibrosis and inflammation may lead to end-stage liver disease, liver cirrhosis, and hepatocellular carcinoma development [4]. The NAFLD pathogenesis may include ‘multiple hits,’ involving oxidative stress, gut endotoxins, lipotoxicity [insulin resistance (IR)], and innate immune responses by toll-like receptors (TLRs) that intercede hepatic inflam- mation [5]. The gut microbiota (GM) has two dominant phyla of bacteria, the Bacteroidetes and Firmicutes, that have been viable in the metabolic syndrome development [6]. In patients with obesity and metabolic syndrome, the equili- brium of these two microorganisms is disturbed, evidenced by many reports showing a reduction of Bacteroidetes and an increased level of Firmicutes, compared with lean par- ticipants [6–8]. Increased fermentation end products such as short-chain fatty acids may be because of more Firmicutes. These short-chain fatty acids play a pivotal function in appetite regulation by acting as signaling bio- markers and diffusing passively into the portal circulation [6,9]. GM may play a major function in the pathogenesis of NAFLD. Surprisingly, overgrowth of small intestinal bac- teria may be observed in patients with NALFD. Gut bac- teria derived-endotoxins and lipopolysaccharides may stimulate liver fibrosis and hepatic injury. The role of GM in the pathogenesis of many hepatic diseases and NAFLD is quickly evolving [10]. Increased intestinal permeability and altered GM composition enhance higher translocation Departments of a Tropical Medicine, b Clinical Pathology, c Pathology, d Internal Medicine, Nephrology and Dialysis Unit, e Internal Medicine, f Medical Microbiology and Immunology, Faculty of Medicine, Mansoura University, Mansoura City, g Department of Tropical Medicine, Faculty of Medicine, Zagazig University, Zagazig City, h Department of Tropical Medicine and i Department of Hepatology, National Liver Institute, Menoufia University, Menoufia City, Egypt Correspondence to Ahmed Abdel-Razik, MD, Department of Tropical Medicine, Faculty of Medicine, Mansoura University, Elgomhoria Street, 35516 Mansoura, Egypt Tel: + 20 100 790 1009; fax: + 20 502 489 383; e-mail: ahmedabdelrazik76@gmail.com Received 1 June 2018 Accepted 3 July 2018 European Journal of Gastroenterology & Hepatology 2018, 00:000–000 Keywords: bacterial endotoxin, gut microbiota, insulin resistance, lipopolysaccharides, rifaximin ’ Original study 0954-691X Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MEG.0000000000001232 1 Copyright r 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.