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Cronobacter sakazakii is a common foodborne pathogen that can tolerate various stress conditions. Acidic environment is a common stress condition encountered by bacteria in food processing and gastrointestinal digestion, including both inorganic and organic acids. In order to elucidate the Acid Tolerance Response (ATR) of C. sakazakii, we performed high-throughput RNA-seq to compare gene expression under hydrochloric acid and citric acid stresses. In this study, 107 differentially expressed genes (DEGs) were identified in both acids, of which 85 DEGs were functionally related to the regulation of acid tolerance. Multiple layers of mechanisms may be applied by C. sakazakii in response to acid stress: Firstly, in order to reduce excessive intracellular protons, C. sakazakii pumps them out through trans-membrane proteins or consumes them through metabolic reactions. Secondly, under acidic conditions, a large amount of reactive oxygen species and hydroxyl radicals accumulate in the cells, resulting in oxidative damage. C. sakazakii protects cells by up-regulating the antioxidant stress genes such as soxS and madB. Thirdly, C. sakazakii chooses energy efficient metabolic pathways to reduce energy consumption and maintain necessary processes. Finally, genes involved in chemotaxis and motility were differentially expressed to respond to different acidic conditions. This study systematically analyzed the acid-resistant mechanism of C. sakazakii under the stress of organic and inorganic acids, and provided a theoretical basis for better control of its contamination in food., Competing Interests: Declaration of Competing Interest The authors declared that there is no conflict of interest., (Copyright © 2019 Elsevier Ltd. All rights reserved.)