Research Article: Enterobacter cloacae administration induces hepatic damage and subcutaneous fat accumulation in high-fat diet fed mice

Date Published: May 30, 2018

Publisher: Public Library of Science

Author(s): Anniina Keskitalo, Eveliina Munukka, Raine Toivonen, Maija Hollmén, Heikki Kainulainen, Pentti Huovinen, Sirpa Jalkanen, Satu Pekkala, Jonathan M. Peterson.


Accumulating evidence indicates that gut microbiota plays a significant role in obesity, insulin resistance and associated liver disorders. Family Enterobacteriaceae and especially Enterobacter cloacae strain B29 have been previously linked to obesity and hepatic damage. The underlying mechanisms, however, remain unclear. Therefore, we comprehensively examined the effects of E. cloacae subsp. cloacae (ATCC® 13047™) administration on host metabolism of mice fed with high-fat diet (HFD). C57BL/6N mice were randomly divided into HFD control, chow control, and E. cloacae treatment groups. The E. cloacae treatment group received live bacterial cells in PBS intragastrically twice a week, every other week for 13 weeks. Both control groups received PBS intragastrically. After the 13-week treatment period, the mice were sacrificed for gene and protein expression and functional analyses. Our results show that E. cloacae administration increased subcutaneous fat mass and the relative proportion of hypertrophic adipocytes. Both subcutaneous and visceral fat had signs of decreased insulin signaling and elevated lipolysis that was reflected in higher serum glycerol levels. In addition, E. cloacae -treated mice had significantly higher hepatic AST and AST/ALT ratio, and their liver histology indicated fibrosis, demonstrating that E. cloacae subsp. cloacae administration promotes hepatic damage in HFD fed mice.

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According to WHO [1], the prevalence of obesity has almost tripled during the past four decades. Consequently, the frequency of obesity-associated metabolic disorders, including non-alcoholic fatty liver disease (NAFLD), has exacerbated. The prevalence of obesity and metabolic disorders is considered to increase due to changes in environmental factors such as diet and lifestyle, and accumulating evidence is indicating that gut microbiota plays a role in the development of these diseases [2]. Gut microbes have an important role in host metabolism, as they, for instance, ferment otherwise indigestible dietary polysaccharides into short-chain fatty acids, promote the absorption of monosaccharides, affect the activity of certain gut enzymes and increase anabolic metabolism [3,4]. In the past decades, several studies have reported associations between gut microbiota composition and obesity; obese individuals seem to have reduced gut microbiota diversity compared to lean individuals (for review, see [5]), and the abundance of specific microbial taxa, functional genes, as well as metabolic activities differ significantly between the obese and lean individuals [6,7]. In addition, gut microbes have been shown to participate in the regulation of host lipogenesis and fat storage [3,8].

Human studies have reported an increased abundance of Enterobacteriaceae in obesity [14,29]. These bacteria have also been related to defective hepatic functions, as the abundance of Proteobacteria phyla including the Enterobacteriaceae family is suggested to gradually increase from healthy to obese subjects, and further to subjects with NASH [30]. In addition, Enterobacteriaceae family has been reported to increase in patients with liver cirrhosis [31]. In this study, we showed that E. cloacae ATCC® 13047™ treatment combined with HFD caused liver damage and seemed to increase adipose tissue hypertrophy in mice. In agreement, Fei & Zhao reported that E. cloacae B29, a close phylogenetic relative to E. cloacae ATCC® 13047™ isolated from a morbidly obese volunteer, induced obesity and liver injure in mice on HFD [14].




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