Gut microbiota modulation with norfloxacin and ampicillin enhances glucose tolerance in mice

Nestlé Research Center, P.O. Box 44, CH 1000 Lausanne, Switzerland.
The FASEB Journal (Impact Factor: 5.04). 08/2008; 22(7):2416-26. DOI: 10.1096/fj.07-102723
Source: PubMed


Recent data suggest that the gut microbiota plays a significant role in fat accumulation. However, it is not clear whether gut microbiota is involved in the pathophysiology of type 2 diabetes. To assess this issue, we modulated gut microbiota via antibiotics administration in two different mouse models with insulin resistance. Results from dose-determination studies showed that a combination of norfloxacin and ampicillin, at a dose of 1 g/L, maximally suppressed the numbers of cecal aerobic and anaerobic bacteria in ob/ob mice. After a 2-wk intervention with the antibiotic combination, both ob/ob and diet-induced obese and insulin-resistant mice showed a significant improvement in fasting glycemia and oral glucose tolerance. The improved glycemic control was independent of food intake or adiposity because pair-fed ob/ob mice were as glucose intolerant as the control ob/ob mice. Reduced liver triglycerides and increased liver glycogen correlated with improved glucose tolerance in the treated mice. Concomitant reduction of plasma lipopolysaccharides and increase of adiponectin further supported the antidiabetic effects of the antibiotic treatment in ob/ob mice. In summary, modulation of gut microbiota ameliorated glucose tolerance of mice by altering the expression of hepatic and intestinal genes involved in inflammation and metabolism, and by changing the hormonal, inflammatory, and metabolic status of the host.

    • "A major effect was observed in male patients who did not have cardiac surgery and were older than 65 since they, indeed, developed obesity. Antibiotic treatment has also been indicated to prevent obesity, by improving glucose tolerance and improving endotoxemia (Cani et al. 2008; Membrez et al. 2008). Evidence in mice suggests that antibiotic therapy has a considerable impact on adiposity and plasma LPS levels, oxidative stress, macrophage infiltration in adipose tissue, inflammation and metabolic disorders (Cani et al. 2008; Bech-Nielsen et al. 2012). "
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    ABSTRACT: Recently, a great deal of interest has been expressed regarding strategies to tackle worldwide obesity because of its accelerated wide spread accompanied with numerous negative effects on health and high costs. Obesity has been traditionally associated with an imbalance in energy consumed when compared to energy expenditure. However, growing evidence suggests a less simplistic event in which gut microbiota plays a key role. Obesity, in terms of microbiota, is a complicated disequilibrium that presents many unclear complications. Despite this, there is special interest in characterizing compositionally and functionally the obese gut microbiota with the help of in vitro, animal and human studies. Considering the gut microbiota as a factor contributing to human obesity represents a tool of great therapeutic potential. This paper reviews the use of antimicrobials, probiotics, fecal microbial therapy, prebiotics and diet to manipulate obesity through the human gut microbiota and reveals inconsistencies and implications for future study.
    Genes & Nutrition 07/2015; 10(4):472. DOI:10.1007/s12263-015-0472-4 · 2.79 Impact Factor
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    • "This process is dose-dependent and does not achieve saturation at up to 920 mg/dL of ethanol [11]. This is in line with the observations that (i) SIBO and gut hyperpermeability are closely associated with the progression from simple steatosis to NASH [6,38–42], (ii) SIBO eradication with oral antibiotics prevents the development of both NAFLD and AFLD [43] [44] [45] [46] [47], (iii) germ-free mice are resistant to both diet-induced obesity and NAFLD [48] [49], (iv) rats with experimentally-induced SIBO produce significantly more EE than controls, and (v) intragastric administration of sucrose in these animals elicits a 3- fold increase in portal concentrations of ACD with only modest elevation of systemic BAC [11]. "
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    ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD) are so similar that only a detailed history of alcohol intake can distinguish one from the other. Because subjects with NAFLD produce significantly more endogenous ethanol (EE) than controls, some researchers suspected that these similarities are not merely coincidental. For this reason, it was attempted to show that NAFLD is actually an endogenous alcoholic fatty liver disease (EAFLD). However, negligible blood-alcohol concentration (BAC) and the inability of gut microbiota to produce hepatotoxic concentrations of EE rejected this hypothesis. To clarify these conflicting results, we provide a mechanistic framework explaining how NAFLD may be an EAFLD. First of all, the key finding is that ethanol is a prodrug, enabling the idea that AFLD may develop with negligible/absent BAC. Second, extrahepatic acetaldehyde (ACD) alone recapitulates AFLD and is about 330-fold more hepatotoxic than that generated inside the liver. Third, gut microbiota can even produce much larger amounts of EE than those currently considered cirrhotogenic for man. Fourth, an extensive gut-liver axis first-pass metabolism of ethanol prevents the development of significant BAC in NAFLD. Fifth, all genes involved in EE metabolism are upregulated in the livers of patients with nonalcoholic steatohepatitis (NASH). Last, overexpression of the gene encoding alcohol dehydrogenase (ADH) 4 implicates liver exposure to high concentrations of EE. In conclusion, this work provides mechanistic explanation supporting the assumption that NAFLD may indeed be an EAFLD. If validated by further testing, the hypothesis may help develop novel therapeutic and preventive strategies against this ubiquitous condition. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Medical Hypotheses 04/2015; 85(2). DOI:10.1016/j.mehy.2015.04.021 · 1.07 Impact Factor
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    • "For example, the improved glucose-tolerance and low-grade inflammation in prebiotic treated-mice have been associated significantly and positively with levels of Bifidobacterium [7]. It has been proposed that the gut microbiota instruct the host to increase hepatic production of triglycerides, which is linked with the development of insulin resistance [8]. In several studies on mice and humans, it has been found that increase in body weight was associated with a larger proportion of Firmicutes and relatively less Bacteroidetes [9] [10]. "
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    ABSTRACT: Imbalances in gut microbiota are associated with metabolic disorder, which are a group of obesity-related metabolic abnormalities that increase an individual’s risk of developing type 2 diabetes (T2D) and Alzheimer’s disease (AD). Although a number of risk factors have been postulated that may trigger the development of AD, the root cause of this disease is still a matter of debate. This review further investigates the etiology of AD by accumulating the current role played by gut microbiota in human, and trying to establish an inter-link between T2D and AD pathogenesis. There is a growing body of evidence which suggests that obesity is associated with alteration in the normal gut flora, reduced bacterial diversity, metabolic pathways and altered representation of bacterial genes. Obesity and T2D are considered to be induced as a result of changes within the composition of gut microbiota. The evidence gathered so far clearly advocates the involvement of gut microbes in causing obesity, a state of chronic and low-grade inflammation. Hence, understanding the microbiota of the gut is significant in relation to inflammation, as it is a key contributor for diabetes which has a direct relation to the AD pathogenesis. Comparative analysis of gut microbiota may enable further novel insight into the complex biology of AD, which is very important in order to take preventive measure such as early diagnosis, identification of new therapeutic targets and development of novel drugs.
    CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) 05/2014; 13(3). DOI:10.2174/18715273113126660151 · 2.63 Impact Factor
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