The Gut Microbiota – A Realistic Therapeutic Target in Obesity and Metabolic Dysregulation

Abstract

Background: The gut microbiota is an environmental regulator of fat storage and fat composition. We and others have shown the primacy of diet in influencing the microbiota in obesity. Whether the microbiota represents a realistic therapeutic target for improving metabolic health is unclear. Aim: To explore two antimicrobial strategies for their impact on metabolic abnormalities in murine diet-induced obesity (DIO) using: (a)oral vancomycin, (b)a bacteriocin- producing probiotic (Lactobacillus salivarius UCC118Bac+) and (c) its bacteriocin-negative derivative (UCC118Bac-). Methods: Male (7-wk-old) C57BL/J6 mice (n=9-10/group) were fed a low-fat diet (lean) or a high-fat diet (DIO) for 20 weeks with/without vancomycin by gavage at 2mg/d, or with/without the Bac+ or Bac- probiotic (each at a dose of 1x109 cfu/day by gavage). Compositional analysis of the microbiota was by metagenomic pyrosequencing. Results: The metabolic abnormalities of diet-induced obesity were associated with increased relative proportions of Firmicutes (60.7+/-2.8 vs 70.2+/-2.4%; p<0.05) and decreased Bacteroidetes (30+/-2.3 vs 19.5+/-1.4%; p<0.05), with no changes in Actinobacteria or Proteobacteria. Vancomycin treatment led to reductions in Firmicutes (70.2+/-2.4 vs 53.9+/-1%; p<0.0001) and Bacteroidetes (19.5+/-1.4 vs 3.5+/-1.9%; p<0.0001) and increased Proteobacteria (3.5+/-1 vs 37.7+/-2.5%; p<0.0001), with no change in Actinobacteria. Vancomycin-treated DIO mice gained less weight (2.9+/-0.5 vs 4.5+/-0.3g; p<0.05) despite similar caloric intake, had lower fasting blood glucose (148.6+/-5.0 vs 166+/-13.6nmol/l; p<0.05), plasma TNF-alpha (0.3+/-0.1 vs 0.7+/-0.1pg/ml; p<0.05) and triglyceride levels (22.1+/-2.6 vs 31.6+/-3.3mg/dl; p=0.06). In addition, there was a strong trend toward reduced TNF-alpha mRNA levels in hepatic and visceral adipose tissue. In contrast, the Bac+probiotic had no significant impact on proportions of Firmicutes but did result in a relative increase in Bacteroidetes (15.3+/-2.4 vs 23.9+/-2.1%; p<0.05) and Proteobacteria (1.0+/-0.2 vs 1.6+/-0.2%; p<0.05) and a decrease in Actinobacteria (4.9+/-1.4 vs 1.5+/-0.4%; p<0.05) in comparison with the Bac- controls. However, no improvement in metabolic profiles was observed in the probiotic-fed DIO mice. Conclusion: Both vancomycin and the bacteriocin-producing probiotic altered the gut microbiota in dietinduced obese mice but in distinct ways. However, only vancomcyin treatment resulted in an improvement in the metabolic abnormalities associated with obesity. The findings confirm a role for the gut microbiota in metabolic dysregulation and show that the gut microbiota is a realistic therapeutic target but specificity of antimicrobial action will be critical.