Abstract

Pulsed antibiotic treatment (PAT) early in life increases risk of obesity. Prebiotics can reduce fat mass and improve metabolic health. We examined if co-administering prebiotic with PAT reduces obesity risk in rat pups weaned onto a high fat/sucrose diet. Pups were randomized to (1) control [CTR], (2) antibiotic [ABT] (azithromycin), (3) prebiotic [PRE] (10% oligofructose (OFS)), (4) antibiotic + prebiotic [ABT + PRE]. Pulses of antibiotics/prebiotics were administered at d19–21, d28–30 and d37–39. Male and female rats given antibiotics (ABT) had higher body weight than all other groups at 10 wk of age. The PAT phenotype was stronger in ABT males than females, where increased fat mass, hyperinsulinemia and insulin resistance were present and all reversible with prebiotics. Reduced hypothalamic and hepatic expression of insulin receptor substrates and ileal tight junction proteins was seen in males only, explaining their greater insulin resistance. In females, insulin resistance was improved with prebiotics and normalized to lean control. ABT reduced Lactobacillaceae and increased Bacteroidaceae in both sexes. Using a therapeutic dose of an antibiotic commonly used for acute infection in children, PAT increased body weight and impaired insulin production and insulin sensitivity. The effects were reversed with prebiotic co-administration in a sex-specific manner.

Highlights

  • The gut microbiota has co-evolved with its human host, conferring a wide-range of metabolic, nutritional, and immunological benefits for the host [1]

  • Previous animal studies demonstrated increased body weight after sub-therapeutic antibiotic exposure [12,34], we aimed to investigate whether therapeutic doses of azithromycin resulted in a similar phenotype

  • Once the antibiotics/prebiotics were discontinued and the experimental groups continued on the high-fat/high sucrose diet (HFS) diet, the ABT group became heavier than all other groups (Figure 1D) despite no differences in caloric intake between the groups (Figure 1Q)

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Summary

Introduction

The gut microbiota has co-evolved with its human host, conferring a wide-range of metabolic, nutritional, and immunological benefits for the host [1]. Disruptions to the microbial community (dybiosis) can contribute to obesity and other metabolic diseases [2]. Alterations to the gut microbiota are more likely to occur early in life due to microbial instability and a higher likelihood of exposure to external factors that could cause perturbations such as antibiotics [3]. Exposure to antibiotics in early life is of particular concern given that ~90% of exclusively breast-fed infant microbiota are bifidobacteria, which are highly susceptible to antibiotics [5]. Reduced bifidobacteria abundance is found in individuals with higher BMI [6,7] and a negative correlation has been shown between Bifidobacterium and visceral adiposity (6).

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