Dietary preservatives alter the gut microbiota in vitro and in vivo with sex-specific consequences for host metabolic development in a mouse model

Abstract

Background

Antibiotics in early life can promote adiposity via interactions with the gut microbiota, but they represent only one possible route of antimicrobial exposure. Dietary preservatives exhibit antimicrobial activity, contain chemical structures accessible to microbial enzymes, and may therefore similarly disrupt microbial contributions to metabolic development.

Objectives

Here, we test the hypothesis that preservatives alter the gut microbiota with consequences for host metabolism.

Methods

We screened common dietary preservatives for in vitro and ex vivo activity against a panel of gut bacteria and whole fecal microbial communities, profiling outcomes via optical density measurements and 16S rDNA sequencing. We then exposed adult mice to diet-relevant doses of 4 preservatives [acetic acid, butylated hydroxyanisole (BHA), ethylenediaminetetraacetic acid (EDTA), and sodium sulfite] or ampicillin (positive control) for 7 d. Finally, we examined the effects of early-life EDTA and low-dose ampicillin exposure starting in gestation in a mouse model, tracking differences in growth and metabolism.

Results

Preservatives altered microbial growth and community structure in vitro, ex vivo, and in vivo, but with compound-specific changes in gut microbiota composition distinct from those of ampicillin. Long-term EDTA exposure from gestation reduced calorie absorption and cecal acetate, resulting in 32% lower gains in body fat in females for a given food intake (±12% standard error, linear mixed effects model). Females exposed to ampicillin exhibited a similar 42% (±11%) reduction in food-adjusted gains in adiposity, along with larger brains and smaller livers. By contrast, among males, EDTA had no detectable metabolic impacts whereas ampicillin exposure increased food-adjusted gain in body fat by 108% (±12%).

Conclusions

Our results highlight the potential for everyday doses of common preservatives to affect the gut microbiota and impact metabolism differently in males and females. Thus, despite their generally regarded as safe designation, preservatives could have unintended consequences for consumer health via their impact on the gut microbiota.