A Metagenomics Investigation of Intergenerational Effects of Non-nutritive Sweeteners on Gut Microbiome.

Weilan Wang,Jodi E Nettleton,Raylene A Reimer,Michael G Gänzle

doi:10.3389/fnut.2021.795848

Abstract

To identify possible mechanisms by which maternal consumption of non-nutritive sweeteners increases obesity risk in offspring, we reconstructed the major alterations in the cecal microbiome of 3-week-old offspring of obese dams consuming high fat/sucrose (HFS) diet with or without aspartame (5–7 mg/kg/day) or stevia (2–3 mg/kg/day) by shotgun metagenomic sequencing (n = 36). High throughput 16S rRNA gene sequencing (n = 105) was performed for dams, 3- and 18-week-old offspring. Maternal consumption of sweeteners altered cecal microbial composition and metabolism of propionate/lactate in their offspring. Offspring daily body weight gain, liver weight and body fat were positively correlated to the relative abundance of key microbes and enzymes involved in succinate/propionate production while negatively correlated to that of lactose degradation and lactate production. The altered propionate/lactate production in the cecum of weanlings from aspartame and stevia consuming dams implicates an altered ratio of dietary carbohydrate digestion, mainly lactose, in the small intestine vs. microbial fermentation in the large intestine. The reconstructed microbiome alterations could explain increased offspring body weight and body fat. This study demonstrates that intense sweet tastants have a lasting and intergenerational effect on gut microbiota, microbial metabolites and host health.

Highlights

Low-calorie sweeteners, known as non-nutritive sweeteners, have been used for decades to replace sugar and reduce the caloric content of foods and beverages while maintaining the sweet taste [1]
We recently reported that maternal consumption of aspartame and stevia altered the expression of genes related to the mesolimbic reward system in 3-week and 18-week old rat offspring, and altered gut microbiota in the 3-week old offspring [9]
Significant litter effects were observed in 3-week old offspring, as indicated by the weighted UniFrac distances (Figure 2A2, R = 0.53, p = 0.001) and a higher number of highly similar (>99.0% average nucleotide identity) bacterial genomes that were shared between offspring from the same dam (Figure 2A3, p < 0.001)

Summary

Introduction

Low-calorie sweeteners, known as non-nutritive sweeteners, have been used for decades to replace sugar and reduce the caloric content of foods and beverages while maintaining the sweet taste [1]. The consumption of non-nutritive sweeteners has raised concerns about potential detrimental effects of long-term intake which have been demonstrated in some rodent studies [2,3,4,5] but less consistently in human studies [4, 6,7,8]. Aspartame and stevia are two commonly used low-calorie sweeteners whose metabolism has been investigated in different species [3, 9,10,11,12,13,14]. Rebaudioside A, the stevia glycoside used in this study, is resistant to hydrolysis by pancreatic or brush border enzymes but is converted to the aglycone steviol by ileal or colonic bacteria expressing. Bacteroides isolates from human microbiota were identified as the most efficient bacteria in hydrolyzing rebaudioside A to steviol [12]

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