Artificial sweeteners stimulate horizontal transfer of extracellular antibiotic resistance genes through natural transformation

Abstract

Antimicrobial resistance has emerged as a global threat to human health. Natural transformation is an important pathway for horizontal gene transfer, which facilitates the dissemination of antibiotic resistance genes (ARGs) among bacteria. Although it is suspected that artificial sweeteners could exert antimicrobial effects, little is known whether artificial sweeteners would also affect horizontal transfer of ARGs via transformation. Here we demonstrate that four commonly used artificial sweeteners (saccharin, sucralose, aspartame, and acesulfame potassium) promote transfer of ARGs via natural transformation in Acinetobacter baylyi ADP1, a model organism for studying competence and transformation. Such phenomenon was also found in a Gram-positive human pathogen Bacillus subtilis and mice faecal microbiome. We reveal that exposure to these sweeteners increases cell envelope permeability and results in an upregulation of genes encoding DNA uptake and translocation (Com) machinery. In addition, we find that artificial sweeteners induce an increase in plasmid persistence in transformants. We propose a mathematical model established to predict the long-term effects on transformation dynamics under exposure to these sweeteners. Collectively, our findings offer insights into natural transformation promoted by artificial sweeteners and highlight the need to evaluate these environmental contaminants for their antibiotic-like side effects.

Good microbes, bad genes? The dissemination of antimicrobial resistance in the human microbiome

“… 24 Other dietary elements such as artificial sweeteners have also been shown (in culture) to induce upregulation of conjugation machinery in response to cell stress that may result in increased ARG transfer. 23 Diseases connected to gut inflammation have also been observed to lead to an expansion of the intestinal resistome, including type 2 diabetes, cirrhosis, obesity, and IBD. 7 , 24 , 57 A common mechanism of increased ARG prevalence across these diseases is likely the blooming of ARG-enriched taxa such as the Enterobacterales in response to a dysbiotic state.…”

“… 17 Functional metagenomics directly screens genes for resistance phenotypes and therefore this approach can identify novel ARGs with high specificity, and can be used for the development and augmentation of custom ARG databases. 18 , 19 Through sequence homology to known ARGs, the widespread use of shotgun metagenomics has further enabled detailed analysis of mammalian-associated resistomes across body sites, 20–22 demonstrating that the resistome displays inter-individual variation and correlates with a number of factors further discussed below, including diet, 23 , 24 travel, 25 antibiotic usage, 2 , 22 , 26 , 27 hospital environments, 28 and breastfeeding. 15 , 27 , 29 Yet, determining the clinical relevance of a given ARG presence within the gut microbiome depends not just on its abundance, but also on the relative risks posed by different ARG classes and the frequencies by which they may transmit to pathogens or pathobionts.…”

The Spread of Antibiotic Resistance Genes In Vivo Model

“…Transformation means that extracellular DNA from lysed donor bacteria is taken up by the recipient bacteria and integrated into their genomes so that the recipient bacteria can acquire new traits [ 31 ]. Extracellular DNA is mostly plasmid DNA and fragmented DNA released during active secretion or lysis by bacteria, often carrying ARG [ 32 ].…”

Food Additives Associated with Gut Microbiota Alterations in Inflammatory Bowel Disease: Friends or Enemies?

“…The functional enrichment analysis indicated that LPS biosynthesis, flagellar assembly, fimbrial synthesis, bacterial toxin and multidrug resistance were possibly relevant [ 66 ]. Recently, NAS including saccharin, sucralose, aspartame and Ace-K were found to promote the bacterial evolution and horizontal transfer of antibiotic tolerance through natural transformation, resulting in an overexpression of genes encoding DNA uptake and translocation machinery [ 100 , 101 , 102 ]. This finding offers some insights into the roles of NAS in the evolution and dissemination of antibiotic tolerance among bacteria.…”