The artificial sweetener acesulfame potassium affects the gut microbiome and body weight gain in CD-1 mice

<div><p>Artificial sweeteners have been widely used in the modern diet, and their observed effects on human health have been inconsistent, with both beneficial and adverse outcomes reported. Obesity and type 2 diabetes have dramatically increased in the U.S. and other countries over the last two decades. Numerous studies have indicated an important role of the gut microbiome in body weight control and glucose metabolism and regulation. Interestingly, the artificial sweetener saccharin could alter gut microbiota and induce glucose intolerance, raising questions about the contribution of artificial sweeteners to the global epidemic of obesity and diabetes. Acesulfame-potassium (Ace-K), a FDA-approved artificial sweetener, is commonly used, but its toxicity data reported to date are considered inadequate. In particular, the functional impact of Ace-K on the gut microbiome is largely unknown. In this study, we explored the effects of Ace-K on the gut microbiome and the changes in fecal metabolic profiles using 16S rRNA sequencing and gas chromatography-mass spectrometry (GC-MS) metabolomics. We found that Ace-K consumption perturbed the gut microbiome of CD-1 mice after a 4-week treatment. The observed body weight gain, shifts in the gut bacterial community composition, enrichment of functional bacterial genes related to energy metabolism, and fecal metabolomic changes were highly gender-specific, with differential effects observed for males and females. In particular, ace-K increased body weight gain of male but not female mice. Collectively, our results may provide a novel understanding of the interaction between artificial sweeteners and the gut microbiome, as well as the potential role of this interaction in the development of obesity and the associated chronic inflammation.</p></div

Sex-Specific Effects of Arsenic Exposure on the Trajectory and Function of the Gut Microbiome

The gut microbiome is deeply involved in numerous aspects of human health; however, it can be readily perturbed by environmental toxicants, such as arsenic. Meanwhile, the interaction among host, gut microbiome, and xenobiotics is a very complex dynamic process. Previously, we have demonstrated that gut microbiome phenotypes driven by host genetics and bacterial infection affect the responses to arsenic exposure. The role of host sex in shaping the gut microbiome raises the question whether sex plays a role in exposure-induced microbiome responses. To examine this, we used 16S rRNA sequencing and metagenomics sequencing to analyze the changes of the gut microbiome and its associated functional metagenome in both female and male C57/BL6 mice. Our results clearly demonstrated that arsenic exposure perturbed the trajectory and function of the gut microbiome in a sex-specific manner

Functional gene enrichment analysis showing that functional genes related to carbohydrate metabolism were significantly decreased in Ace-K-treated female mice (p<0.05 for all genes listed here).

<p>Functional gene enrichment analysis showing that functional genes related to carbohydrate metabolism were significantly decreased in Ace-K-treated female mice (p<0.05 for all genes listed here).</p

Effects of four weeks of Ace-K consumption on the body weight gain and gut microbiome composition of CD-1 mice.

<p>(A) The body weight gain of Ace-K-treated male mice was significantly higher than that of the control male mice, while the body weight gain of female mice was not significantly different from that of the controls. (B) Ace-K consumption altered the composition of gut bacteria in female mice. The abundances of <i>Lactobacillus</i>, <i>Clostridium</i>, an unassigned <i>Ruminococcaceae</i> genus and an unassigned <i>Oxalobacteraceae</i> genus were significantly decreased, and the abundance of <i>Mucispirillum</i> was increased after Ace-K consumption. (C) Ace-K consumption altered the composition of gut bacteria in male mice. The abundances of <i>Bacteroides</i>, <i>Anaerostipes</i> and <i>Sutterella</i> were significantly increased after Ace-K consumption (*p<0.05, **p<0.01, ***p<0.001, N.S. p>0.05).</p

Ace-K consumption changed the fecal metabolome of female (A, B) and male (C, D) mice, as illustrated by the cloud and PLS-DA plots.

<p>Ace-K consumption changed the fecal metabolome of female (A, B) and male (C, D) mice, as illustrated by the cloud and PLS-DA plots.</p

Ace-K consumption significantly altered key fecal metabolites in female (A) and male (B) mice (*p<0.05, **p<0.01).

<p>Ace-K consumption significantly altered key fecal metabolites in female (A) and male (B) mice (*p<0.05, **p<0.01).</p

Nicotine Alters the Gut Microbiome and Metabolites of Gut–Brain Interactions in a Sex-Specific Manner

As the primary active substance in tobacco, nicotine affects the activity of the central nervous system, and its effects are sex-dependent. There are complex interactions between the gut and brain, and the gut microbiome can influence neuronal activity and host behavior, with diverse chemical signaling being involved. However, it is unclear whether nicotine can affect the normal gut microbiome and associated chemical signaling of the gut–brain axis. Sex is an important factor that shapes the gut microbiome, but the role of sex in the interaction among nicotine, gut bacteria, and related metabolites remains unknown. In this study, we applied high-throughput sequencing and gas chromatography–mass spectrometry (GC–MS) to explore how nicotine exposure affects the gut microbiome and its metabolism in female and male C57BL/6J mice, with a focus on the chemical signaling involved in gut–brain interactions. 16S sequencing results indicated that the community composition of the gut microbiome was differentially perturbed by nicotine in females and males. Differential alterations of bacterial carbohydrate metabolic pathways are consistent with lower body weight gain in nicotine-treated males. Oxidative stress response and DNA repair genes were also specifically enriched in the nicotine-treated male gut microbiome. The fecal metabolome indicated that multiple neurotransmitters, such as glutamate, gamma-aminobutyric acid (GABA), and glycine, were differentially altered in female and male mice. Some neuroactive metabolites, including leucine and uric acid, were also changed. This study demonstrates a sex-dependent effect of nicotine on gut microbiome community composition, functional bacterial genes, and the fecal metabolome

Gut Microbiome Phenotypes Driven by Host Genetics Affect Arsenic Metabolism

Large individual differences in susceptibility to arsenic-induced diseases are well-documented and frequently associated with different patterns of arsenic metabolism. In this context, the role of the gut microbiome in directly metabolizing arsenic and triggering systemic responses in diverse organs raises the possibility that gut microbiome phenotypes affect the spectrum of metabolized arsenic species. However, it remains unclear how host genetics and the gut microbiome interact to affect the biotransformation of arsenic. Using an integrated approach combining 16S rRNA gene sequencing and HPLC-ICP-MS arsenic speciation, we demonstrate that IL-10 gene knockout leads to a significant taxonomic change of the gut microbiome, which in turn substantially affects arsenic metabolism

Gut Microbiome Perturbations Induced by Bacterial Infection Affect Arsenic Biotransformation

Exposure to arsenic affects large human populations worldwide and has been associated with a long list of human diseases, including skin, bladder, lung, and liver cancers, diabetes, and cardiovascular disorders. In addition, there are large individual differences in susceptibility to arsenic-induced diseases, which are frequently associated with different patterns of arsenic metabolism. Several underlying mechanisms, such as genetic polymorphisms and epigenetics, have been proposed, as these factors closely impact the individuals’ capacity to metabolize arsenic. In this context, the role of the gut microbiome in directly metabolizing arsenic and triggering systemic responses in diverse organs raises the possibility that perturbations of the gut microbial communities affect the spectrum of metabolized arsenic species and subsequent toxicological effects. In this study, we used an animal model with an altered gut microbiome induced by bacterial infection, 16S rRNA gene sequencing, and inductively coupled plasma mass spectrometry-based arsenic speciation to examine the effect of gut microbiome perturbations on the biotransformation of arsenic. Metagenomics sequencing revealed that bacterial infection significantly perturbed the gut microbiome composition in C57BL/6 mice, which in turn resulted in altered spectra of arsenic metabolites in urine, with inorganic arsenic species and methylated and thiolated arsenic being perturbed. These data clearly illustrated that gut microbiome phenotypes significantly affected arsenic metabolic reactions, including reduction, methylation, and thiolation. These findings improve our understanding of how infectious diseases and environmental exposure interact and may also provide novel insight regarding the gut microbiome composition as a new risk factor of individual susceptibility to environmental chemicals