Gut Microbiome Response to Sucralose and Its Potential Role in Inducing Liver Inflammation in Mice

Abstract

Sucralose is the most widely used artificial sweetener, and its health effects have been highly debated over the years. In particular, previous studies have shown that sucralose consumption can alter the gut microbiota. The gut microbiome plays a key role in processes related to host health, such as food digestion and fermentation, immune cell development, and enteric nervous system regulation. Inflammation is one of the most common effects associated with gut microbiome dysbiosis, which has been linked to a series of human diseases, such as diabetes and obesity. The aim of this study was to investigate the structural and functional effects of sucralose on the gut microbiota and associated inflammation in the host. In this study, C57BL/6 male mice received sucralose in their drinking water for 6 months. The difference in gut microbiota composition and metabolites between control and sucralose-treated mice was determined using 16S rRNA gene sequencing, functional gene enrichment analysis and metabolomics. Inflammatory gene expression in tissues was analyzed by RT-PCR. Alterations in bacterial genera showed that sucralose affects the gut microbiota and its developmental dynamics. Enrichment of bacterial pro-inflammatory genes and disruption in fecal metabolites suggest that 6-month sucralose consumption at the human acceptable daily intake (ADI) may increase the risk of developing tissue inflammation by disrupting the gut microbiota, which is supported by elevated pro-inflammatory gene expression in the liver of sucralose-treated mice. Our results highlight the role of sucralose-gut microbiome interaction in regulating host health-related processes, particularly chronic inflammation.

Keywords: artificial sweetener; gut microbiota; inflammation; metabolomics; sucralose.

Figure 1

Sucralose altered the dynamics of gut microbiome development in C57BL6/J mice. Bacterial genera exhibited different patterns over time between the control and sucralose-treated mice. ^*p < 0.05.

Figure 2

Enrichment of bacterial pro-inflammatory genes after 6 months of sucralose treatment (^*p < 0.05, ^**p < 0.01), including genes involved in LPS (A), flagella (B), and fimbriae synthesis (C) as well as toxins (D) and multidrug resistance genes (E).

Figure 3

Sucralose changed the fecal metabolome, as illustrated by the Cloud plot (A), PLS-DA plot (B), and heat map (C). A total of 1,764 molecular features were significantly different (p < 0.05 and fold change>1.5) between sucralose-treated mice and controls.

Figure 4

Quorum sensing signals were altered by sucralose consumption. ^*p < 0.05, ^***p < 0.001.

Figure 5

Amino acids and derivatives altered by sucralose. ^*p < 0.05, ^**p < 0.01, ^***p < 0.001) (A) tryptophan metabolites; (B) tyrosine metabolites.

Figure 6

Sucralose altered bile acids in the fecal samples of mice treated with sucralose for 6 months. ^*p < 0.05, ^**p < 0.01.

Figure 7

Sucralose consumption increased the gene expression of inflammatory markers in the liver, as examined by qRT-PCR. The mRNA expression of matrix metalloproteinase 2 (MMP-2) and inducible nitric-oxide synthase (iNOS) was elevated in sucralose-treated mice. ^*p < 0.05, N.S., no statistical significance.

Figure 8

Proposed functional link between sucralose-induced gut microbiota alterations and host inflammation. Sucralose perturbs the gut microbiome and its metabolic functions, inducing the enrichment of bacterial pro-inflammatory mediators, and disrupting metabolites involved in inflammation regulation. Together, these consequences may contribute to the induction of liver inflammation in the host.