Impaired Intestinal Akkermansia muciniphila and Aryl Hydrocarbon Receptor Ligands Contribute to Nonalcoholic Fatty Liver Disease in Mice

Abstract

Noncaloric artificial sweeteners (NAS) are extensively introduced into commonly consumed drinks and foods worldwide. However, data on the health effects of NAS consumption remain elusive. Saccharin and sucralose have been shown to pass through the human gastrointestinal tract without undergoing absorption and metabolism and directly encounter the gut microbiota community. Here, we aimed to identify a novel mechanism linking intestinal Akkermansia muciniphila and the aryl hydrocarbon receptor (AHR) to saccharin/sucralose-induced nonalcoholic fatty liver disease (NAFLD) in mice. Saccharin/sucralose consumption altered the gut microbial community structure, with significant depletion of A. muciniphila abundance in the cecal contents of mice, resulting in disruption of intestinal permeability and a high level of serum lipopolysaccharide, which likely contributed to systemic inflammation and caused NAFLD in mice. Saccharin/sucralose also markedly decreased microbiota-derived AHR ligands and colonic AHR expression, which are closely associated with many metabolic syndromes. Metformin or fructo-oligosaccharide supplementation significantly restored A. muciniphila and AHR ligands in sucralose-consuming mice, consequently ameliorating NAFLD. IMPORTANCE Our findings indicate that the gut-liver signaling axis contributes to saccharin/sucralose consumption-induced NAFLD. Supplementation with metformin or fructo-oligosaccharide is a potential therapeutic strategy for NAFLD treatment. In addition, we also developed a new nutritional strategy by using a natural sweetener (neohesperidin dihydrochalcone [NHDC]) as a substitute for NAS and free sugars.

Proteomics and metabolic phenotyping define principal roles for the aryl hydrocarbon receptor in mouse liver

“…This finding may have implications for human health. For example, some AHR ligands have demonstrated anti-inflammatory actions in fatty liver disease models 16 , 43 , 44 . Perhaps these AHR-ligands could increase glucocorticoid receptor signaling to decrease liver inflammation.…”

T Cell Subsets and Natural Killer Cells in the Pathogenesis of Nonalcoholic Fatty Liver Disease

“…A valuable new insight relating to metabolic inter-communication between the host and gut microbiota, aryl hydrocarbon receptor (AHR) has caught researchers worldwide since many microbial metabolites can modulate AHR activity [105,106]. According to recent studies, tryptophan metabolites which are potent AHR ligands, have been found to activate AHR, subsequently reducing inflammation and increasing metabolic activity by downregulating de novo lipogenic genes thus ameliorating NAFLD [107,108]. Intriguingly, liver-specific knockout of AHR worsened the high-fat diet induced steatosis, and inflammatory responses in the liver simultaneously causing lipotoxicity to non-adipose tissues.…”

Network pharmacology‐based investigation to explore the effect and mechanism of Erchen decoction against the nonalcoholic fatty liver disease

“…The microbiota in NASH patients with severer condition was significantly enriched in lipid metabolism (fatty acid biosynthesis and lipid biosynthesis) (Boursier et al, 2016). What's more, Akkermansia is particularly effective in enhancing mucus thickness and strengthening gut barrier function (Geerlings, Kostopoulos, de Vos, & Belzer, 2018;Shi et al, 2021). Bacteroides fragilis could attenuate the decrease of transepithelial electrical resistance, ZO-1, and Muc-2 loss induced by Clostridium difficile infection (Deng et al, 2018).…”