Role of the Aryl Hydrocarbon Receptor and Gut Microbiota-Derived Metabolites Indole-3-Acetic Acid in Sulforaphane Alleviates Hepatic Steatosis in Mice

Abstract

Scope: Gut microbiome-derived metabolites are the major mediators of diet-induced host-microbial interactions. Aryl hydrocarbon receptor (AHR) plays a crucial role in glucose, lipid, and cholesterol metabolism in the liver. In this study, we aimed to investigate the role of indole-3-acetic acid (IAA) and AHR in sulforaphane (SFN) alleviates hepatic steatosis in mice fed on a high-fat diet (HFD).Methods and Results: The HFD-fed male C57BL/6 mice were intervened with SFN for 6 weeks. HFD-mice showed classical pathophysiological characteristics of hepatic steatosis. The results showed that SFN significantly reduced body weight, liver inflammation and hepatic steatosis in HFD-fed mice. SFN reduced hepatic lipogenesis by activating AHR/SREBP-1C pathway, which was confirmed in HepG2 cell experiments. Moreover, SFN increased hepatic antioxidant activity by modulating Nrf-2/NQO1 expression. SFN increased serum and liver IAA level in HFD mice. Notably, SFN manipulated the gut microbiota, resulting in reducing Deferribacteres and proportions of the phylum Firmicutes/Bacteroidetes and increasing the abundance of specific bacteria that produce IAA. Furthermore, SFN upregulated Ahr expression and decreased the expression of inflammatory cytokines in Raw264.7 cells.Conclusions: SFN ameliorated hepatic steatosis not only by modulating lipid metabolism via AHR/SREBP-1C pathway but regulating IAA and gut microbiota in HFD-induced NAFLD mice.

Intestinal Microbiomics and Metabolomics Insights into the Hepatoprotective Effects of Lactobacillus paracasei CCFM1222 Against the Acute Liver Injury in Mice

“…A previous study suggested that Lactobacillus casei intervention ameliorates the gut healthy by promoting the production of pipecolinic acid [45]. Gut microbiome-derived 3-indole propionic acid and indole-3-acetic acid act as the microbiota-speci c AhR ligand, and their concentrations are negatively associated with the relative abundance of Bi dobacterium [46][47]. Among these, indole-3-acetic acid alleviates LPSstimulated in ammatory response and free radical generation by regulating the expression of HO-1 and eliminating the free radicals [48].…”

Metabolomic Profile of Different Dietary Patterns and Their Association with Frailty Index in Community-Dwelling Older Men and Women

“…Unexpectedly, 3-IAA was negatively associated with adherence to the MDS and AHEI. Both 3-IAA and 3-IPA have shown antioxidant and low pro-oxidative properties [ 43 , 44 ] and immune regulation through the activation of the aryl hydrocarbon receptor [ 45 , 46 ], and 3-IPA has been inversely associated with diabetes and inflammation [ 47 ]. The divergent association between IPA and IAA may have resulted from microbial changes, as dietary patterns have been shown to change gut microbiota composition [ 48 ].…”

Interventions for non-alcoholic liver disease: a gut microbial metabolites perspective

“… 46 , 78 Reportedly, microbiota-derived indole and 5-HT improved hepatic steatosis and gut-barrier function. 79 …”

“…Indole and its derivatives, including indole-3-propionic acid (IPA), indole-3-aldehyde (I3A), indoleacrylic acid, and indole-3-acetic acid (IAA), are aryl hydrocarbon receptors (AhRs) agonists to stimulate CD4+ T cells differentiation toward regulatory T cells and regulate lipid metabolism. 79 In inflammatory bowel disease (IBD), indole alleviated intestinal inflammation by upregulating interleukin 22 (IL-22) and downregulating interferon gamma in lamina propria mononuclear cells. 78 Among NAFLD patients, the plasmatic indole concentration was inversely correlated to hepatic fat content and pro-inflammatory macrophage polarization.…”

“…46,78 Reportedly, microbiota-derived indole and 5-HT improved hepatic steatosis and gut-barrier function. 79 Indole and its derivatives, including indole-3-propionic acid (IPA), indole-3-aldehyde (I3A), indoleacrylic acid, and indole-3-acetic acid (IAA), are aryl hydrocarbon receptors (AhRs) agonists to stimulate CD4+ T cells differentiation toward regulatory T cells and regulate lipid metabolism. 79 In inflammatory bowel disease (IBD), indole alleviated intestinal inflammation by upregulating interleukin 22 (IL-22) and downregulating interferon gamma in lamina propria mononuclear cells.…”