Improving insulin resistance by sulforaphane via activating Bacteroides & Lactobacillus-SCFAs-GPR-GLP1 signal axis

Abstract

Background: Insulin resistance (IR) is a key incentive to non-alcoholic fatty liver disease (NAFLD) and gut microbiome contributes to the development of NAFLD. Sulforaphane (SFN) is a phytochemical in cruciferous vegetables, which could improve lipid metabolism disorder. But whether SFN can alleviate IR in NAFLD by regulating intestinal flora remains unclear. Methods: SFN was administered to high fat diet (HFD) fed Wistar rats for 10 weeks. Gut microbiota was analysed by 16S rRNA sequencing and short chain fatty acids (SCFAs) by gas chromatography. The expression of tight junction protein and the number of Lactobacillus, Bacteroides and Bifidobacterium were determined by qPCR. The expression of G-protein coupled receptor 41 /43(GPR41/43) was determined by Western blot. A randomized controlled trial (RCT) was conducted in NAFLD patients with broccoli seed tablets (rich in SFN 42 mg/d) intervention for 12 weeks. 36 volunteers with the abnormal glucose before broccoli seed tablets treatment were selected in intervention group to analyze the blood glucose, insulin, homeostasis model assessment-insulin resistance index (HOMA-IRI), homeostasis model assessment- insulin sensitivity index (HOMA-ISI) and glucagon-like peptide (GLP-1). Results: SFN reduced blood glucose and HOMA-IRI while increased insulin sensitivity in HFD rats. SFN reduced glycogen synthase kinase 3 (GSK-3) and phosphoenol pyruvate carboxykinase (PEPCK) activity and phosphorylation of serine residues of IRS-2 induced by HFD. SFN reshaped the gut microbiota composition of HFD-induced rats, especially increased the content of Bacteroidaceae, Lactobacillaceae and Bifidobacteriaceae, which related to the improvement of SFN on blood glucose and HOMA-IRI. The increased number of Bacteroides and Lactobacillus was the target of SFN to enhance the expression of tight junction proteins ZO-1 and Occludin, thereby declined LPS content to reduce inflammation, ultimately alleviating IR. Bacteroides and Lactobacillus produced SCFAs which activated GPR41/43 to secrete GLP1. Moreover, it was also confirmed in RCT that SFN intervention increased the level of GLP1 in NAFLD patients, which was positively correlated with the reduction of blood glucose and HOMA-IR. Conclusions: SFN alleviated IR in NAFLD via Bacteroides & Lactobacillus-SCFAs-GPR41/43-GLP1 axis and protected intestinal mucosal barrier to decrease inflammation.