Exploring the Effects of Effective Parts of Schisandra sphenanthera on the Gut‐Brain Axis of Type 2 Diabetes Mellitus Rats Based on Metabolomic and Proteomic Approaches

ABSTRACT Schisandra sphenanthera ( Schisandra sphenanthera Rehd. et Wils) is first recorded in the Shennong Bencao Jing (Shennong's Classic of Materia Medica). It is clinically effective in Neire Xiaoke. In traditional Chinese medicine, type 2 diabetes mellitus (T2DM) can be broadly classified as a “thirst‐quenching disease” based on its clinical manifestations. However, the mechanism of action of S. sphenanthera in the treatment of T2DM remains unclear. This study aims to investigate the mechanism of the total dichloromethane extraction phase of ethanol extract from S. sphenanthera (T‐SDP) in treating T2DM and preventing its complication‐ brain injury by regulating the gut‐brain axis. The main ingredients of T‐SDP were identified by gas chromatograph‐mass spectrometer analysis. High‐sugar and high‐fat feeding combined with streptozotocin injection‐induced T2DM rats were used to assess the antidiabetic effect and mechanism of T‐SDP. We performed untargeted metabolomics to analyze intestinal contents and polymerase chain reaction and western blot to analyze the expression of intestinal sweet taste receptors (STRs). Additionally, we employed proteomics and immunohistochemistry to detect protein changes in rat brain tissue. The data revealed that T‐SDP was mainly composed of lignins and terpenes. It improved glucose and lipid metabolism, insulin resistance, and antioxidant capacity of brain tissue in T2DM rats. T‐SDP regulated intestinal metabolite levels and increased the expression of T1R2, T1R3, TRPM5, Ga gust, and PG mRNA and TRPM5, T1R3, Ga gust, and GLP‐1 proteins in the intestine. In addition, T‐SDP regulated proteins in brain tissues of T2DM rats. T‐SDP is effective in treating T2DM and its complication–brain injury by modulating intestinal metabolites and STR pathway to activate the gut‐brain axis and increase synaptic plasticity in brain tissue to lower blood glucose and improve insulin resistance.