Atractylenolide III Alleviates the Lipid Metabolic Disorders in Ovariectomy‐Induced Estrogen‐Deficient Mice Through Repairing Intestinal Inflammation and Microenvironment

ABSTRACT Objective To investigate the mechanism by which Atractylenolide III (ATIII) alleviates ovariectomy‐induced, estrogen‐deficient lipid metabolism disorders through the repair of intestinal inflammation and the barrier microenvironment. Methods Female C57BL/six mice (8 weeks old) were randomly assigned to three groups: a blank control group (Con, n  = 10), a sham surgery group (Sham, n  = 10), and an ovariectomized (OVX) group ( n  = 70). The OVX group was further subdivided into a model group (OVX + HFD), low‐ and high‐dose ATIII groups (ATIII‐L, ATIII‐H), an estradiol (E2) group, and groups receiving fecal microbiota transplantation (FMT) from the blank control, model, or high‐dose ATIII donors. After 60 days on a high‐calorie diet, treatments were administered for 28 consecutive days. Serum, liver, and intestinal tissues, and cecal contents were collected from six randomly selected mice per group. Body weight was monitored; hepatic and colonic morphology was assessed by H&E staining; serum lipid profiles were determined using an automated biochemical analyzer; ELISA quantified estradiol and inflammatory cytokine levels; expression of colonic barrier‐related proteins was evaluated by Western blot; and gut microbiota composition was analyzed via 16S rRNA sequencing. Results Under conditions of estrogen deficiency, a high‐calorie diet mimicking modern human intake predisposed mice to significant weight gain ( p  < 0.05) and dyslipidemia, accompanied by a spectrum of pathological alterations including intestinal barrier dysfunction (evidenced by downregulated tight junction proteins), systemic inflammation (reflected by elevated pro‐inflammatory cytokines), hepatic steatosis, colonic inflammatory damage, and gut microbiota dysbiosis. ATIII intervention effectively mitigated these abnormalities, as demonstrated by reduced body weight, improved lipid profiles, repaired hepatic and colonic injuries, upregulated intestinal barrier proteins, downregulated inflammatory cytokines, a tendency toward elevated estrogen levels, and enhanced gut microbial diversity. Conclusions ATIII ameliorates ovariectomy‐induced estrogen‐deficient dyslipidemia by repairing intestinal barrier function and modulating intestinal inflammation. Concurrently, it exerts beneficial effects on estrogen levels and gut microbiota composition, in which the gut microbiota plays a mediating role. The experiment demonstrated that the active ingredients of traditional Chinese medicine hold significant value in treating lipid metabolism disorders in perimenopausal women, and there is potential for further in‐depth research into the mechanism by which they enhance efficacy through modulating gut microbiota.