Formononetin (FMNT) is an isoflavone that has been studied for its anti-hyperglycemic and anti-diabetic effects. However, the effect of FMNT on gut dysbiosis and metabolic complications associated with western-style diet consumption has not been reported yet. This study aimed to investigate how FMNT can reshape the gut microbiota at a specific dosage and ameliorate the symptoms of obesity-related metabolic disorders in both genders. Results indicate that FMNT at 60 mg per kg bodyweight dosage can effectively control body weight, hyperglycemia, and insulin resistance, leptin levels and improve HDL to LDL ratio. FMNT treatment suppressed Porphyromonadaceae () and augmented maximum genera from families Lachnospiraceae and Clostridiacea, but at species level, formononetin increased , , ; acetate and butyrate-producing bacteria. Moreover, formononetin regulated the expression of specific liver miRNA involved in obesity and down-regulated mRNA expression levels of pro-inflammatory cytokines IL-6, IL-22 and TNF-α. Additionally, FMNT maintained intestinal membrane integrity by regulating the expression of Muc-2 and occludin. Our findings indicate that FMNT could be a potential prebiotic that can effectively regulate the gut microbiota, improve host metabolism and systemic inflammation, and prevent deleterious effects of a western-style diet by elevating acetate lactate and lactate butyrate producers.
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