Background: As an ancient concept and practice, “food as medicine” or “medicine–food homology” is receiving more and more attention these days. It is a tradition in many regions to intake medicinal herbal food for potential health benefits to various organs and systems including the kidney. Kidney diseases usually lack targeted therapy and face irreversible loss of function, leading to dialysis dependence. As the most important organ for endogenous metabolite and exogenous nutrient excretion, the status of the kidney could be closely related to daily diet. Therefore, medicinal herbal food rich in antioxidative, anti-inflammation micronutrients are ideal supplements for kidney protection. Recent studies have also discovered its impact on the “gut–kidney” axis. Methods: Here, we review and highlight the kidney-protective effects of botanicals with medicine–food homology including the most frequently used Astragalus membranaceus and Angelica sinensis (Oliv.) Diels, concerning their micronutrients and mechanism, offering a basis and perspective for utilizing and exploring the key substances in medicinal herbal food to protect the kidney. Results: The index for medicine–food homology in China contains mostly botanicals while many of them are also consumed by people in other regions. Micronutrients including flavonoids, polysaccharides and others present powerful activities towards renal diseases. Conclusions: Botanicals with medicine–food homology are widely speeded over multiple regions and incorporating these natural compounds into dietary habits or as supplements shows promising future for renal health.

Polygala tenuifolia Willd., a widely used traditional Chinese medicine, has the function of coordinating heart and kidney and eliminating swelling. However, its renal-protective efficacy and possible material basis remain unknown. The aim of the study was to investigate the renal-protective effect of Polygala tenuifolia Willd. and identify the potential active substance and molecular mechanism. A gentamicin-induced kidney injury model was established to investigate efficacy. Secondly, potential active substances and molecular mechanisms were studied through integrated gut microbiota–drug interaction analysis and network pharmacology at a cellular level. Finally, 16S rRNA sequencing and untargeted metabolomics were used to elucidate the gut microbiota composition and metabolic profile change. Polygala tenuifolia Willd. extracts (PWE), with tenuifoliside A (TFSA) as the key compound, significantly reversed gentamicin-induced acute kidney injury in mice. The gut microbiota-derived carboxylesterase metabolized TFSA into four characteristic metabolites (M1–M4). Notably, both TFSA and M4 were detected in kidney and exerted protective effects via inhibiting TLR4–NF-κB pathway. Furthermore, metabolic pathways and gut microbiota composition change were identified. PWE treatment significantly increased the abundance of beneficial bacteria such as Akkermansia and Blautia, while reducing the abundance of harmful bacteria such as Oscillospira. Subsequently, PWE can reverse amino acid metabolic abnormalities by regulating the biosynthesis of phenylalanine, tyrosine, and tryptophan and ameliorating tryptophan metabolism disorder. This study was the first to verify the renal-protective effect of PWE and identify the effective substance basis (TFSA) and the molecular mechanism, providing a scientific foundation for the development of kidney drug treatment strategies targeting the intestinal flora.