Insights into the renal protective effects of 7-phenylheptanoic acid in chronic kidney disease mice: Modulation of indoxyl sulfate production and gut microbiome homeostasis

7-Phenylheptanoic acid (7-PH) has been reported to slow the progression of chronic kidney disease (CKD) in mice. Although the mechanism behind this renal protection remains unclear, it is strongly linked to reduced production of indoxyl sulfate (IS), a uremic toxin derived from dietary L-tryptophan through a multistep enzymatic process. It is also known that there is a strong association between CKD progression and gut microbiome dysbiosis. This study aimed to determine the involvement of each enzymatic step and identify the primary target enzymes through which 7-PH suppresses IS production, as well as investigate whether the protective effects of 7-PH involve microbiome modulation. First, we evaluated the effects of 7-PH on tryptophan indole-lyase (TIL), cytochrome P450 2E1 (CYP2E1), and sulfotransferase enzymes using in vitro enzyme kinetic studies. We then analyzed the impact of 7-PH on gut microbiome homeostasis in adenine-induced CKD mice using high-throughput 16S rRNA gene sequencing of fecal samples. Our findings indicate that 7-PH primarily targets the conversion of L-tryptophan to indole by acting as a competitive inhibitor of TIL (Ki = 92 μM). It also exhibits weak noncompetitive inhibition of CYP2E1 but does not affect sulfotransferase activity. Microbiome analysis revealed that 7-PH attenuates CKD-associated gut microbiota dysbiosis by selectively preserving beneficial bacterial taxa, such as Muribaculaceae and Alloprevotella, while inhibiting dysbiotic and opportunistic pathogenic groups, including Staphylococcus and Oligella. Therefore, the renal protective effects of 7-PH involve at least 2 interconnected mechanisms: the suppression of IS production through TIL inhibition and the modulation of the gut microbiome. SIGNIFICANCE STATEMENT: The mechanisms behind the renal protective effects of 7-phenylheptanoic acid (7-PH) in chronic kidney disease mice have been clarified. 7-PH reduces indoxyl sulfate production by primarily inhibiting tryptophan indole-lyase activity. Additionally, 7-PH modulates the gut microbiome by preserving beneficial bacterial taxa while selectively suppressing opportunistic pathogens, thereby attenuating chronic kidney disease-associated microbiome dysbiosis.