Huangjin Shuangshen Jiawei decoction alleviated coronary heart disease comorbid with depression partly through gut microbiota-mediated regulation of the SRSF1-p53-ASPP1 signaling axis.

BACKGROUNDCoronary heart disease comorbid with depression (CHDD) was associated with poor clinical outcomes and was increasingly linked to gut microbiota dysregulation. Huangjin Shuangshen Jiawei decoction (HJSSJW) showed therapeutic potential in CHDD; however, the microbiota-dependent mechanisms underlying its protective effects remained unclear.

PURPOSEThis study was designed to evaluate the effects of HJSSJW on the gut microbiota in murine models of CHDD and to elucidate the potential molecular mechanisms underlying its protective effects.

METHODSThe protective effects of HJSSJW were evaluated in a murine model of CHDD using cardiac ultrasound, histopathological analysis, behavioral assessments, and immunofluorescence staining. To investigate the role of the gut microbiota, microbiota depletion was achieved through antibiotic (ABX) treatment, and fecal microbiota transplantation (FMT) was performed to assess microbiota-mediated effects. In parallel, three bacterial strains enriched in CHDD patients following HJSSJW treatment-Faecalibacterium prausnitzii, Parabacteroides goldsteinii, and Butyricicoccus pullicaecorum-were identified and selected for further validation. Their protective effects were further evaluated through colonization experiments in ABX-treated CHDD mice.

RESULTSHJSSJW markedly improved cardiac function in CHDD mice, significantly reduced serum myocardial injury markers, decreased cardiomyocyte apoptosis, and alleviated depressive-like behaviors. In ABX-treated CHDD mice, gut microbiota depletion attenuated the therapeutic efficacy of HJSSJW, whereas FMT from HJSSJW-treated donors partially reproduced these protective effects, suggesting that its actions were at least partially mediated by the gut microbiota. Moreover, colonization with Faecalibacterium prausnitzii, Parabacteroides goldsteinii, or Butyricicoccus pullicaecorum similarly improved cardiac function, reduced myocardial injury markers, attenuated cardiomyocyte apoptosis, and ameliorated depressive-like behaviors in CHDD mice, supporting the contributory roles of these bacteria in the protective effects of HJSSJW.

CONCLUSIONHJSSJW exerted coordinated cardioprotective and antidepressant effects in CHDD, which were at least partially mediated by the gut microbiota and were associated with the restoration of the dysregulated SRSF1-p53-ASPP1 signaling axis in cardiac and brain tissues. These findings suggested that HJSSJW might represent a multitarget therapeutic strategy for CHDD and further supported gut microbiota-targeted interventions as a promising therapeutic approach for CHDD.