Farnesoid X Receptor Deletion Protects Against Hypertension, Remodels Gut Microbiome, and Improves Cardiovascular Function

Introduction: Bile acids, synthesized by hepatocytes, are metabolized by microbiota within the gut-liver axis. Recent reports indicate that both bile acids and gut microbiota significantly contribute to hypertension. However, the role of bile acid receptors, specifically the farnesoid X receptor (FXR), in blood pressure (BP) regulation is completely unknown. Therefore, we focused on FXR, which is the key bile acid nuclear receptor. Since FXR is a negative regulator of bile acid synthesis, which can also reshape the gut microbiome, we hypothesized that the genetic ablation of FXR lowers BP by increasing bile acid levels and remodeling gut microbiota composition. Methods: To test the hypothesis, we generated the first global FXR knockout ( Fxr KO) rat model on the genetic background of hypertensive Dahl Salt-Sensitive (S) rat using the CRISPR/Cas9 technology. Adult 10-week-old male Fxr KO (n=9) and control S (n=8) rats were studied, and BP was measured by radiotelemery for five weeks. Gut microbiota composition was analyzed using fecal 16S rRNA gene sequencing and Oxford Nanopore whole-genome sequencing. Microbial bile salt hydrolase activity, an enzyme involved in bile acid deconjugation, was quantified by ninhydrin colorimetry. Cardiac function was examined by echocardiography, and vascular function was studied ex vivo by wire myography. Serum total bile acids were measured via colorimetric assay. Kidney function was characterized by urinary protein excretion (UPE) and histopathological analysis. Results: The loss of FXR resulted in elevated serum total bile acids (45.6 μM vs 15.06 μM, p=0.0003). This was accompanied by a substantial reduction in systolic BP (171.1 mm Hg vs 199.6 mm Hg, p<0.0001), diastolic BP (130 mm Hg vs 151.4 mm Hg, p<0.0001), and mean arterial pressure (149.7 mm Hg vs 174.7 mm Hg, p<0.0001). Frx KO rats showed improved cardiac function, as evidenced by increased ejection fraction (87.24 % vs 81.48 %, p=0.0003) and fractional shortening (58.39 % vs 51.43%, p=0.0005). Vascular function analysis in the dorsal aorta of Fxr KO rats further revealed increased sensitivity to both endothelium-dependent, (acetylcholine, Ach) and endothelium-independent vasodilators (sodium nitroprusside, SNP), with both exhibiting lower EC 50 values (-log EC 50 , Ach: -7.5±0.3 vs -7±0.2, and SNP: -8.8±0.2 vs -8.1±0.1). UPE was significantly decreased in Fxr KO rats compared to S rats (28.2 mg/24-hour vs 69.6 mg/24-hour, p=0.0064), with reduced hyaline casts and fibrosis in renal tissues. Moreover, Microbiota analysis revealed significant rearrangement of gut microbiota composition in Fxr KO rats compared to S rats (α-diversity, p<0.01; β-diversity, p<0.001). Notably, the abundance of Akkermansia muciniphila, a gut commensal with known probiotic properties, was significantly higher in the Fxr KO rats (p<0.0001). Remodeling of gut microbiome in Fxr KO rats resulted in significantly higher bile salt hydrolase activity (1.24 mM/min vs 0.65 mM/min, p<0.0001), which showed a significant negative correlation with systolic BP (r= -0.7, p=0.0024). Conclusions: Our study is the first Fxr KO rat model that demonstrates FXR deletion in hypertensive S rats is protective against hypertension, which could be attributed to a combination of improved cardiovascular and renal function. Importantly, the remodeled gut microbiome and increased microbial bile salt hydrolase activity suggest a novel link between bile acid deconjugation and the observed BP reduction. While further mechanistic studies are warranted, these findings establish FXR as a critical regulator of BP through bile acid-gut microbiota interactions and highlight bile acid modulation as a promising therapeutic strategy for hypertension. NIH R01HL171401-01 to Dr. Bina Joe and AHA Predoc 24PRE1186688 to Ishan Manandhar This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.