Abstract P001: Repurposing A Drug Targeting Inflammatory Bowel Disease For Lowering Hypertension

Abstract

Both the gut per se and its residents, the gut microbiota are linked to blood pressure (BP) regulation, whereby, the gut can be recognized as a previously neglected target organ for hypertension. Hypertension and gut diseases such as inflammatory bowel disease (IBD) share commonalities of host inflammation in the gut and microbiota dysbiosis. Therefore, we reasoned that current treatments to remedy gut inflammation and dysbiosis in IBD could be repurposed to ameliorate hypertension. IBD is commonly treated with 5-Aminosalicylic acid (5-ASA, Mesalamine), which is a selective PPAR-γ agonist to prevent gut inflammation. Clinical use of 5-ASA is also reported to ameliorate gut dysbiosis in IBD. Based on this premise, in this study we chose to test our hypothesis that 5-ASA is an antihypertensive drug owing to its dual ability to enhance PPAR-γ in the gut and to correct gut dysbiosis. 2 groups of 11-12 weeks old male genetically hypertensive Dahl salt-sensitive (S) rats were radiotelemetrically monitored for BP, and orally gavaged with (n=9) or without (n=7) 5-ASA (150 mg/kg) for 4 weeks. PPAR-γ expression was assessed by RT-qPCR. Fecal microbiota were profiled by 16S gene sequencing. Lastly, for translational significance, F/B ratio of non-IBD (n=611) patients was compared with that of IBD (n=631) patients in the American Gut Project data for their Firmicutes/Bacteroidetes (F/B) ratio, elevation of which is a marker of gut dysbiosis. 5-ASA significantly lowered BP of the S rat (mean BP without 5-ASA, 153±1 mm Hg; mean BP with 5-ASA, 145±1 mm Hg, P <0.0001). PPAR-γ gene expression was significantly higher in proximal colon, but not in the heart or kidney. In addition, treatment with 5-ASA corrected gut dysbiosis as observed by a significant reduction in the F/B ratio compared to control. In accordance, humans without IBD had a similar lower F/B ratio, which was consistent with the data presented here comparing S rats with 5-ASA. Collectively, these data support our hypothesis that 5-ASA, an FDA-approved anti-IBD drug, could be repurposed to treat hypertension by specifically enhancing the gut PPAR-γ mediated anti-inflammatory effect while also correcting microbiota dysbiosis to lower BP.