The Gut Microbiome is Central to the Mechanistic Adverse Effect of the Environmental Herbicide Glyphosate on Elevating Blood Pressure

Introduction: Hypertension is the leading contributor to human mortality through cardiovascular diseases. Multiple recent population studies suggest that individuals exposed to the widely used herbicide, glyphosate present with elevated blood pressure (BP) or hypertension. However, the mechanism by which glyphosate contributes to hypertension is unknown. Glyphosate was developed as an herbicide based on its inhibitory effect on a plant enzyme, which is absent in humans. However, this enzyme, 5-enolpyruvylshikimate-3-phosphate synthase, is also present in microbiota. Previously, we and others have demonstrated that gut microbiota causally contributes to BP regulation. Therefore, we hypothesized that gut microbiota is the primary target of glyphosate to elevate BP. Methods: Four groups of adult hypertensive male Dahl Salt-Sensitive (S) rats were studied. Groups 1 and 2 (n=7/group) were with and without exposure to glyphosate (175 mg/kg/day) in drinking water up to three weeks. Groups 3 and 4 (n=6/group) were with and without exposure to glyphosate administered subcutaneously. BP was monitored by radiotelemetry. Gut microbiome composition was examined by fecal 16S rRNA gene sequencing and Oxford Nanopore whole-genome sequencing. Sympathetic nerve activity was studied by in situ whole nerve recordings, and serum norepinephrine levels were quantified by ELISA. Total serum bile acids were measured using colorimetric assay, and targeted bile acid profiling was via UHPLC-MS. Results: Compared to controls, rats orally administered with glyphosate had significantly higher systolic BP (195 mm Hg vs. 176 mm Hg, p<0.0001), diastolic BP (142 mm Hg vs. 135 mm Hg, p<0.0001), and mean arterial pressure (168 mm Hg vs. 155 mm Hg, p<0.0001).16S rRNA data revealed significant alterations in gut microbiota composition with reduced α-diversity (Shannon entropy; p<0.05) and β-diversity (Bray-Curtis; p<0.02) in glyphosate-treated rats. Nanopore metagenomics further showed a significant depletion of bacterial species, including Lactobacillus johnsonii, Bifidobacterium pseudolongum and Faecalibacterium rodentium, which are known to produce beneficial metabolites in the host. Interestingly, there was a significant negative correlation between serum norepinephrine and the abundance of Lactobacillus johnsonii (r=-0.6, p<0.05), suggesting a potential role of the gut microbiota-brain axis in mediating glyphosate-induced hypertension. In support, both sympathetic nerve activity (35% higher, p<0.05) and serum norepinephrine levels were elevated as early as one week of glyphosate exposure (5.85 ng/mL vs. 4.77 ng/mL, p<0.05), which continued to increase at week three of glyphosate exposure (13.31 ng/mL vs. 6.16 ng/mL, p<0.001). In addition, total bile acids, which are crucial metabolites in the liver-gut microbiota interactions, were significantly reduced (12.71 μM vs. 23.45 μM, p<0.05), and lower bile acids were negatively correlated with systolic BP (r=-0.62, p=0.02). Targeted bile acid profiling further revealed depletion of various unconjugated primary and secondary bile acids. To further affirm the role of gut microbiota, we administered glyphosate subcutaneously to bypass its effects on the gut microbiota. No significant changes in BP were observed by subcutaneous glyphosate, supporting our hypothesis that gut microbiota is the central mediator of glyphosate-induced hypertension. Conclusions: Our is the first study to demonstrate herbicide glyphosate aggravates hypertension through mechanisms involving gut microbiota disruptions, sympathetic overdrive, and alterations in the bile acid pool, further highlighting the role of gut-brain and gut-liver axes in BP regulation. 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.