Glyphosate, the active ingredient of RoundUp, promotes gut dysbiosis, vascular dysfunction and hypertension

Introduction: Glyphosate was developed and marketed as an herbicide by Monsanto, USA, in the 1970s. Since then, multiple studies have documented its adverse effects on human health, whereby the use of glyphosate is banned in Europe and its renewal is currently under discussion by European policy. However, glyphosate remains the most widely used herbicide in the United States. Glyphosate exposure can occur through consumption of genetically modified crops tolerant to glyphosate. Glyphosate targets 5-enolpyruvylshikimate-3-phosphate synthase, which is only present in plants and microbes. Therefore, glyphosate is considered safe for humans. However, humans are holobionts with symbiotic gut microbiota, which can be targeted by glyphosate to result in gut dysbiosis. Because our previous studies demonstrate that gut microbiota dysbiosis causes hypertension, we hypothesized that exposure to glyphosate aggravates gut dysbiosis-mediated hypertension. Methods: Two groups of adult (8–10 week old) genetically hypertensive Dahl salt-sensitive (S) male rats were surgically implanted with radiotelemetry transmitters to monitor blood pressure (BP) and administered with or without glyphosate (175 mg/kg body weight per day) in drinking water for 3 weeks (Glyphosate-treated group, n=8; control, n=6). Fecal 16S rRNA gene sequencing and Oxford Nanopore whole genome sequencing were performed for microbiota analyses. Vascular function was examined ex vivo in isolated mesenteric arteries using wire myography. Results: As early as 1 week of exposure to glyphosate was suffcient to significantly increase systolic (173 mmHg vs. 160 mmHg, p<0.0001) and mean arterial pressure (148 mmHg vs 141 mmHg, p<0.0002), but not diastolic BP of S rats. Diastolic BP (142 mmHg vs 135 mmHg, p<0.0001), systolic BP (195 mmHg vs 176 mmHg, p<0.0001), and mean arterial pressure (168 mmHg vs 155 mmHg, p<0.0001) were all significantly increased by week 3, indicating a temporally sustained detrimental effect of glyphosate on BP. The elevation in BP was accompanied by increased contractility of isolated mesenteric resistance arteries as determined by their increased vasocontractile response to phenylephrine (p=0.034), and decreased vasorelaxant response to acetylcholine (p=0.047). 16S metagenomics data revealed distinct rearrangement of gut microbiota composition in the glyphosate-treated group compared to control. Significant shifts in both α-diversity (Shannon entropy; p=0.049) and β-diversity (R=0.24, p<0.032) were observed in the glyphosate-treated group. Bacterial genera such as Candidatus, Erysipelatoclostridium, and Ruminicoccus were more abundant in the glyphosate group whereas Bifidobacterium that produces short-chain fatty acids, was depleted. Summary: Oral glyphosate exposure resulted in elevated BP, increased vascular contractility, and altered gut microbiota composition. Conclusion: This is the first proof-of-concept study to demonstrate that glyphosate is harmful for human health as it contributes to the escalation of hypertension. While more mechanistic studies are warranted, our study supports the reasoning that the unabated use of glyphosate could be a contributor to the rising incidence of hypertension in the western society. NHLBI to Bina Joe (R01HL1430820). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.