Abstract 082: Dysregulated Microbiota-indole Axis In Male, Not Female Ace2 Deficient Salt-sensitive Hypertension

Abstract

Introduction: Aberrant tryptophan (Trp) absorption may promote hypertension (HTN) due to gut microbiota converting Trp to pro-hypertensive indoles. Intestinal Ace2 regulates Trp homeostasis, but its role in salt-sensitive HTN is unknown. Further, lack of Ace2 can affect males and females differently because Ace2 is transcribed from the X-chromosome in a genomic region which escapes X-inactivation. Therefore, we hypothesized that sex-specific intestinal ACE2 dependent transport of Trp contributes to salt-sensitive HTN via the microbiota-indole axis. Methodology: 8-10-week-old Dahl salt-sensitive (S) rats and newly generated CRISPR/Cas9 Ace2 deficient S rats of both sexes (N= 7 rats/group) were maintained on either a low (0.3 % NaCl, LS) or high (2 % NaCl, HS) salt diet for 21 days. BP was measured by radiotelemetry for 24 hours on day 21. Serum and cecal content were collected for indole measurement and microbiota analysis. Results: Mean arterial BP of S Ace2 deficient rats on LS was elevated in females by 38 mmHg (S Ace2 -/- 170 ± 10 vs. S 132 ± 3; P =0.0028) and in males by 18 mmHg (S Ace2 -/Y 140 ± 6 vs. S 122 ± 1.5; P =0.01), and further elevated on HS by 68 mmHg in females (S Ace2-/- 211 ± 14 vs. S 143 ± 4.5; P =0.0003) and by 40 mmHg in males (S Ace2-/Y 182 ± 9 vs. S 142 ± 3; P =0.0009). These were associated with elevated serum indole levels mainly in male S Ace2 -/Y rats, compared to S rats on both LS (1.2 ± 0.2 vs. 0.3 ± 0.2 μM; P =0.02) and HS (1.5 ± 0.25 vs. 0.2 ± 0.03 μM; P =0.0001). Microbiota analysis revealed (1) significant shifts in β-diversity in Ace2 deficient rats of both sexes with a higher R value and a lower P value in HS males; (2) Ace2 deficiency resulted in higher abundance of Trp-utilizing, indole-producing bacteria Escherichia - Shigella in males on both LS ( P <0.05) and HS ( P <0.0001). Strikingly, none of these differences were found in females. Conclusion: Lack of Ace2 led to increased mean BP regardless of sex and salt intake. In males, Ace2 deficiency led to increased indole levels with higher abundance of Escherichia - Shigella . Overall microbial changes by salt and ACE2 deficiency were found mainly in males, suggesting a more resilient microbiota in females. Thus, the microbiota-indole axis may be a potential therapeutic target for BP control in males with altered Trp metabolism.