P177 MICROBIAL TRYPTOPHAN-INDOLE PATHWAY REGULATES BLOOD PRESSURE (BP) IN A SEX SPECIFIC MANNER

Introduction: Aberrant tryptophan absorption promotes hypertension as gut microbiota converts tryptophan to pro-hypertensive indole. Intestinal Ace2 regulates tryptophan homeostasis, but its role in salt-sensitive hypertension is unknown. Ace2 functions differently in males and females. Therefore, we hypothesized that sex-specific intestinal ACE2 dependent transport of tryptophan contributes to salt-sensitive hypertension via microbiota-indole axis. Methods: 10-week-old Dahl salt-sensitive (S) rats and novel Ace2 KO S rats of both sexes were maintained on either a low (LS) or high (HS) salt diet for 21 days. BP was measured by radiotelemetry. Gut microbiota and indole were analyzed. Results: Mean arterial BP of S Ace2 KO rats on LS was elevated in females by 38 mmHg (SAce2KO 170 ± 10 vs. S 132 ± 3; P=0.0028) and in males by 18 mmHg (SAce2KO 140 ± 6 vs. S 122 ± 1.5; P=0.01), and further elevated on HS by 68 mmHg in females (SAce2KO 211 ± 14 vs. S 143 ± 4.5; P=0.0003) and by 40 mmHg in males (SAce2KO 182 ± 9 vs. S 142 ± 3; P=0.0009). These were associated with elevated serum indole mainly in male SAce2KO 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 significant shifts in β-diversity in Ace2 KO rats of both sexes with more changes in HS males; and Ace2 KO induced more tryptophan-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. Conclusions: Lack of Ace2 increased BP regardless of sex and salt. In males, Ace2 KO increased indole levels and abundance of Escherichia-Shigella. Microbial changes by salt and ACE2 KO were found mainly in males, suggesting a more resilient microbiota in females. Thus, the microbiota-indole axis may be a therapeutic target for BP control in males with altered tryptophan metabolism.