Dietary Supplementation with Cysteine during Pregnancy Rescues Maternal Chronic Kidney Disease-Induced Hypertension in Male Rat Offspring: The Impact of Hydrogen Sulfide and Microbiota-Derived Tryptophan Metabolites

Maternal chronic kidney disease (CKD) is linked to offspring hypertension. The gut microbiome and its tryptophan metabolites, nitric oxide (NO), and renin–angiotensin system (RAS) are closely related to the development of hypertension. Hydrogen sulfide (H2S) has shown an anti-hypertensive effect. Our objective was to test whether L-or D-cysteine supplementation in pregnancy can prevent hypertension programmed by maternal CKD in adult offspring and to explore the protective mechanisms. CKD was induced in pregnant Sprague Dawley rats by a 0.5% adenine diet for 3 weeks. L-or D-cysteine was supplemented at 8 mmol/kg body weight/day during pregnancy. Male offspring were sacrificed at the age of 12 weeks (n = 8 per group). Maternal CKD-induced hypertension was similarly prevented by L-or D-cysteine supplementation. The protective effects of L-and D-cysteine are related to reducing oxidative stress, rebalancing the RAS, and reshaping the gut microbiome. L-cysteine therapy protected adult offspring against hypertension and was associated with enhanced H2S production, restoration of NO bioavailability, enhancement of beneficial genera Oscillibacter and Butyricicoccus, depletion of indole-producing genera Alistipes and Akkermansia, and the reduction of several indole metabolites. D-cysteine treatment increased kynurenic acid, 3-hydroxykynurenine, and xanthurenic acid in the kynurenine pathway, decreased 5-hydroxytryptophan and serotonin in the serotonin pathway, and enriched genera Bacteroides and Odoribacter abundance. In summary, these results suggest that L-and D-cysteine protect against maternal CKD-induced offspring hypertension, likely by enhancing H2S production, modulating gut microbiota and its derived metabolites, and the restoration of NO and RAS.