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.

Chien-Ning Hsu,Guo-Ping Chang-Chien,Chih-Yao Hou,Sufan Lin,You-Lin Tain

doi:10.3390/antiox11030483

Abstract

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.

Highlights

An increasing body of data highlights pregnancy and lactation as a critical period upon which maternal insults may shape health and disease in the resulting offspring, referred to as the Developmental Origins of Health and Disease (DOHaD) [1]
hydrogen sulfide (H2 S) can regulate microbial tryptophanase activity [10,16], we aimed to examine whether maternal L- or D-cysteine supplementation can afford protection for offspring rats against hypertension induced by maternal chronic kidney disease (CKD) and elucidate underlying mechanisms with a focus on gut microbiota and tryptophan-derived metabolites
Considering H2 S can regulate microbial tryptophanase activity to affect the degradation of tryptophan to indole [11,16], our results demonstrate the feasibility of altering the production of indole metabolites through manipulation of the gut microbiota by L-cysteine treatment

Summary

Introduction

An increasing body of data highlights pregnancy and lactation as a critical period upon which maternal insults may shape health and disease in the resulting offspring, referred to as the Developmental Origins of Health and Disease (DOHaD) [1]. Our prior research reported that maternal adenine-induced CKD induces blood pressure (BP) elevation in adult offspring, which coincided with alterations of gut microbiota composition, changes of derived metabolites, and increases of uremic toxins [3]. Indole metabolites of tryptophan (i.e., indoxyl sulfate and indoleacetic acid) are a key group of gut microbiota-derived uremic toxins, which play a crucial role in the pathogenesis of CKD [6]. Tryptophan-derived uremic toxins can activate aryl hydrocarbon receptors (AHR) to induce oxidative stress through the activation of NADPH oxidase and the inhibition of antioxidant defense mechanisms [6,7]. It is well known that oxidative stress plays a key role in the pathogenesis of CKD and hypertension in developmental origins [8]. Little information exists on whether tryptophan-derived metabolites are beneficial or harmful to maternal CKD-induced hypertension in adult offspring

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