4.3.3. TMAO

TMAO is an end-product of microbial carnitine and choline metabolism [89]. TMAO is converted from trimethylamine (TMA) by flavin-containing monooxygenase (FMO). TMAO is able to activate nuclear factor-κB (NF-κB) signaling, enhance leukocyte-endothelial cell adhesion, and induce inflammatory gene expression, all of which are related to the development of hypertension [111].

Maternal exposure to TMAO results in hypertension in adult male offspring [103]. Conversely, microbe-dependent TMA and TMAO formation can be inhibited by 3,3-dimethyl-1 butanol (DMB), a structural analogue of choline [112].

In a maternal high-fructose diet model, maternal DMB therapy showed protection against hypertension in adult rat offspring, which was relevant to the reduction of TMA and TMAO levels [94]. Another study demonstrated that perinatal resveratrol therapy protected adult rat offspring against maternal CKD-induced hypertension, which was associated with a decrease of the TMAO-to-TMA ratio [113]. These observations suggest a pathogenic link between the TMAO metabolic pathway and hypertension of developmental origins.

#### *4.4. Core Mechanisms Linking to Gut Microbiota*

Considering that various early-life insults during fetal development produce the same outcome—hypertension in adulthood—there might be some core mechanisms involved in the pathogenesis of hypertension of developmental origins. A number of mechanisms so far have been proposed, such as aberrant RAS, oxidative stress, reduced nephron numbers, dysregulated nutrient-sensing signals, inflammation, sex differences, epigenetic regulation [7–9,11–14]. Among them, some are interconnected to gut microbiota dysbiosis and will be discussed in turn.

#### 4.4.1. Oxidative Stress

During pregnancy, the presence of excessive reactive oxygen species (ROS) under suboptimal in utero conditions may prevail over the defensive antioxidant system and compromise fetal development, leading to oxidative stress damage [114]. A review elsewhere indicated that there are various types of in utero insult stimuli linked to oxidative stress in mediating hypertension of developmental origins [115]. The main mechanisms underlying the actions of oxidative stress-related hypertension of developmental origins include increased ROS-producing enzyme expression [116], increased ROS formation [117], decreased antioxidant capacity [118], impaired NO signaling pathway [27], increased lipid peroxidation [119], increased oxidative DNA damage [43], and increased peroxynitrite production [120].

Data from several animal models listed in Table 1 shows that the connections between gut microbiota dysbiosis and oxidative stress may be involved in the pathogenesis of programmed hypertension, including maternal CKD [43], high-fructose diet [95], and high-fat diet models [110]. Gut microbial communities are able to elicit redox signaling and

maintain host–microbiota homeostasis [121]. An imbalance in the redox state can lead to inflammatory responses and gut damage, resulting in gut microbiota dysbiosis. In a maternal CKD model, offspring developed hypertension related to increased oxidative stress and impaired NO signaling [43]. In a subsequent study, perinatal resveratrol therapy protected adult offspring against hypertension programmed by maternal CKD, accompanied with reshaping the gut microbiota and reducing oxidative stress concurrently [113].

Together, oxidative stress may work together with the gut microbiota under hypertension of developmental origins. More attention needs to be paid to evaluate how the gut microbiota interconnects with oxidative stress to elicit organ-specific programming processes behind hypertension, and whether antioxidant therapy in pregnancy may also benefit the gut microbiota to protect adult offspring against hypertension of developmental origins.
