**1. Introduction**

Up to 10% of the population worldwide is affected by chronic kidney disease (CKD) [1]. CKD can be attributed to different negative conditions in early life [2–4], and therefore, World Kidney Day 2016 made efforts to keep the public informed of the need to focus on kidney disease in childhood and the antecedents of adult kidney disease [5]. During development, the fetal kidney is susceptible to a suboptimal in utero environment, resulting in alterations in function and structure by so-called renal programming [6]. The phenomenon of adverse conditions during organ development resulting in adult disease in later life is now termed "developmental origins of health and disease" (DOHaD) [7]. Conversely, adverse fetal programming could be reprogramming before clinical onset of the disease by early therapeutic intervention [8]. Accordingly, a shift of focus from treatment of established CKD towards the prevention of kidney disease in the earliest stage is highly needed.

Although various organ systems can be programmed in response to in utero suboptimal conditions, renal programming is considered key in the development of CKD and its comorbidities [6,9]. Renal programming is likely to constitute a first hit to the kidney, which makes the kidney more vulnerable to postnatal insults (i.e., second hit) to develop CKD in

**Citation:** Hsu, C.-N.; Tain, Y.-L. Chronic Kidney Disease and Gut Microbiota: What Is Their Connection in Early Life? *Int. J. Mol. Sci.* **2022**, *23*, 3954. https://doi.org/ 10.3390/ijms23073954

Academic Editor: Andrea Huwiler

Received: 25 February 2022 Accepted: 31 March 2022 Published: 2 April 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

later life. Up to now, researchers have proposed some mechanisms associated with renal programming. These mechanisms, such as dysregulated nutrient-sensing signals [9], oxidative stress [10], nitric oxide (NO) signaling [11], aberrant activation of the renin–angiotensin system (RAS) [12], and gut microbiota dysbiosis [13,14], have been contributing to CKD in later life [2–4,6,8,9].

Due to the low antioxidant capacity of embryos [15], the developing kidney is extremely vulnerable to oxidant stress injury. As reviewed elsewhere [16], a number of animal models support that NO/reactive oxygen species imbalance-induced oxidative stress is involved in renal programming. On the other hand, increasing evidence suggests antioxidants can be used as reprogramming strategies to prevent kidney disease and hypertension of developmental origins [17]. In the developing kidney, the RAS components are highly expressed and play a key role in mediating proper physiological function and renal morphology [18]. A transient biphasic response with downregulation of the classical RAS axis in the neonatal stage becomes normalized with age [19,20]. Data from renal programming models reported that various early-life insults can disturb this normalization in adults, and consequently, the classical RAS axis is inappropriately activated, leading to the development of kidney disease in adulthood [6,19,20]. Conversely, emerging evidence supports that early RAS-based interventions could reverse programming processes to prevent kidney disease of developmental origins [12]. Additionally, nutrient-sensing signals play an essential role in normal renal physiology and the pathogenesis of kidney disease [21]. Early-life nutritional insults can impair nutrient-sensing signals that affect fetal development and, consequently, program chronic disease in later life [22]. Dysregulated nutrient-sensing signals, such as AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptors (PPARs), have been linked to renal programming and the risks for developing kidney disease in later life [23,24]. Despite the fact that the complete mechanisms are still inconclusive, there seem to be interrelated aspects among them. Since detailed reviews of each mechanism are beyond the scope of this paper, readers are referred elsewhere [8–14].

Recent studies have focused on the impact of the gut microbiome in CKD and its associated complications [14]. Microbial metabolites can act as signaling compounds via systemic circulation [14]. Currently, there are some proposed mechanisms linking dysbiotic gut microbiota to CKD and related complications, such as alterations of the gut microbiome, dysregulation of short-chain fatty acids (SCFA) and their receptors, activation of aryl hydrocarbon receptor (AHR), increases of trimethylamine-N-oxide (TMAO), and microbiota-derived uremic toxins [14,25–29]. Maternal insults have been shown to change gut microbiome balance, leading to an increased risk of adult diseases [29]. Nevertheless, relatively little is known about whether and how diverse prenatal insults could influence gut microbiota, leading to CKD and its comorbidities in adult offspring.

This scoping review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) to identify and examine the evidence around the impact of gut microbiota behind the programming of kidney disease evidence documenting prevention of CKD and its related complications by early-life gut microbiota-targeted therapy [30]. Our search strategy was designed to retrieve literature relating to DOHaD, gut microbiota, and pediatric kidney disease from PubMed/MEDLINE databases. We used the following search terms: "chronic kidney disease", "developmental programming", "DOHaD", "reprogramming", "gut microbiota", "probiotics", "prebiotics", "synbiotics", "postbiotics", "mother", "pregnancy", "gestation", "offspring", "progeny", "uremic toxin", "nephrogenesis", "nephron number", "kidney", "aryl hydrocarbon receptor", and "hypertension". Additional studies were then selected and assessed based on fitting references in eligible papers. The last search was conducted on 25 January 2022.
