Chronic kidney disease (CKD), a condition characterized as a persistent kidney damage or glomerular filtration rate (GFR) <60 mL/min/1.73 m² for more than three months, has increased dramatically in recent years, with a global prevalence of between 8 and 16% ^[1][2][1,2]. As CKD is often asymptomatic in its early stages, less than 5% of patients with early stage CKD are aware of their disease [3]. There are 5 stages of CKD, based on glomerular filtration rate and albuminuria, irrespective of the cause of CKD [3]. In addition to the high risk of progression to end-stage kidney disease (ESKD), CKD also increases cardiovascular complications, the leading cause of morbidity and mortality in CKD [4]. For decades, much research has investigated well-accepted pathogenic factors contributing to CKD onset and progression, such as obesity, hypertension, dyslipidemia, and diabetes mellitus. Accumulated evidence has suggested that pathogenic mechanisms, including mitochondria dysfunction, oxidative stress, inflammation, and dysregulation of the gut microbiome, play pivotal roles in the development and progression of CKD. The implementation of current evidence-based clinical practices succeeds in only delaying the development of kidney failure. Death, transplantation, or dialysis are the consequence of kidney failure, resulting in a significant burden on the health system. There is an urgent demand for novel therapies for CKD treatment.

Mitochondria serve as the cellular “powerhouses” of cells, synthesizing adenosine triphosphate (ATP). They are also a potent mediator of primary intracellular reactive oxygen species (ROS). Maintaining mitochondrial function and structure is critical to cellular metabolism, homeostasis, and survival ^[5][19]. The kidney, a high-energy demand organ requiring large quantities of ATP energy to actively maintain its normal function ^[6][20], is rich in mitochondria. Hence, the kidney is susceptible to mitochondrial dysfunction, which is increasingly recognized to play a pivotal role in the progression of CKD ^[7][21]. Mitochondrial defects, including a decrease in the quality and quantity of mtDNA, have been documented in experimental models and in patients with CKD ^{[8][9][10][11]}[22,23,24,25]. In addition, the accumulation of damaged mtDNA and fragmented mitochondria leads to mitochondrial dysfunction, which is a hallmark of tubular injury, particularly in patients with diabetic kidney disease (DKD) ^[12][26]. Similarly, lower mitochondrial content and reduced mitochondrial proteins, including the mitochondrial transcription factor A (TFAM), an essential regulator of the mitochondrial genome, have been reported in patients with CKD and in mouse models of folic acid (FA) and unilateral ureteric obstruction (UUO)-induced CKD ^[13][27]. Overexpression of carnitine palmitoyl-transferase 1A (CPT1A), the fatty acid shuttling enzyme involved in the fatty acid oxidation, alleviated kidney fibrosis and improved kidney function in three experimental models of CKD by enhancing fatty acid oxidation and restoring impaired mitochondrial function with increased mitochondrial mass, and normalized bioenergetics and ATP production ^[14][28].

In addition, mitochondrial dysfunction also contributes to CKD progression via oxidative stress which occurs due to an imbalance between the overproduction of mitochondrial reactive oxygen species (mtROS) and reduced antioxidant systems ^[15][29]. Increased oxidative stress has been observed in CKD and dialysis patients ^[16][30]. In the kidney, excessive mtROS production, mainly produced by deregulated mitochondrial respiratory chain via oxidative phosphorylation system, cannot be removed by antioxidant systems and consequently leads to oxidation of cellular components such as DNA, proteins, and lipids, resulting in kidney cells damage ^[17][18][31,32]. For example, Huang et al. reported oxidative stress damage in DKD rats, evidenced by increased expression of malondialdehyde and decreased superoxide dismutase (SOD). In addition, researchers indicated that treatment with Dencichine, an active component in Chinese medicinal herbs, attenuated diabetes-induced kidney injury in DKD rats by inhibiting oxidative stress responses, enhancing the antioxidant capacity, and normalizing autophagy as well as reducing renal cell apoptosis ^[19][33]. A clinical study identified that oxidative stress marker, including increased advanced oxidation protein product, myeloperoxidase, malondialdehyde, nitric oxide, oxidized low-density lipoprotein, and decreased glutathione, are closely related to the carotid atherosclerosis process in patients with CKD, indicating those oxidative markers may serve as the markers to predict the progression of CKD ^[20][34].

Therefore, mitochondrial dysfunction and oxidative stress derived from damaged mitochondria contribute to the pathogenesis of CKD. A therapeutic strategy targeting mitochondria to improve mitochondrial function or relieve oxidative stress is thus likely to be beneficial in improving kidney function in CKD.

Inflammation is characterized by the activation of a variety of inflammatory markers, such as cytokines, chemokines, and cell adhesion molecules, mainly produced by the innate immune system. Inflammation is triggered by injury during a complex biological preventive and reparative process. Many studies have elucidated that inflammatory molecules and signaling pathways are directly involved in the development and progression of CKD ^[10][21][24,35].

Cytokines are proteins of molecular weight between 15 and 20 kDa that interplay with the development and activity of the immune system, such as interleukins (ILs), tumor necrosis factor alpha (TNF-α), interferon (IFN-γ), and transforming growth factor-beta 1 (TGF-β1). They play an essential role in paracrine, autocrine, and endocrine signaling ^[22][36]. Interleukin 6 (IL-6) is one of the interleukins secreted by leukocytes and the most studied in kidney disease due to its pro-inflammatory effects. The serum level of IL-6 is significantly increased in CKD patients compared to healthy subjects ^[23][37]. Of interest, Tocilizumab, an IL-6 receptor-targeted drug, significantly reduced the glomerular and tubulointerstitial fibrosis via inhibiting the IL6/ERK signaling pathway in the UUO model of CKD ^[24][38]. Milas et al. found that increased levels of pro-inflammatory interleukins, such as IL-1α, IL-8, and IL-18, were associated with podocyte injury and proximal tubular dysfunction in the early stage of DKD in patients with type 2 diabetes mellitus ^[25][39]. Additionally, elevated serum IL-9 levels have been found in patients with primary focal and segmental glomerulosclerosis, suggesting that the up-regulated expression of IL-9 was induced by glomerular injury in humans ^[26][40]. TNF-α is secreted by invading immunologic cells, specifically by monocytes/macrophages ^[27][41]. A clinical study with 133 CKD patients found that TNF-α and INF-γ, Th1 (T helper cell type 1) cytokines significantly increased in CKD patients, suggesting that Th1 cells were activated in the inflammatory response induced by CKD ^[28][42]. It is well known that TGF-β1 is a key mediator of kidney fibrosis, with the TGF-β1 pathway shown to be modified by photobiomodulation ^[29][18]. Conversely, recent studies have identified TGF-β1 as a potent anti-inflammatory cytokine, which negatively regulates renal inflammation ^[30][31][43,44]. The anti-inflammatory effect of TGF-β1-partially explains the negative trials of TGF-β1 antibodies in human CKD ^[32][45]. The diverse roles of TGF-β1 in kidney fibrosis and inflammation has been well summarized ^[33][46].

Dysregulated composition and function of the gut microbiome, termed gut microbiota dysbiosis, has been recognized as a pathogenic mechanism in many diseases, including CKD ^[34][47]. Previous studies have shown that gut bacteria dysbiosis contributes to CKD via several mechanisms, such as accumulation of uremic toxins, decreased production of short-chain fatty acids (SCFAs), disturbed enteroendocrine, and leaky gut barrier [2].

Significant alterations in the gut microbiome composition, richness, diversity, and blood and fecal metabolic composition have been found in patients with CKD and kidney failure, supporting a crucial role of gut dysbiosis in the pathogenesis of CKD ^[35][36][37][48,49,50]. Transferring gut microbiota from patients with kidney failure into CKD models of germ-free mice and antibiotic-treated rats resulted in increased uremic toxins, enhanced oxidative stress, and aggravated renal fibrosis, confirming a causative contribution of the aberrant gut microbiota to CKD ^[38][51]. In a clinical study with 73 pre-dialysis and dialysis patients with kidney failure and 19 healthy controls, gut microflora was measured via high-throughput sequencing. The results indicated that hemodialysis, but not peritoneal dialysis, mitigated gut microbiota disorders by increasing the richness of beneficial bacteria and reducing some potential pathogenic bacteria compared to pre-dialysis patients with kidney failure ^[39][52].

Uremic toxins, produced by gut bacterial metabolism, typically accumulate at the early stage of CKD, and contribute to progressive kidney function loss [1]. Dysregulated gut bacteria in CKD are associated with increased production of gut-derived uremic toxins, including p-cresyl sulfate, p-cresyl glucuronide, indoxyl sulfate, indole acetic acid, and trimethylamine n-oxide (TMAO) in the gut lumen and blood circulation, which is facilitated by increased intestinal barrier permeability and impaired excretory function ^[40][41][53,54]. The study by Gryp et al. found increased protein-bound uremic toxins, including p-cresyl sulfate, p-cresyl glucuronide, indoxyl sulfate, and indole acetic acid, in plasma but not in feces and urine from CKD patients, indicating that the accumulated plasma protein-bound uremic toxins are likely due to the impaired kidney function ^[42][55]. In addition, increased circulating TMAO and its three main precursors, choline, betaine, and L-carnitine, were found to be closely correlated with the grade of CKD and estimated glomerular filtration rate, suggesting that the gut microbiota metabolite TMAO and its precursors together could be potential non-invasive biomarkers for CKD ^[43][44][56,57]. Similarly, Sun and his team found that elevated serum 3-indole propionic acid level, a microbial tryptophan metabolite, is negatively correlated with CKD development, indicating 3-indole propionic acid may be a key biomarker and protective factor for CKD ^[45][58].

SCFAs are derived from anaerobic bacterial fermentation of indigestible foods in the large intestine and then absorbed into the systemic circulation. The primary SCFAs produced in humans include acetate, propionate, and butyrate ^[46][47][59,60]. SCFAs regulate regional inflammation and cellular metabolism in kidneys via binding to G-protein coupled receptors (GPCRs) such as GPR43, GPR41, and GPR 109a ^[48][61], which are expressed on almost all immune cells ^[49][62]. Reduced levels of SCFAs were observed in patients with CKD ^[50][51][63,64]. For example, significantly lower levels of fecal SCFAs, including acetic acid, propionic acid, butyric acid, iso-butyric acid, and caproic acid, have been found in patients with IgA nephropathy, which is accompanied by altered gut microbiota diversity ^[50][63]. The beneficial effect of SCFAs has been further confirmed in different mouse models of CKD, including diabetic- and folic acid-induced CKD models ^[52][53][65,66]. A recent study highlighted the reno-protective effect of dietary fiber by promoting the expansion of the SCFAs-producing bacterial population, leading to increased SCFAs concentration. SCFA supplementation treatment further confirmed the direct beneficial effect of SCFAs in the CKD mice through SCFA mediated histone deacetylase activity and the GPR pathway ^[54][67].

Collectively, these data suggest that modifying the gut microbiota dysbiosis observed in patients with CKD may provide a new therapeutic strategy for treatment.