Gut microbiota-kidney cross-talk in acute kidney injury

Summary

The recent surge in research on the intestinal microbiota has greatly changed our understanding of human biology. Significant technical advances in DNA sequencing analysis and its application to metagenomics and metatranscriptomics has profoundly enhanced our ability to quantify and track complex microbial communities and to begin understanding their impact on human health and disease. This has led to a better understanding of the relationships between the intestinal microbiome and renal physiology/ pathophysiology. In this review, we discuss the interactions between intestinal microbiota and kidney. We will focus on select aspects including the intestinal barrier, immunologic and soluble mediators of microbiome effects, and effects of dysbiosis on AKI. Relevant studies on microbiome changes in other renal diseases are highlighted. We also introduce potential mechanisms of intervention with regards to gut microbiota in renal diseases.

1. Dysbiosis of the microbiota causes disease

The human gut microbiome consists of at least 1000 genera of bacteria which build their own community [1]. Although there is a lack of clear understanding on what constitutes a ‘healthy’ gut microbiota, it is increasingly clear that imbalance of the gut microbiota, dysbiosis, is associated with disease development both in the intestine and in other organs. The intestinal epithelial barrier plays a key role in maintaining homeostasis of intestinal microbiota. In healthy individuals, this barrier largely prevents intestinal bacteria and toxins from crossing the intestinal mucosa into the circulatory system, or to other tissues and organs. As depicted in Figure 1, the intestinal epithelial barrier can be divided into three components – a biological barrier, a physical barrier, and an immune barrier – each of which can become dysfunctional.

Fig.1. Intestinal barrier to bacteria.

A) Gut microbiota plays a direct protective role as a biological barrier. They are closely attached to the surface of the intestinal mucosa and compete with pathogenic bacteria and thus can inhibit the colonization and excessive growth of pathogens. B) The intestinal epithelial layer acts as a physical barrier. Tight junction proteins play an important role in the establishment and maintenance of cell polarity within tissues. They function as a fence that restricts the intermixing of lipid and protein components of apical and basolateral membrane domains, regulate the permeability of solutes and ions through the paracellular space and prevent pathogens from reaching the subepithelial tissue. C) Microbiota and epithelial cells interact with each other and regulate subsequent immune response. Translocation of bacterial products across the leaky intestinal barrier activates the immune system, resulting in systemic inflammation. IgA released from Paneth cells plays a fundamental role in mucosal immunity, mainly in response to colonization by specific commensal bacteria. Activation of DCs activated by intestinal microbes results in the secretion of proinflammatory cytokines such as IL-12, IL-6. These DCs promote the differentiation of naïve CD4⁺ T cells into regulatory T (Treg) cells and the maturation of B cells into IgA-secreting plasma cells. Th17-inducing bacteria may promote Th17 immunity via IL-17A/IL-17F induction, which may involve signaling mediated by the TLR ligands. Finnally, innate lymphoid cells(ILCs) function by limiting macrophage production of the pro-inflammatory cytokines IL-1β, IL-12, IL-23, IL22 and IFNγ.

The biological barrier is composed of bacterial and fungal symbionts. Large numbers of primarily anaerobic symbionts defend against pathogens by secreting antimicrobial proteins (AMPs) via Paneth cells to disrupt the surface structure of bacteria [2]. The commensal bacteria also yield short chain fatty acids (SCFAs); these end-products of carbohydrate digestion and fermentation are associated with pH reductions in the intestinal tract [3]. Symbionts are closely attached to the intestinal mucosal surface, and compete with pathogenic bacteria to inhibit the colonization and excessive growth of pathogens. This phenomenon, known as colonization resistance, plays a major role in maintaining intestinal homeostasis [4].

The physical barrier refers to the intestinal epithelial cells, whose apical tight junctions (TJs) form a defensive wall that prevents free diffusion from the intestinal lumen to the basolateral lamina propria. TJs of intestinal epithelial cells are mainly composed of transmembrane proteins and cytoplasmic proteins. These TJs serve two main functions. (1) They maintain the permeability barrier. Changes in TJs can lead to increased permeability through the physical barrier, ultimately allowing bacteria, endotoxins, and/or macromolecules to enter the circulatory system [5]. (2) TJs also maintain the polarity of intestinal epithelial cells. The fusion points between the plasma membranes of adjacent epithelial cells form a continuous apical surface and maintain cell polarity by restricting free diffusion of lipids and intact membrane proteins in different liquid spaces of cells [6].

The activation of the immune barrier response is the third strategy for maintaining microbial homeostasis. Dendritic cells (DC) in the lamina propria activate T cells to evoke an adaptive immune response. A key feature of the adaptive response is DC-mediated recruitment of regulatory T cells (Tregs), which critically depends on the activation of non-classical autophagy pathways [7–9]. Epithelial release of nuclear factor- κB (NF-κB) also plays a critical role in controlling proinflammatory response, as well as the nod-like receptor pyrin domain containing 3 (NLRP3) inflammasome [10]. Innate lymphoid cells (ILCs) located in the gut epithelium also have key defensive functions, producing or activating the release of immune-activating cytokines (i.e. IL- 22 [11], IFN-γ [11,12], IL-1β, IL-12 and IL-23 [13]) via adaptive and innate immune responses. Furthermore, the secretion of AMPs and IgA by Paneth cells protects mucosal surfaces and contributes to host-microbiota mutualism [14].

2. Microbiota-derived metabolites affect kidney function

Communication between gut and kidney occurs not only through the direct contact between host and microbiota, but also through indirect communication via microbiota-derived metabolites.

2.1. Short-chain fatty acids

As mentioned above, the gut microbiota produce SCFAs, including acetate, propionate, and butyrate, during the fermentation of dietary fibers. SCFAs are being increasingly recognized for their roles in regulating the dynamic balance between the microbes and host. The fact that SCFAs cannot be detected in germ-free (GF) mice suggests that SCFA production requires the presence of bacteria [15,16].

SCFAs primarily signal through G-protein-coupled receptors (GPCRs), a large protein family that detects molecules outside the cell and activates internal signal transduction pathways. GPR41, GPR43, and GPR109A are the major GPCRs activated by SCFAs. GPR41 is expressed in a variety of tissues and cell types, including the colon, kidneys, sympathetic nervous system, and blood vessels [17,18]. It is implicated in inhibiting cell proliferation and inducing apoptosis [19], energy homeostasis [20], T-cell differentiation, and immunity [21]. GPR43 knock-out (GPR43⁻/⁻) mice have decreased SCFA-induced release of glucagon-like peptide-1 (GLP-1), a key hormone that controls insulin release, and affects satiety and intestinal transit [22]. GPR43 mRNA and protein can be detected in eosinophils, basophils, neutrophils, monocytes, DCs, and mucosal mast cells [23,24], suggesting a broad role of GPR43-targeting SCFAs in immune responses. GPR109A is also expressed by immune cells and plays an important role in reducing the progression of atherosclerosis [25]. Additionally, another SCFA receptor named Olfr78 was recently found to play a functional role in the modulation of blood pressure [26]. Figure 2 shows a model of SCFAs and their GPRs in modulating kidney disease.

Fig.2. SCFAs and the receptors in kidney.

GPR41, GPR43, GPR109A and Olfr78 are four SCFA receptors identified in kidney. GPR41and GPR43 are activated by acetate, propionate, butyrate, and isobutyrate and function as regulators of the immune system. Luminal butyrate exerts anti-inflammatory effects via GPR109A and HDAC inhibition. SCFAs also regulate cytokine expression in T cells and generation of Tregs through HDAC inhibition. Effector Th17 cells have enhanced aerobic glycolysis, and inhibition of glycolysis promotes Treg cell generation. The activation of GPR41 can reduce blood pressure, whereas Olfr78, upon stimulation by acetate and propionate, increases blood pressure. SCFAs-mediated cytokines include IL-8, IL-6, IL-1β, TNFα, TGFβ, and IL-10.

SCFAs also act as histone deacetylase (HDAC) inhibitors that can regulate the epigenome by altering chromatin remodeling [27]. Pharmacologic HDAC inhibition has demonstrated anti-fibrotic, anti-inflammatory, and immunosuppressant effects in obstructed kidney and was found to reduce cyst formation in polycystic kidney disease [28]. By inhibiting HDAC activity, SCFAs increase the acetylation of histone, consequently modulating the expression of immune-regulating genes, including NF-κB, myogenic differentiation antigen, tumor protein p53, and nuclear factor of activated T cells (NFAT) [29]. These observations are consistent with studies showing that SCFAs, particularly acetate, play a crucial role in kidney disease. In a mouse model of kidney ischemia-reperfusion injury (IRI), acetate treatment administered in two separate intraperitoneal dosages (initially 30 minutes before ischemia induction and secondly at the moment of reperfusion) diminished serum levels of creatinine and urea [30]. Additionally, in a mouse model of experimental sepsis-induced AKI, acetate administration attenuated HDAC activity in T cells, resulting in restoration of oxidant-antioxidant balance [31]. Together, these data support a beneficial effect of SCFAs in kidney injury.

2.2. Trimethylamine-N-Oxide (TMAO)

Trimethylamine-N-oxide (TMAO), a small colorless amine oxide, is a by-product of phosphatidylcholine metabolism in the gut microbiota. It is directly derived from the metabolism of trimethylamine (TMA), which is synthesized exclusively by gut microbiota from dietary nutrients such as choline, an essential nutrient that forms the headgroup of the phospholipid phosphatidycholine, and carnitine, an amino acid with key metabolic functions. A clinical study of 283 individuals reported a correlation between elevated TMAO levels in plasma and an increased risk for major adverse cardiovascular events and death [32]. Gut microbiota-derived TMAO also contributes to renal interstitial fibrosis as shown in a mouse model of diet-induced obesity [33]. In C57BL/6J mice, a diet containing choline or TMAO led to tubulointerstitial fibrosis, collagen deposition, and phosphorylation through the TGFβ/Smad3 signaling pathway [34]. Chronic kidney disease (CKD) patients with increased plasma TMAO levels had lower long-term survival rate [35]. In hemodialysis patients, high TMAO level is associated with higher risk of sudden cardiac and all-cause mortality compared to those with lower TMAO level, especially in Caucasians [36] [37]. Cumulatively, these data suggest an important role for TMAO as a potential gut-derived toxin. To date, there is no published study on the effects of gut microbiota-derived TMAO levels in AKI, but limited CKD data and evidences from studies in related fields suggest that increased TMAO may worsen kidney function during AKI.

3. Gut microbiota and host immunity

Microbiota appear to promote the development of gut-associated lymphoid tissues (GALTs) and intestinal immune homeostasis through the regulation and induction of both adaptive and innate immune responses.

3.1. Tregs mediate intestinal immunity

Tregs exhibit diverse phenotypes depending on their origin (thymic vs. peripheral) and location (lymphoid vs. tissue-resident). DCs in the intestinal lamina propria induce the differentiation of gut-resident naïve T cells into intestinal Tregs following stimulation with lumen-derived antigens. These intestinal Tregs likely regulate effector T-cell responses to gut bacteria, including the expression of cell surface proteins and cytokine production [38]. Treg frequency is reduced several-fold in GF mice compared with mice housed in specific-pathogen free (SPF) facilities, indicating that gut microbiota regulate the Treg population [39]. Additional studies have shown that induced Tregs participate in maintaining tolerance to intestinal antigens [40]. Increasing evidence further demonstrates that the development of colonic Tregs occurs in response to species-specific bacterial antigens. Peripherally-derived Tregs (pTreg) have also been identified in a population of pathobiont-specific Tregs that selectively regulate pathobiont-driven inflammation in healthy mice [41]. In addition to their local effects on the intestinal Treg population, gut microbiota have also been found to affect peripheral Treg differentiation [42].

It appears that Treg induction serves as a strategy to establish commensalism, not only by helping the microorganisms to colonize their niche, but also by protecting the host from inflammation. Furthermore, Tregs appear to reinforce intestinal homeostasis by promoting tolerance to commensal bacterial and related-proteins [43]. These changes depend on the activity of T helper 17 (Th17) cells, a subset CD4 T helper (Th) cells that are defined by their production of the proinflammatory interleukin-17 (IL-17) [41]. The aryl hydrocarbon receptor/IL-22 axis in group 3 innate lymphoid cells (ILC3) has been shown to contribute to the suppression of inflammatory Th17 cell responses that maintains Treg-mediated gut homeostasis [44]. Thus, it is possible that ILC3 and Th cells share a number of features, and that ILCs may not only impair intestinal immunity against pathogen infection, but also induce autoimmunity in the gut by disturbing commensal flora [44].

3.2. IgA function in relation to intestinal microbiota

Immunoglobulin A (IgA) is essential for maintaining the symbiotic balance between the intestinal bacterial community and the host immune system [45]. The multiple functions of IgA in relation to intestinal microbiota include neutralizing toxins and viruses, blocking excessive live bacterial adherence or translocation, clearing unwanted macromolecular structures at the epithelial surface, and directed-sampling of luminal antigen [46]. IgA is produced by plasma cells in the small intestine by mechanisms that are independent of exogenous antigens and T cell contributions. In the steady state, IgA secreted by resident plasma cells act as natural polyreactive antibodies [47]. They possess innate-like recognition properties that may facilitate adaptation to the vast and dynamic array of exogenous microbiota and dietary antigens encountered at mucosal surfaces [48]. In the T cell transfer model of colitis, co-transfer of Tregs was required to limit pathology, maintain intestinal microbial diversity, and induce IgA [49]. In another study, depletion of Tregs reduced intestinal IgA level, suggesting that Tregs may directly induce IgA via secretion of TGFβ [50]. These findings indicate that there is an important Treg/IgA pathway at the host-microbiota interface.

3.3. Host immune response affects kidney disease

Emerging evidence from experimental models and human studies supports a key role of Th17 cells in renal injury. It has been shown that the induction and suppression of Th17 cells in the intestine leads to their migration and activation in kidney [51]. It appears that gut-derived Th17 cells can be recruited to inflamed kidney via a CCL20/CCR6 axis [52]. In addition, reduction of microorganisms by antibiotics reduces Th17 response and tissue damage in murine experimental crescentic glomerulonephritis [53]. Th17 cells are abundant in patients with autoimmune kidney diseases, such as anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, and disease activity correlates with IL-17 serum levels [54]. Interestingly, cultured microbiota isolated from stools of systemic lupus erythematosus (SLE) patients, but not healthy controls‟ promoted lymphocyte activation and naïve CD4⁺ T cell differentiation into Th17 cells [55].

4. Microbiome and AKI

Acute kidney injury (AKI) involves multiple and overlapping immunological, biochemical, and hemodynamic mechanisms. Recent experimental data has revealed that the intestinal microbiota significantly affect outcomes in AKI [56]. Despite increasing data on microbiome and kidney diseases, there has been limited mechanistic or clinical data on AKI.

4.1. Gut microbiota and kidney inflammation

AKI is associated with intrarenal and systemic inflammation [57]. One mechanism by which gut microbiota reduces inflammation in kidney is through secretion of SCFAs. Four SCFA receptors have been reported in kidney: GPR41, GPR43, Olfr78, and GPR109a. GPR41 and GPR43 expression in the whole kidney and in the renal artery has been detected by RT-PCR [58]. In a mouse model of IRI, acetate treatment increased expression of GPR43 in kidney tissue [30,31]. Olfr78 is expressed in the renal juxtaglomerular apparatus, where it mediates renin secretion in response to SCFAs [58]. Finally, GPR109a has been reported in adipose tissue associated with the kidney at a relatively low level and its function in kidney disease remains unclear [59].

A number of findings suggest a beneficial effect of SCFAs in AKI. Recent data shows intraperitoneally administered SCFAs reduced kidney injury by modulating the inflammatory response, apoptosis and autophagy in a murine IRI model of AKI. Treatment with SCFAs not only decreased production of reactive oxygen species (ROS), but also diminished production of cytokines and chemokines such as IL-1β, IL6, TNF-α, and MCP-1. In addition, low levels of mRNA of the toll-like receptor 4 (TLR4) and its endogenous ligand were detected in kidney tissue, activation of NF-κB was inhibited in kidney epithelial cell line. Furthermore, in vitro analyses showed that SCFAs decreased maturation of DCs and inhibited the capacity of these cells to induce CD4 and CD8 T cell proliferation. SCFAs ameliorated the effects of hypoxia in kidney epithelial cells by improving mitochondrial biogenesis [30]. All these findings indicate that modulation of SCFAs in the gut could be a novel therapeutic approach against AKI. Mechanistic insights have also been gleaned from a rat model of contrast-induced nephropathy (CIN): administration of sodium butyrate decreased IL-6 levels in kidney tissue, preventing the translocation of NF-κB into the nucleus, and reducing inflammation and oxidative damage in the kidney after CIN [60]. This result suggests that SCFA-mediated HDAC inhibition may evoke therapeutic effects through a similar mechanism.

An emerging concept across biomedical research is that the use of “squeaky clean” mice can significantly alter research findings [61]. While searching for the reason at why murine kidney contains has abundant immune cells, including lymphocytes, it was hypothesized that GF mice may lack bacteria as well as kidney lymphocytes [62]. Contrary to expectations, ample kidney lymphocytes, including increased natural killer T (NKT) cells, and IL-4 cytokine, were found in kidneys of normal GF mice. Furthermore, the GF status worsens kidney histological and functional responses to IRI, with enhanced CD8 T cell trafficking. Conventionalized GF mice, in which normal gut bacteria have been reconstituted, appear to be protected from kidney injury: After IRI, 11-week-old conventionalized GF mice had less injury in the outer medulla and inner medulla compared with age-matched GF mice and 6-week-old GF mice, revealing the promise of therapeutic bacteria for AKI [62]. In another study, broad-spectrum antibiotics protected mice against IRI-induced kidney injury by reducing the maturation status of F4/80+ renal-resident macrophages and bone marrow-derived monocytes.

Furthermore, transplant of fecal material from untreated mice to microbiota depleted mice abolished this protective effect [63]. Thus, the relevance of antibiotic treatment and its effects on the intestinal microbiota are worth noting. Patient data suggests these effects are not limited to rodents: Long-term use of rifaximin, an oral broad-spectrum antibiotic that concentrates in the gastrointestinal tract, was found to increase glomerular filtration rate and natriuresis, thus improving systemic hemodynamics and renal function in patients with advanced cirrhosis [64,65].

4.2. Microbiome and uremic toxins

Normally, intestinal bacteria can generate uremic toxins that are absorbed into the blood and cleared by the kidney. However, changes in the microbiome composition can lead to excessive secretion of uremic toxins, which may damage renal tubular cells [66]. Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are protein-bound uremic toxins generated from colonic bacterial fermentation of dietary protein. Free serum levels of p-cresol (the precursor of PCS) are associated with increased mortality in hemodialysis patients [67]. The generation of p-cresol and indole (the precursor of IS) were also upregulated in patients on hemodialysis in comparison to healthy individuals [68]. TMA is another important urinary compound metabolized by gut microbiota and choline. It has been shown that the serum level of TMAO and related metabolites affect kidney functions and are associated with an increased risk of CKD and its complications, such as atherosclerosis [69]. Recent evidence from studies on AKI-to-CKD transition and end-stage renal disease (ESRD) indicate that changes in intestinal microbiota do occur in kidney diseases and reversing microbiota dysbiosis may prevent toxins and pathogens from permeating the intestinal barrier [56]. Hemodialysis or peritoneal dialysis may also induce intestinal barrier permeability in patients and contribute to the translocation of endotoxins from intestinal lumen to kidney [70].

4.3. Microbiome and blood pressure.

Arterial hypertension is a frequent finding in both acute and chronic kidney diseases. Recent studies have focused on the connection between the microbiome and hypertension. In GF mice, angiotensin II treatment was unable to induce hypertension [71]. In a model using chronic high salt intake, conventional mice developed early renal injury and hypertension. However, transplantation of fecal microbiota from conventional mice on chronic high salt diet to conventional mice on normal diet causes gut leakiness and renal injury. This indicates that high-salt-diet causes enteric dysbiosis that triggers renal injury and dysfunction [72]. Hydrogen sulfide (H₂S) has been shown to be an important player in a variety of physiological functions, particularly in the renal vasculature. Deregulation of H₂S biosynthesis causes or contributes to existing high blood pressure [73]. These limited results have highlighted the need for new research into the roles of gut microbiota in the development of hypertension and their influence on physiological levels of H₂S, which could lead to novel strategies for exploiting microbiota for treatment of hypertension.

5. Modulation of gut microbiota in kidney disease

5.1. Probiotics and prebiotics

A number of therapeutic opportunities for targeting IS and PCS have been proposed, including inhibition of colonic bacterial biosynthesis, suppression of absorption, augmentation of clearance, and modulation of cellular pathways [74]. For example, orally administered AST-120, a highly potent activated charcoal adsorbent, reduces systemic toxin absorption through gastrointestinal sequestration, which may slow disease progression in CKD patients [75]. Probiotics consist of living bacteria, such as bifidobacterium species, lactobacilli, and streptococci can alter gut microbiota and affect the inflammatory response. Lactobacillus treatment can restore mucosal barrier function by increasing the expression of the TJ-associated protein zona occuldens-1 (ZO-1) [76]. Hemodialysis patients treated with oral Lactobacillus acidophilus showed decreased serum dimethylamine, a potential uremic toxin. A double-blind placebo-controlled randomized cross-over trial using synbiotics (co-administration of pre- and probiotics) showed beneficial effects on CKD stage 4–5 patients [77]. Table 1 summarizes recent advances in the use of probiotics and prebiotics as novel treatments for kidney disease [78,79][80] [81] [82] [83] [84] [85] [86].

Table.

Prebiotics and probiotics in kidney disease.

	Strain	Disease type	Effect	Year	Reference
probiotics	Lactobacillus. acidophilus	CKD stage3,4	Decrease Bun, Cr, uric acid, uremic toxins	2009 2010	[78,79]
		Diabetic + HD	Glucose homeostasis, Inflammation, oxidative stress	2017	[80]
		Aging mice	Kidney klotho marker	2012	[81]
	Lactobacillus. casei	LPS induced acute inflammatory model	Regulate immuno-coagulative response	2018	[82]
	Lactobacillus. rhamnosus	MRL/lpr lupus nephritis model	Anti-inflammatory, decreased IgG2a in kidney, adjust immunity	2017	[83]
	Bifidobacteria. bifidum	Mice model of primary hyperoxaluria	Limiting absorption across intestine	2015	[84]
prebiotics	Oat and barley beta-glucans	Healthy individuals	Decrease p-cresyl sulfate	2017	[85]
	xylooligosaccharide	Obese rats	Decrease renal oxidative stress and apoptosis	2018	[86]

Abbreviations: CKD: chronic kidney disease; Bun: blood urea nitrogen; Cr: creatinine; HD: hemodialysis; LPS: Lipopolysaccharide.

5.2. Targeting immune pathways

Direct targeting of immune responses downstream of microbial regulation has been explored as a strategy for limiting kidney damage. Kidney-infiltrating Th17 cells that mediate microbiome effects can be therapeutically targeted at multiple levels of the immune response. IL-23, a pro-inflammatory cytokine belonging to the IL-12 cytokine family, and Th17 cells identify a newly discovered axis for therapeutic intervention. Th17 cell expansion and maintenance can be disrupted using monoclonal antibodies against IL-23 (e.g. guselkumab [87]), and IL-23/IL-12 (e.g. ustekinumab [88]). IL-17A, secreted by Th17 cells, might be the most promising target and can be blocked with monoclonal anti-IL-17A antibodies, such as secukinumab and ixekizumab [89,90]. Alternatively, monoclonal antibodies such as brodalumab inhibit IL-17 receptor (IL-17R) signaling [91]. In addition to secretion of IL-17, Th17 cells are characterized by the expression of transcription factor RORγt. Several RORγt inhibitors are under development and might represent a promising approach for patients with immune-mediated kidney disease.

Strategies targeting the microbial source of immune regulation also show promise. The presence of lactic acid bacteria (Lactobacillales) in the gut microbiota can promote Treg cells and suppress disease-causing Th17 cells in kidney to attenuate kidney inflammation in lupus-prone mice [83]. Oral administration of Lactobacillus acidophilus ATCC 4356 led to attenuation of atherosclerotic progression through modulation of oxidative stress and inflammatory process in apoliprotein-E knockout (ApoE^−/−) mice [92]. IgA produced in programmed cell death protein-1 (PD-1)-deficient (PD-1^−/−) mice reduced bacterial-binding capacity and changed the microbial composition of the intestinal tract [93]. Additional data shows that intestinal microbiota enhances the efficacy of PD-1 and its ligand (PD-L1) therapy [94]. The ability of the intestinal microbes to rapidly respond to changes in the environment through dynamic alterations in gene expression renders microbial regulation of the immune barrier highly plastic. The use of functional metagenomics screening methods to study intestinal microbes is an exciting prospect for new therapeutic discovery [95].

Conclusion

The pathogenesis of AKI involves immunological, biochemical and hemodynamic mechanisms. Research on the microbiome has revealed new opportunities to better understand AKI. Figure 3 summarizes the key mechanisms by which microbiome dysbiosis can influence AKI. Experimental data in animal models has demonstrated the impact of intestinal microbiota on the process and outcome of AKI and highlighted the promise of treatment using prebiotics, probiotics or both. In the future, it will be important to determine whether targeted modulation of the intestinal microbiome can act as a potential therapeutic tool for AKI.

Fig.3. Dysbiosis during AKI.

AKI involves multiple and overlapping immunological, biochemical, and hemodynamic mechanisms. Gut dysbiosis generates SCFAs, which regulate systemic consequences of AKI. TMA/TMAO, combined with uremic toxins and other gut-derived toxins, contributes to nephrotoxicity-induced AKI.