Abstract
Chronic kidney disease (CKD) is a progressive condition that is associated with a number of serious cardiovascular comorbidities. These are caused by the accumulation of uremic retention solutes (URSs) such as protein-bound uremic toxins, which include indoxyl sulfate, p-cresyl sulfate and trimethylamine-N-oxide. These toxins are metabolized from dietary precursors by the gut microbiota and liver enzymes. Elevated levels of uremic toxins intensify renal and cardiovascular tissue damage by augmenting oxidative stress and inflammation, culminating in adverse outcomes such as atherosclerosis, fibrosis and endothelial dysfunction. Kidney transplantation has been demonstrated to normalize these URS levels, thereby underscoring the pivotal role of renal function in the clearance of these toxins. Conversely, alterations in the composition of the gut microbiota may provide a potential avenue for the reduction of uremic toxin levels and the associated complications. In this review, studies from the 2020 to 2024 period were examined, and the microbiota taxa that are particularly relevant to uremic toxin production were grouped. In addition, their roles in the pathophysiology of CKD were addressed, thereby underscoring the significance of the gut–kidney axis. In the study, the taxa that have attracted attention in studies conducted in the relevant years were discussed separately according to their phylum, family, genus and species.
Introduction
Chronic kidney disease (CKD) patients suffer from cardiovascular comorbidities, which lead to poor survival rates. Apart from traditional risk factors, such as diabetes mellitus and hypertension, elevated circulating metabolites, known as uremic retention solutes (URSs), accelerate adverse cardiovascular-related outcomes. Epidemiological findings are supported by animal models demonstrating how high levels of URSs can damage renal and cardiovascular tissue. L-carnitine and choline, tryptophan and phenylalanine and tyrosine are dietary forerunners of TMAO (trimethylamine-N-oxide), IS (indoxyl sulfate) and PCS (p-cresyl sulfate), respectively, which are altered by the intestinal microbiota to form intermediary metabolites that are then transformed via hepatic enzymes to form the ultimate URS. These URSs are expelled via the kidneys in healthy adults, leading to low levels of circulation. Elevated blood URS levels have been observed in CKD patients experiencing kidney failure. Following a successful kidney transplant, these levels return to those of healthy adults, signifying the influence of kidney function on the elevation of serum URS levels. Potential therapies to reduce the production of URSs and thereby potentially reducing circulating levels and the associated adverse outcomes include dietary modifications and therapeutics that may modulate the gut microbiota.
CKD
The kidney is an essential organ that serves a multitude of functions, such as regulating water, salt and acid levels in the body, eliminating metabolic waste and producing hormones and prostaglandins. Due to its intricate structure, kidney diseases can be complex and are evaluated based on four units: glomerular, tubular, interstitial and vascular structures (Khan et al. 2013). CKD is a condition that results in irreversible renal dysfunction caused by damage to any of these components (Felizardo et al. 2016).
CKD significantly influences incidence and mortality from noncommunicable diseases. Between 7 and 12% of the world’s population has CKD, which has become a global medical issue (Klinkhammer & Boor 2023). In 2017, CKD caused an estimated 1.2 million deaths. By 2019, CKD had become the 18th leading cause of death and the 8th among individuals aged 50–74 (Vos et al. 2020). More than 2.5 million individuals are undergoing renal replacement therapy, with projections indicating that this figure will reach 5.4 million by 2030 (Liyanage et al. 2015), and it is projected that CKD will be the 5th leading cause of death by the year 2040 (Foreman et al. 2018). Regrettably, in various nations, access to renal replacement services is limited. This shortage of treatment options has resulted in an estimated 2.3–7.1 million adults dying prematurely (Liyanage et al. 2015).
The leading causes of CKD vary by region, with diabetes and hypertension being the most common causes (Couser et al. 2011). HIV may also contribute to the development of CKD in developing countries (Ekrikpo et al. 2018), as can exposure to toxins or heavy metals (Jha et al. 2013). The root cause is still unknown in some regions where CKD is highly prevalent (Correa-Rotter et al. 2014). On the other hand, age, gender, high blood pressure, ethnicity, socioeconomic factors and genetic factors are thought to be risk factors for CKD. Acute renal failure, glomerulonephritis, diabetes mellitus, genetic diseases, cardiovascular diseases (CVDs), multisystem diseases, drugs, urological conditions and infections are among the reported causes of CKD (Lucas & Taal 2023).
CVD is a major cause of mortality in people with CKD. For example, people with CKD appear at an increased risk of major adverse cardiovascular events, including atherothrombotic disease leading to myocardial infarction and stroke, heart failure, arrhythmias and sudden cardiac death in adults and children (Charytan 2018, Weaver & Mitsnefes 2018).
Along with diabetes mellitus and hypertension, elevated levels of URSs in the bloodstream have the potential to increase the risk of negative cardiovascular outcomes (Schiattarella et al. 2017). Three frequently researched URS metabolites are IS, PCS and TMAO (Vaziri et al. 2016, Jian et al. 2023).
The URS metabolites in question are a byproduct of the metabolic processes of L-carnitine and choline, resulting in the production of TMAO (Yu et al. 2019), tryptophan, which results in the production of IS (Imazu et al. 2017, Graboski et al. 2023), and tyrosine and phenylalanine, which results in the production of PCS (Di Paola et al. 2023). There are three steps involved in their synthesis: i) tryptophan, tyrosine, phenylalanine, L-carnitine and choline are obtained from the diet and encounter the intestinal microbiota; ii) the intestinal microbiota processes the nutrients to produce intermediate or final metabolites; and iii) metabolic intermediates undergo modification by the intestinal mucosa and/or gut microbiota before their transportation to the liver via the portal circulation. Once there, hepatic enzymes engage in further modification of these metabolites, resulting in the production of IS, PCS and TMAO, the final products (Daneshamouz et al. 2021, Di Paola et al. 2023).
Based on evidence from both animal and human studies, it is known that impaired elimination of uremic toxins from the intestinal microbiota exerts a detrimental effect on cardiovascular and renal tissues, primarily through the formation of fibrosis and impairment of endothelial function (Koppe et al. 2018). In non-CKD adults, the kidneys eliminate gut-derived URSs, causing a decrease in circulating levels. However, elevated levels of URSs in the bloodstream have been documented in individuals with renal failure. Upon successful kidney transplantation, URS concentrations return to levels similar to those found in non-CKD adult patients (Stubbs et al. 2016). However, it has also been observed that the levels of some uremic toxins increase again over time after renal transplantation (Liabeuf et al. 2018).
Microbiota
The term microbiota denotes the community of microorganisms present in a specific sample or location. While it broadly encompasses bacteria, viruses, fungi and protozoa, the term is most commonly used to refer to bacterial communities (Snelson et al. 2020). Nonetheless, it also includes commensal populations of archaea and protists (Matijašić et al. 2020). The basis of studies conducted in the field of microbiota in recent years is the determination of the factors affecting the microbiota in health or disease. When an organ precedes the term microbiota, it refers to the microbial community in that area like the ‘gut microbiota’ that we generally refer to in this study. A healthy microbiota needs to be diverse and in a dynamic balance. Unless the change caused by external factors is large enough, the microbiota tends to return to a stable state. However, severe and continuous change, along with the underlying genetic predisposition and medications used due to chronic diseases, cause an imbalance in the flora called dysbiosis. Many factors play a role in the emergence of dysbiosis. Inflammation and past infections, diet and xenobiotics, genetic structure, familial transmission, disruption of circadian rhythm, pregnancy, maternal malnutrition and physical damage are the leading factors among these factors.
The gut microbiota has recently become a subject of remarkable research due to its relationship with kidney diseases. The initial elucidation and definition of the ‘gut–kidney axis’ theory clarified the possible mechanisms by which gut microbiota-derived metabolites mediate this relationship and that changes in the composition or dysbiosis of the gut microbiota may influence these metabolites, thereby affecting the pathogenesis of CKD (Meijers & Evenepoel 2011, Wu et al. 2011). It is noteworthy that an increasing number of studies emphasize the critical role of the gut microbiota in the progression of CKD (Wu et al. 2011, Natarajan et al. 2014, Yang et al. 2018, Ren et al. 2020).
Uremic toxins, metabolic products of the intestinal microbiota associated with kidney disease, are often bound to proteins. This binding makes their filtration through the glomerular barrier more difficult. Accumulation of these urotoxins is a sign of decreased kidney function (Luo et al. 2022). The production of these metabolites is also the primary means by which the microbiota exerts its effects on the host. The effects of interventions on the microbiota are monitored by measuring these metabolites (Jin et al. 2019). As we explained earlier, frequently investigated metabolites are indoxyl sulfate, p-cresyl sulfate and trimethylamine-N-oxide (Vaziri et al. 2016, Jian et al. 2023). Comprehensive information regarding uremic toxins can be found in the relevant sections.
We performed a comprehensive literature review focusing on studies addressing microbiota and associated uremic toxins published between 2020 and 2024. This review identified pivotal research relevant to specific aspects of microbiota–toxin dynamics. The findings from these studies are systematically presented under the section titled ‘key findings from screening: microbiota–toxin interactions’ accompanied by detailed tables and explanatory notes to ensure clarity and comprehensiveness. Fungal and viral communities were not included in this study due to the primary focus on bacterial taxa. In addition, the current literature on the role of fungi and viruses in CKD-related microbiome alterations remains limited, requiring further comprehensive investigations.
URS
Individuals who suffer from CKD frequently expel harmful substances called uremic toxins through their urine. This can result in a range of health problems including renal fibrosis, anemia, bone diseases and CVDs. Further analysis of the pathophysiology of uremia has revealed that oxidative stress and inflammation are both factors that contribute to and are caused by this condition in CKD patients (Mutsaers et al. 2013, Hoyer & Nahrendorf 2019).
In cases of CKD, the body typically eliminates uremic toxins through urine to prevent the onset of various ailments such as anemia, renal fibrosis, bone diseases and CVDs. Upon closer inspection, it becomes apparent that uremia can both be a consequence and a catalyst of inflammation and oxidative stress in patients grappling with CKD (Zemaitis et al. 2024).
In recent years, there has been growing acceptance of the toxicity of uremic solutes. To date, over 150 molecules have been documented. IS, a highly researched protein-bound uremic toxin, is directly linked to cardiovascular events. Further research reveals that IS contributes to the advancement of renal fibrosis, bone deformities and neurological degradation (Hoyer & Nahrendorf 2019). In a study of TMAO, it has been shown that circulating TMAO levels increase due to CKD, which increases vascular oxidative stress and inflammation, contributing to endothelial dysfunction and CVD (Li et al. 2018).
The taxa associated with the increase or decrease of the relevant uremic toxins are indicated in the respective tables where applicable.
Indoxyl sulfate
Indoxyl sulfate (IS) is a harmful metabolite that can build up in the body as a result of the breakdown of dietary tryptophan. Specifically, the tryptophanase enzyme found in intestinal bacteria, such as Escherichia coli, converts tryptophan to indole, which then transforms in the liver to become IS. Once it has been absorbed by the intestines, the kidneys are responsible for removing it from the proximal tubules (Imazu et al. 2017).
IS is a metabolite that predominantly binds to serum albumin in the bloodstream, with over 90% of the compound being attached to this protein (Niwa & Shimizu 2012). Due to this robust binding, dialysis is not an effective means of removing the molecule from the body. Notably, as CKD progresses, the likelihood and severity of inflammation also increase (Niwa & Shimizu 2012, Lu et al. 2023).
IS is recognized to be efficient in the development of atherosclerosis and vascular inflammation by increasing oxidative stress in the endothelium. In individuals with CKD, IS levels increase inversely with glomerular filtration rate, and IS levels had an inverse association with renal function and a direct relationship with aortic calcification and mortality (Caldiroli et al. 2021, Wu et al. 2021).
Studies have shown that IS can have a notable impact on the emergence of CVD in patients with CKD, serving as a critical connection between these two conditions (Kaminski et al. 2019, Lin et al. 2020, Lu et al. 2023). In patients with stage 3–4 CKD, URSs, such as IS and PCS, have been found to elevate levels of inflammatory markers, such as interleukin-6 and glutathione peroxidase. In addition, these toxins have been linked to systemic inflammation and atherosclerosis (Lau et al. 2015). In addition, an old study discovered that IS can initiate inflammatory responses by inhibiting lymphoblast and interleukin-2 (Kawashima 1989).
A very important study on IS and its cardiovascular relationships was conducted in 2006 (Yamamoto et al. 2006). As a result of the study, it was determined that there was a significant correlation between IS and the development of atherosclerosis and vascular inflammation. Their findings showed that IS increased oxidative stress in the endothelium (Yamamoto et al. 2006). Later studies involving 139 patients in 2009 showed a direct relationship between IS levels and CKD as the glomerular filtration rate decreases. In this group, IS levels were also associated with aortic calcification and mortality (Barreto et al. 2009).
Exposure to IS has been observed to increase the expression and activation of ERK, P38 mitogen-activated protein kinases and NFkB, which have the potential to impact cardiac remodeling. In addition, renin receptors and angiotensin receptors are activated by IS, leading to harmful effects on cardiomyocytes, cardiac fibroblasts and cardiac endothelial cells. These negative effects ultimately contribute to cardiovascular dysfunction (Imazu et al. 2017).
During the initial phases of CKD, elevated IS levels have been associated with left ventricular dysfunction, coronary atherosclerosis, coronary stent restenosis and cardiac fatality (Ravid et al. 2021). Nonetheless, in advanced CKD, like that experienced by hemodialysis patients, the relationship between high IS levels and cardiovascular incidents, and cardiac death, is not straightforward. Studies discovered that heightened IS levels were not connected to cardiovascular morbidity and mortality, potentially due to end-organ damage already caused by advanced CKD and the reduced impact of uremic toxins (Ackley et al. 2017, Ravid et al. 2021, Li et al. 2022c , Takkavatakarn et al. 2022).
Numerous studies have shown that IS and PCS, which are protein-bound uremic toxins, can lead to the development of CKD by causing oxidative stress in renal tubular cells. Moreover, these toxins can also contribute to CVDs associated with CKD by inducing oxidative stress in endothelial cells and vascular smooth muscle cells. A vital study revealed that IS and PCS both significantly contribute to the advancement of CKD and its associated complications (Asai et al. 2018).
A study found that IS has pro-fibrotic, pro-hypertrophic and pro-inflammatory effects on NCF (neonatal rat cardiac fibroblasts), NCM (neonatal rat cardiac myocytes),and THP-1 (human monocytic cell line) cells. This suggests that reducing IS or its activated pathways could be a promising approach to treat CVDs associated with CKD (Lekawanvijit et al. 2009).
In a study, it was shown that IS levels were high for CKD and end-stage renal disease (ESRD), but decreased in the first phase of renal transplantation (1 month) and could remain at the current level without increasing again in the early transplant phase (within 12 months) (Liabeuf et al. 2018). In another study, it was reported that IS levels increased as a result of malnutrition in renal transplant patients and as a result, it was possible to increase renal dysfunction (Huang et al. 2012).
A review of more recent literature suggests that similar views are still valid that IS levels are associated with CKD progression (Cheng et al. 2020, Holle et al. 2020, Lu et al. 2021). Similarly, studies have been conducted to determine the relationship between IS and CVDs, with a particular focus on patients with CKD. In these studies, elevated levels of IS observed in patients with CKD have not been associated with heart failure (Iwasaki et al. 2024); however, they have been linked to vascular calcification (Gao et al. 2024) and atherosclerotic mechanisms (Wakamatsu et al. 2024).
P-cresyl sulfate
P-cresyl sulfate (PCS) is a tyrosine metabolite produced by the gut microbiota. It is processed in four steps: the first three of which are carried out in gut microbes to form intermediates, namely 4-hydroxyphenylpyruvate, 4-hydroxyphenylacetate and p-cresol. The final step is the formation of PCS in the gut mucosa or liver. PCS, like IS, induces NADPH oxidase activity and reactive oxygen species production, which contributes to direct cytotoxicity to cardiomyocytes, facilitating cardiac apoptosis and resulting in diastolic dysfunction (Zhao & Wang 2020).
PCS plays a significant role in CKD-related pathophysiology by activating protumorigenic processes such as chronic systemic inflammation, increased oxidative stress through free radical production and immune dysfunction (Simeoni et al. 2024a ). It is also known that circulating PCS levels are an independent marker for predicting the risk of CKD progression and various clinical events by exerting prooxidant and pro-inflammatory effects on complex organ systems (Chang et al. 2020).
A study investigated the potential links between blood antioxidant levels, oxidative stress, arterial thickness and various inflammatory parameters. The findings showed a correlation between serum-free and total IS and PCS levels and inflammatory markers, and a positive association was observed between PCS levels and IL-6 and arterial stiffness (Rossi et al. 2014).
The fermentation of the amino acid tyrosine forms p-cresol. This fermentation process is carried out by bacteria such as Bifidobacterium, Clostridium difficile, Faecalibacterium prausnitzii, Lactobacillus and Subdoligranulum. Then p-cresol reacts with sulfate in the liver and gets converted into PCS (Nallu et al. 2017).
Studies have indicated that PCS and IS have the potential to harm kidney cells by triggering specific pathophysiological alterations (Mutsaers et al. 2015). These alterations can arise through a range of mechanisms, including oxidative stress, cytokine and inflammatory gene expression, renal fibrosis, nephrosclerosis, differentiation of epithelial cells into mesenchymal cells, activation of the renin–angiotensin–aldosterone system (Delgado-Valero et al. 2021, Sapian et al. 2022, Zhang et al. 2023), methylation of the Klotho gene and the induction of intercellular adhesion molecule-1 (ICAM-1). These effects not only cause renal damage but also have cytotoxic effects that lead to cardiovascular and inflammatory changes. Several studies suggest that these toxins may serve as dependable biomarkers for predicting CKD-related cardiovascular and inflammatory consequences (Biagi et al. 2010, Cigarran Guldris et al. 2017, Delgado-Valero et al. 2021).
Recent studies also report that PCS, like IS, has a role in CKD (Corradi et al. 2024) and is also associated with CVD (Zwaenepoel et al. 2024). Studies also show that PCS correlates with diabetes (Oladi-Ghadikolaei et al. 2023). There are also recent studies reporting the association of IS and PCS with cancer progression (Simeoni et al. 2024a , b ).
Trimethylamine-N-oxide
Trimethylamine-N-oxide (TMAO) is a gut microbiota-dependent degradation product of dietary trimethylamine precursors (mainly choline and carnitine). Its metabolism consists of three steps: first, intestinal microbial degradation of dietary trimethylamine precursors; second, conversion of trimethylamine to TMAO by liver enzymes; and finally, elimination of TMAO by the kidney. Trimethylamine is oxidized in the liver by FMO (flavin-containing monooxygenases), especially FMO3, to produce TMAO (Yu et al. 2019).
The mechanisms by which TMAO may exacerbate kidney damage and worsen nephropathy are not fully understood. However, the potential of TMAO to aggravate kidney disease by activating the inflammatory response should be considered (Zixin et al. 2022). TMAO activates the NLRP3 inflammasome, leading to the release of IL-1β and IL-18, thereby accelerating renal inflammation (Fang et al. 2021). Beyond intensifying inflammation, TMAO is also known to contribute to oxidative stress in CKD patients (Ribeiro et al. 2024). High TMAO concentrations are known to induce vascular oxidative stress and inflammation, reducing NO production, which may trigger endothelial dysfunction and CKD-related complications such as CVD (Li et al. 2019).
The concentration of TMAO in human blood plasma is increased in patients with renal failure. It can range from 3 mmol/L in healthy individuals to 40 mmol/L in those with renal failure. However, information on the amount of TMAO found in other tissues is limited (Koeth et al. 2013). Research has indicated that individuals who suffer from advanced kidney disease frequently exhibit elevated TMA and TMAO levels within their system. This may be attributed to a decline in kidney function and a diminished capacity to eliminate TMAO from the bloodstream. Furthermore, kidney impairment stemming from inadequate blood flow to the kidneys could also play a role in heightening TMAO levels in both urine and plasma (Ufnal et al. 2014).
Recent research suggests that elevated levels of TMAO in the bloodstream may increase the likelihood of developing CVD, regardless of the presence of other known risk factors such as diabetes or renal failure (Zixin et al. 2022). However, it is worth noting that individuals with high TMAO levels exhibit additional risk factors such as hypertension, diabetes and impaired renal function (Gruppen et al. 2017).
In a study, TMAO levels were measured in the healthy control group, individuals with CKD in the 3rd, 4th and 5th stages of the disease, ESRD patients and transplantation patients. As a result of the study, it was observed that TMAO levels were normal in healthy individuals and increased as CKD stages progressed. The mean concentration in ESRD patients was reported to be approximately 30 times higher than the mean in the control group with normal renal function. In addition, TMAO concentrations were measured before and 3 months after the transplant in six individuals who had successful renal transplantation, and it was reported that a rapid decrease was encountered (Stubbs et al. 2016). Similarly, a different study observed a significant decline in TMAO levels following kidney transplantation, which remained stable for at least 2 years posttransplantation (Missailidis et al. 2016).
In a prospective study, the levels of various uremic toxins were measured in 51 kidney transplant recipients at four time points: at the time of transplantation and then on day 7, month 3 and month 12. The results showed that all analyzed uremic toxins dropped significantly within the first 7 days posttransplant. Among patients with CKD, serum TMAO levels showed a marked decrease by day 7 compared to healthy individuals. However, this decrease became much less significant by month 3 and beyond (Poesen et al. 2016).
Key findings from screening: microbiota–toxin interactions
This study is not a meta-analysis study, but is planned as a general evaluation of studies conducted in the period 2020–2024. This review was created by examining approximately 600 studies as a result of searching the terms ‘uremic toxins, TMAO, PCS, IS and microbiota’ in ScienceDirect and PubMed. Studies containing uremic toxins or their metabolites (such as IS and PCS or tryptophan and indole derivatives instead) were evaluated. The tables presented in this study were prepared based on the key bacterial taxa identified in the reviewed literature. The selection of these taxa was guided by their association with uremic toxins or related complications, as highlighted in the studies. Specifically, bacterial taxa demonstrating notable changes in composition were prioritized. These changes in microbiome density, as reported in the reviewed studies, formed the basis for the analysis. Taxonomic groups at the phylum, family and genus levels were considered. From each study, the 5–7 taxa exhibiting the most significant changes in microbiota composition were included, and the corresponding studies were referenced in the tables. Consequently, pie charts were generated to represent the taxa most frequently analyzed across the studies. Explanations for certain taxa have been provided within the tables.
Please refer to Table 1 for the phylum group, Table 2 for the family and Table 3 for the genus. The studies from which the relevant elements were taken are referenced in these tables. The graphs illustrate which bacterial taxonomic group is mentioned more frequently based on the numbers of these reference studies. The frequency of bacterial taxa, based on the reference counts from the compiled studies, is presented in pie charts. Fig. 1 illustrates the frequency of taxa from Table 1, Fig. 2 corresponds to Table 2, and Fig. 3 represents the data from Table 3.
Bacterial groups that attracted attention on the basis of phylum in the studies carried out in 2020–2024.
DKD, diabetic kidney disease; CKD, chronic kidney disease.
Graph of the most mentioned bacteria by phylum in the studies conducted in 2020–2024.
Citation: Microbiota and Host 3, 1; 10.1530/MAH-24-0012
Bacterial groups that attracted attention based on family in the studies carried out in 2020–2024.
| Family | Annotation | References |
|---|---|---|
| Alcaligenaceae | Pan et al. (2020) | |
| Bacteroidaceae | In healthy adults, approximately 20–80% of the gut microbiota is associated with the Bacteroidetes phylum, which includes the genera Parabacteroides, Bacteroides, Alistipes and Prevotella. In general, a decrease in CKD is noted; however, some studies report no difference or even an increase compared to healthy controls. Possible roles in uremic toxin production | Asgharian et al. (2022), Liu et al. (2022b), Tran et al. (2023), Pan et al. (2020), Pivari et al. (2022) |
| Bifidobacteriaceae | Asgharian et al. (2022) | |
| Christensenellaceae | Pivari et al. (2022) | |
| Clostridiaceae | Liu et al. (2022a), Bian et al. (2024) | |
| Coriobacteriaceae | Jiang et al. (2024) | |
| Cyanobiaceae | Hsu et al. (2021) | |
| Enterobacteriaceae | An increase in CKD supports PCS production. TMAO promotes the proliferation of this family | Sun et al. (2023), Pivari et al. (2022) |
| Erysipelotrichaceae | An increase in CKD is correlated with high TMAO levels. In some species, it is associated with increased IS and PCS levels | Liu et al. (2022b), Pan et al. (2020), Sohn et al. (2024), Hsu et al. (2021), Bian et al. (2024) |
| Fusobacteraceae | Tran et al. (2023), Sun et al. (2023) | |
| Lachnospiraceae | In CKD, some species show a decrease while others show an increase. Certain species are associated with uremic toxin production | Liu et al. (2022b), Tran et al. (2023), Yan et al. (2023), Zhu et al. (2023), Huang et al. (2023), Jiang et al. (2024), Bian et al. (2024) |
| Lactobacillaceae | Beneficial taxa show a decrease in CKD. Their increase in gut content offers promising potential for CKD improvement and the reduction of uremic toxins | Asgharian et al. (2022), Pan et al. (2020), Liu et al. (2022a), Yan et al. (2023), Huang et al. (2023), Bian et al. (2024) |
| Methanosperaceae | Cason et al. (2020) | |
| Micrococcaceae | Liu et al. (2022a) | |
| Moraxellaceae | Liu et al. (2022a) | |
| Muribaculaceae | Wu et al. (2024), Huang et al. (2023) | |
| Oscillospiraceae | Yan et al. (2023) | |
| Peptostreptococcacea | Tran et al. (2023), Bian et al. (2024) | |
| Prevotellaceae | The taxon potentially exerting a protective role in CKD demonstrates a negative correlation with CRP, suggesting that its reduction in CKD may contribute to increased inflammation. Furthermore, this taxon exhibits negative correlations with TMAO, IS and PCS levels | Asgharian et al. (2022), Tran et al. (2023), Pan et al. (2020), Liu et al. (2022a), Pivari et al. (2022) |
| Rikenellaceae | Liu et al. (2022b), Jiang et al. (2024) | |
| Ruminococcaceae | In patients with CKD, an increased abundance is observed, with involvement in the production of IS, PCS and TMAO. | Liu et al. (2022b), Hsu et al. (2022), Tran et al. (2023), Pan et al. (2020), Sohn et al. (2024), Yan et al. (2023), Attaye et al. (2023) |
| Staphylococcaceae | Yan et al. (2023) |
CKD, chronic kidney disease.
Graph of the most mentioned bacteria by family in the studies conducted in 2020–2024.
Citation: Microbiota and Host 3, 1; 10.1530/MAH-24-0012
Bacterial groups that attracted attention based on genus in the studies carried out in 2020–2024.
CKD, chronic kidney disease.
Graph of the most mentioned bacteria by genus in the studies conducted in 2020–2024.
Citation: Microbiota and Host 3, 1; 10.1530/MAH-24-0012
It is known that metabolic disorders, including CKD, affect the intestinal flora, thereby increasing intestinal permeability and causing dysbiosis, leading to systemic inflammatory conditions (Anders et al. 2013). Although research in this area does not have a very old history, it is possible to say that studies investigating the relationship between intestinal microbial composition and CKD have been carried out for a significant period of time.
Despite the existence of numerous studies encompassing a vast array of data, a single study has indicated that the intestinal density of Proteobacteria, Enterobacteria, Escherichia coli, Acinetobacter, Proteus species and Clostridium is elevated in CKD patients relative to healthy controls. Conversely, the intestinal density of Lactobacillus and Bifidobacterium species has been demonstrated to be diminished in CKD patients (Guldris et al. 2017).
A study revealed that CKD patients have a decrease in the abundance of Lactobacillaceae and Prevotellaceae, while the levels of Enterobacter and Enterococcus are significantly higher (Vaziri et al. 2013). Another study found that the intestinal microbiota in end-stage renal disease patients is associated with inflammation and renal function, with a decrease in the proportion of bacteria ranging from Prevotella to Bacteroides (Jiang et al. 2017). Both dialysis and non-dialysis CKD patients have been found to have alterations in their gut bacteria. Peritoneal dialysis patients show a decrease in the abundance of Firmicutes (Bacillota) and Actinobacteria, while hemodialysis patients show an increase in the abundance of Bacteroides (McIntyre et al. 2011).
These changes in the microbiota appear to be closely related to the presence of uremic toxins in CKD patients (Pluznick 2016). Animal models of CKDs have shown that excessive uremia can lead to dysbiosis in the gut and dysfunction of the intestinal barrier and bacterial translocation (Andersen et al. 2017). A recent study was conducted to analyze the microbial diversity present in the intestinal flora. In this study, a reduction in the diversity of the intestinal flora and alterations in the communities were observed in peritoneal dialysis patients, in whom microbial diversity was found to be positively correlated with albumin level. A total of 20 gut flora phyla were identified in 166 fecal samples, which were divided into three dominant gut types: Bacteroides, Firmicutes (Bacillota) and Proteobacteria. Further analysis revealed the presence of 198 genera, of which 86 exhibited a significant difference in abundance. At the genus level, Faecalibacterium and butyrate-producing taxa, namely Bifidobacteriaceae and Prevotellaceae, were observed to be the dominant genera in the control, CKD and hemodialysis groups, although not necessarily respectively. Conversely, the dominant genera in the peritoneal dialysis patients group were those containing urease, forming indole and p-cresol, namely Escherichia, at the genus level and Enterobacteriaceae and Enterococcaceae at the family level (Hu et al. 2020).
In patients with normal gut health, many bacterial genera are responsible for the production of uremic toxins. IS is typically derived from the precursor indole, which is extracted from tryptophan by tryptophanase. This enzyme is found in the genera Citrobacter, Proteus and Escherichia. The liver enzyme cytochrome P450-2E1 (CYP2E1) is responsible for the absorption and processing of indole into indoxyl. Subsequently, indoxyl is sulfated by sulfotransferase (SULT), resulting in the formation of IS as the reaction product. Several studies demonstrated that an increase in dietary tryptophan results in elevated IS production (Banoglu et al. 2001, Lauriola et al. 2023).
It is established that PCS is the result of a conjugation reaction between sulfate and p-cresol in the intestinal wall (Vandaele 2023). P-cresol is a phenol that is formed from tyrosine and phenylalanine by anaerobic commensals, including Bacteroides, Lactobacillus, Clostridium and Bifidobacterium (Lauriola et al. 2023).
TMAO is one of the uremic toxins of intestinal origin. A study reported that TMAO levels were associated with inflammatory markers. An increased Firmicutes (Bacillota)/Bacteroidota ratio resulting from increased TMAO concentrations, increased Streptococcus, Pseudomonas and unclassified Clostridia UCG 014 density, and a decreased Rothia and RB41 density were reported to be effective in this relationship (Xie et al. 2024). The use of a dietary supplement formulated with the bacterial species Lactobacillus plantarum and Bifidobacterium lactis has been shown to significantly reduce TMAO levels in the body. Given the established role of elevated TMAO concentrations as a risk factor for CVDs, this reduction may contribute to a cardioprotective effect (Qiu et al. 2017, 2018).
It has been previously proposed that TMAO is produced from TMA, which is generated within the intestine. A review of the literature reveals that numerous bacterial species are involved in TMA production, including Clostridium difficile, Proteus species and Shigella species (Rath et al. 2017). Further research has indicated that several bacterial genera, including Clostridium, Lachnospira, Ruminococcus, Desulfovibrio and Candidatus Arthromitus, have the potential to influence circulating TMAO levels (Zhu et al. 2016, Fu et al. 2020). It can be argued that there are significant differences in the composition of the gut microbiota between individuals with low and high levels of TMAO production. Studies have also identified the gut bacteria Emergencia timonensis and Ihubacter massiliensis as key species responsible for the conversion of carnitine to TMAO (Wu et al. 2019).
A substantial body of research exists examining the correlation between specific species and uremic toxins. This expansive framework, however, is beyond the scope of the present study and merits a dedicated review in its own right. In this investigation, we have compiled a list of species that have been administered as supplements with the objective of influencing the composition of the microbiota, or the relationship between these species and the microbiota, and have presented this information in a table with references (see Table 4).
The list of significant bacterial species proposed for uremic toxins and microbiota composition.
| Species | Annotations | References |
|---|---|---|
| Akkermansia muciniphila | Improves renal function, restores the gut microbiome, enhances the intestinal mucosal barrier, reduces systemic inflammation and mitigates interstitial fibrosis in rats with CKD. It may reduce TMAO production | Xu et al. (2024), Pei et al. (2023) |
| Bifidobacterium longum | A beneficial bacterium in CKD that reduces TMAO production | De Mauri et al. (2020), Lúcio et al. (2024), Wang et al. (2022) |
| Bifidobacterium animals subs lactis | It may reduce PCS production | Zhu et al. (2023) |
| Bifidobacterium lactis | A beneficial bacterium in CKD known for reducing inflammation and uremic toxins, particularly IS. | Mitrović et al. (2023) |
| Bacteroides pleibius | Potential roles in IS and PCS production | Lin et al. (2022) |
| Bacteroides ovatus | ||
| Bacteroides fragilis | ||
| Bacteroides caccae | ||
| Clostridium coccoides | Positively correlated with PCS production | Miyata et al. (2021) |
| Clostridium leptum | ||
| Clostridium perfringens | Potential roles in PCS production | Pan et al. (2023), Lee et al. (2020) |
| Clostridium sporogenes | Pan et al. (2023), Zhu et al. (2023) | |
| Enterococcus faecalis | Improved renal failure symptoms, including the accumulation of uremic toxins | Takemura et al. (2024) |
| E. coli | An increase in uremic toxin production and a decrease in the abundance of beneficial bacteria contribute to the worsening of CKD. | Lin et al. (2022), Lee et al. (2020) |
| Faecalibacterium prausnitzii | Potential role in reducing uremic toxin production in CKD recovery | Li et al. (2022a) |
| Fusobacterium nucleatum | Inhibitory effect on PCS production | Zhu et al. (2023) |
| Haemophylus parainfluenza | Associated with elevated levels of IS | Stanford et al. (2021) |
| Lactobacillus casei | In CKD, a known species that reduces inflammation and uremic toxins, particularly indoxyl sulfate (IS) | Mitrović et al. (2023) |
| Lactobacillus acidophilus | In CKD, a known species that reduces inflammation and uremic toxins, particularly indoxyl sulfate (IS) | Mitrović et al. (2023), Park et al. (2024) |
| Lactobacillus reuteri | Potential role in the reduction of uremic toxins | De Mauri et al. (2020) |
| Lactobacillus plantarum | One of the species important in CKD recovery | Huang et al. (2021), Nissen et al. (2024), Pan et al. (2023) |
| Lactobacillus paracasei | Another important species in CKD recovery | Huang et al. (2021) |
| Lactobacillus plantarum subs plantarum | A reduction in renal damage observed in CKD, improvement in BUN levels and a potential decrease in IS production | Lee et al. (2020) |
| Lactobacillus paracasei subs paracasei | ||
| Lactobacillus pentosus | Potential important roles in the reduction of IS. | Lim et al. (2021) |
| Lactobacillus lactis subs lactis | Lim et al. (2021) | |
| Lactobacillus salivarius | Lim et al. (2021) | |
| Lactiplantibacillus paraplantarum | Decreased serum phosphate levels and reduced blood indoxyl sulfate concentration | Moon et al. (2022) |
| Streptococcus salivarius subs thermophilus | A reduction in renal damage observed in CKD, improvement in BUN levels and a potential decrease in IS production | Lee et al. (2020) |
CKD,chronic kidney disease.
Conclusion
A plethora of studies have addressed the relationship between microbiota and CKD from disparate angles, yielding a multitude of results. It appears to be a formidable challenge to consolidate these findings into a unified framework. The objective of this study was to establish a comprehensive framework for the consideration of taxonomic changes. In addition, we have provided a separate table with references for a limited number of species-based studies, which illustrate specific examples from the broader context.
Uremic toxins have been demonstrated to play a pivotal role in the pathogenesis of CKD and in the development of numerous other diseases. Accordingly, our study was designed within the context of uremic toxins and microbiota, with an expanded framework encompassing uremic toxins and CKD. The review revealed a need for more specialized studies to clarify the data on uremic toxins, related metabolites, microbiota and related diseases. It is anticipated that future studies targeting the composition of the microbiota will yield promising results for many diseases, including CKD. Given the importance of disease pathways in determining therapeutic targets, it can be said that microbiota and microbiota-derived metabolic products represent an important field of study that requires further investigation.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this work.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Author contribution statement
ZR took the lead in conceptualizing the review topic and formulating the study idea. She conducted a significant portion of the literature review, analyzed the findings, synthesized the results and drafted the manuscript. In addition, ZR coordinated the writing process and ensured the logical flow and coherence of the text. GAP contributed to the literature search, assisted in data collection and analysis and collaborated on drafting specific manuscript sections. GAP also reviewed and refined the written content to ensure accuracy and clarity. IMV was involved in performing the final checks on the manuscript, ensuring its alignment with the journal’s guidelines, and preparing it for submission. IMV also provided critical feedback throughout the process to enhance the overall quality and impact of the review.
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