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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 8  |  Issue : 1  |  Page : 8

Traditional chinese medicine in ameliorating diabetic kidney disease via modulating gut microbiota


Pharmacology and Toxicology Research Center, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Date of Submission17-May-2021
Date of Decision26-Jun-2021
Date of Acceptance05-Jul-2021
Date of Web Publication09-Sep-2021

Correspondence Address:
Dr. Chongming Wu
Pharmacology and Toxicology Research Center, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, 9 Dongdan 3rd Alley, Dongcheng District, Beijing 100193
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/imna.imna_28_21

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  Abstract 


Diabetic kidney disease (DKD), a major microvascular complication of diabetes mellitus, has become the second cause of end-stage renal disease enhancing the mortality rate of diabetes. However, there are still few treatment approaches to combat it. Traditional Chinese medicine (TCM) has been applied for a long time to treat DKD. However, there is a lack of research on how does TCM plays the role in treating DKD due to the complex of composition of TCM. In recent decade, gut microbiota is increasingly recognized for its contributions to host health, and the occurrence of gut–kidney axis also attracts many interests about microbiota in kidney injury. Some of the studies have already revealed that TCM can alleviate the symptoms of DKD through regulating gut microbiota and ameliorate a vicious circle caused by imbalance of gut–kidney axis. However, the problems of which specific species mediates the efficacy of TCM and how gut microbiota influences the process of DKD are urgent to solve. Therefore, this review systematically summarized the application of TCM and the importance of gut microbiota in DKD. More importantly, the review provided a new insight to find biomarkers for diagnosis and treatment of DKD. In future study, targeted manipulation of the gut microbiota will be progressively recognized as a way to enhance human health.

Keywords: Diabetic kidney disease, gut microbiota, gut-kidney axis, traditional Chinese medicine


How to cite this article:
Yang Y, Wu C. Traditional chinese medicine in ameliorating diabetic kidney disease via modulating gut microbiota. Integr Med Nephrol Androl 2021;8:8

How to cite this URL:
Yang Y, Wu C. Traditional chinese medicine in ameliorating diabetic kidney disease via modulating gut microbiota. Integr Med Nephrol Androl [serial online] 2021 [cited 2021 Nov 29];8:8. Available from: http://www.journal-imna.com/text.asp?2021/8/1/8/325833




  Introduction Top


Diabetic kidney disease (DKD) is a typical microvascular complication of both two types of diabetes mellitus and has become the second cause of end-stage renal disease following glomerulonephritis. The clinical manifestations of DKD are proteinuria, edema, hypertension, and even along with renal failure, which will endanger the patient's life. In recent decades, mesenchymal stem or stromal cells,[1] noncoding RNAs,[2] exendin-4, and islet transplantation[3] are regarded as novel therapeutic ways for fighting DKD. In addition, sirtuins, notch and thyroid hormone signal transduction, and renin-angiotensin system[4] also play important roles in DKD therapy. Unfortunately, all these treatments have shortcomings, such as an antitransplant reaction. Hence, it is necessary to identify novel pharmacological targets and develop some safe and effective drugs to prevent or treat DKD.

Traditional Chinese medicine (TCM), which has been used to treat diabetes, atherosclerosis, and some difficult and complex diseases for thousands of years in China, also has been recognized as one of the effective approaches to combat DKD. It is characterized by high safety and less damage to the body compared with chemical or biological drugs due to its natural source. In addition, the therapeutic theory of TCM is regulating body function as a whole to relieve symptoms. DKD is caused by metabolic disease and diabetes, which accompanied with the disorder of overall metabolism, so the TCM has potential advantages for DKD treatment. Researches showed that Ophiopogon japonicus,[5] Morus alba leaf,[6] formononetin from Astragalus membranaceus,[7] heteropolysaccharide from Moutan cortex,[8] loganin from Cornus officinalis,[9] astragaloside IV,[10] and berberine[11] are all good candidates for promoting the treatment of DKD.

However, the TCM is such a complex system that is difficult to explore the potential mechanism about how TCM could relieve DKD symptoms. Recently, a mounting number of studies focus on explaining the relationship between gut microbiota and human health. It is realized that gut microbiota not only plays a role in intestinal diseases and metabolic diseases, such as inflammatory bowel disease,[12] diabetes,[13] and hyperlipidemia,[14] but also affects the development and treatment of some nervous system diseases and nephropathy, which is known as “gut–brain axis”[15] and “gut–kidney axis.”[16] Consequently, it is feasible to explore the therapeutic mechanism of TCM in ameliorating DKD based on gut microbiota.

Although some studies have been carried out to explore the role of gut microbiota in the diagnosis and treatment of DKD with TCM, these studies are relatively discrete, either focusing on the changes of microbiota or the effects of some intestinal metabolites. It did not connect the changes with the functions systematically, which will lead to a lack of profound understanding of the effect of gut microbiota on DKD development. Therefore, this review aimed to link the changes of gut microbiota with metabolic function and reveal the internal mechanism of TCM in treating DKD by regulating gut microbiota. Simultaneously, it provides a possible direction to explain the mechanism of TCM with modern pharmacology.


  Advances in the Treatment of Diabetic Kidney Disease with Traditional Chinese Medicine Top


Traditional Chinese medicine or its active component alleviates diabetic kidney disease

One of the results of diabetic is leading to the occurrence of DKD, so the glycometabolism plays a crucial role in the development of DKD. The progressing researches have proved that some TCMs can alleviate the disorder of glycolipid metabolism, podocyte injury, basement membrane thickening, and glomerulosclerosis to alleviate the symptoms of DKD. For example, marein, the component of Coreopsis tinctoria Nutt, can protect renal injury by directly activating AMP-activated protein kinase/acetyl-CoA-carboxylase-2/peroxisome proliferator-activated receptor-gamma coactivator-1α signaling pathway and inhibiting sodium glucose transporter 2 expression.[17] Mulberry leaf polysaccharide significantly reduces serum insulin, fasting blood glucose, 24-h urinary protein, and connective tissue growth factor (CTGF) in streptozotocin (STZ)-induced diabetic nephropathy rats.[18]

Podocyte, attached to the outside of glomerular basement membrane, is an important barrier of glomerular hemofiltration. The occurrence of DKD always accompanied with the injury of podocyte.[19] Research showed that the ATP-mediated intracellular calcium flux in the podocytes increased in DKD rat models.[20] The podocyte-specific Dach1 transgenic overexpression can protect mice from DKD.[21] Thus, targeting podocyte is an effective method for DKD therapy. Berberine, which is a quaternary ammonium alkaloid isolated from Coptis chinensis, can eliminate the activation of dynamin-related protein 1 induced by palmitic acid to stabilize the mitochondrial morphology of podocytes.[22] Arctigenin is the main active component extracted from Fructus arctii, which increases the podocyte viability and function in DKD by improving podocyte adhesion, reducing motility, and regulating actin cytoskeleton,[23] so it is a potential component that can be used to treat DKD. In addition, alleviating the symptom of DKD by astragaloside IV depends on transient receptor potential cation channel subfamily C member 6-mediated Ca2+ influx, which in turn reduces the podocyte apoptosis.[24]

Inflammation is another typical symptom of DKD. A great deal of studies have revealed that the transforming growth factor (TGF)-β/mesenchymal transition or transdifferentiation (EMT),[25] p38 mitogen-activated protein kinase (MAPK)/nuclear factor kappa B (NF-κB),[26] Toll-like receptor 4 (TLR4)/NF-κB, and TGF-β1/small mothers against decapentaplegic (Smad)[27] signaling pathways have a significant effect on diagnosis and treatment of DKD. Chrysophanol, also known as 1,8-dihydroxy-3-methyl-anthraquinone, a natural component from Rheum undulatum L., can downregulate the expression of p-smad2 and p-smad3 and deactivate the TGF-β/EMT signal in mice induced by high glucose so as to significantly alleviate the progression of DKD.[25] Cordyceps cicadae polysaccharides[27] and Bupleurum polysaccharide[28] can relieve tubulointerstitial fibrosis in DKD rats through blocking the TLR4/NF-κB and TGF-β1/Smad signaling pathway and reducing inflammatory cytokine tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 levels and TGF-β1-induced fibroblast activation. In addition to some phytomedicine, animal medicine, such as hirudin, can also reduce apoptosis of podocytes induced by high glucose and inhibit the expression of pro-inflammatory cytokines in the podocytes. These effects are achieved via inhibiting p38 MAPK/NF-κB activation in renal tissues and podocytes.[26]

In a word, TCM or its active component alleviates the symptoms of DKD through protecting podocyte injury, improving metabolism, and reducing inflammation [Table 1].
Table 1: The origin of active component in traditional Chinese medicine and its pathway or roles in diabetic kidney disease

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Traditional Chinese herbal formula alleviates the symptoms of diabetic kidney disease

The traditional Chinese herbal formula is formed based on the theory of “TCM formulation (Jun Chen Zuo Shi),” which can enhance curative effect and reduce toxicity. Some of the formulas used in the treatment of DKD are shown in [Table 2]. The Sang Tong Jian, from mulberry leaf, improves metabolic parameters related to blood glucose and blood lipids and then alleviates the damage of chronic diabetic nephropathy.[29] However, QiDiTangShen granules obviously decrease urinary albumin excretion in db/db mice and reduces renal pathological damage without affecting body weight and blood glucose levels.[30] It is speculated that different formulations have different effects on glucose in diabetic nephropathy mice, and further studies about whether the treatment of DKD is accompanied by the improvement of blood glucose level are needed. In addition, the serum metabolomics revealed that bekhogainsam decoction can change the pathway of metabolism, mainly including pathways of amino acid synthesis and metabolism, such as valine, leucine, isoleucine, tryptophans, and alanine.[31]
Table 2: The composition of Traditional Chinese Medicine formula and the pathway of its action

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Tangshen formula, which is the classical formulation used to treat diabetic nephropathy, can inhibit Jun N-terminal kinases and NF-κB signals so as to suppress the inflammation in the kidney.[32] Meanwhile, Shenyan Kangfu tablet improving renal injury is also related to the inhibition of NF-κB in vivo and in vitro.[33] Bu-Shen-Huo-Xue decoction improves renal function and podocyte epithelial–mesenchymal transition by inhibiting the Rac1/p21-activated kinase 1/p38 MAPK signaling pathway in high-fat diet/STZ-induced diabetic mice.[34] In addition, jowiseungki decoction relieves the injury of diabetic nephropathy by improving renal interstitial fibrosis via NF-κB/α-smooth muscle actin pathway.[35] Therefore, regulating inflammation can effectively ameliorate the symptoms of DKD.


  The Gut Microbiota is Involved in the Progress of Diabetic Kidney Disease Top


Gut microbiota is a vital bridge that links the gut and kidney, which is known as “gut–kidney axis.” Specifically, the disorder of the normal gut microbiota can give rise to the injury of intestinal barrier. Then, the gut microbiota metabolites, such as trimethylamine N-oxide (TMAO),[36] indoxyl sulfate (IS), and p-cresyl sulfate (PCS),[37] will enter the body circulation and cause inflammation. In addition, the decrease of some probiotics and increase of some pathogenic bacteria also directly affect the normal renal function. Therefore, finding out whether gut microbiota mediates the treatment of DKD is the essential step to elaborate the mechanism of benefit effect of TCM. The changes of gut microbiota structure, usually assessed by its α-diversity and β-diversity, are the primary index to evaluate whether it is involved in the disease process. The DKD patients not only have decreased α-diversity of the gut microbiota but also have significantly changed β-diversity.[38] There is a research showing that the combination of Scutellaria baicalensis Georgi. (SB) and Sophora japonica L. (SJ) can increase the α-diversity in hypertensive nephropathy rats.[39] Simultaneously, Shenyan Kangfu tablet can change the structure of gut microbiota community assessed by β-diversity.[33] Hence, it appears that gut microbiota indeed contributes to DKD therapeutic effect of TCM.

The study revealed that the species of Eggerthella lenta, Flavonifractor plautii, Alistipes finegoldii, and Alistipes shahii were enriched in patients with end-stage renal disease, while Prevotella copri and several butyrate producers, such as Roseburia spp., Faecalibacterium prausnitzii, and Eubacterium rectale, were depleted in patients.[40] At the same time, the gut microbiota can interact with host genetics, which involved in the pathogenesis of immunoglobulin A nephropathy. Specifically, the risk genotype lysozyme-like 1, associated with higher serum levels of galactose-deficient-IgA1 and lower body mass index, was related to lower abundances of Dialister. The risk genotype signal-induced proliferation-associated 1-like protein 3, associated with a younger age, was related to lower abundances of Bacilli. However, the risk genotype phospholipid transfer protein, associated with worse kidney function and more severe microscopic hematuria, was relevant to higher abundances of Erysipelotrichaceae. The risk genotype AL365503.1, associated with a younger age and more severe hematuria, was relevant to higher abundances of Lachnobacterium.[41] Therefore, the gut microbiota play an essential role in the renal disease. Similar to the end-stage renal disease and IgA nephropathy, a study showed that the genera of Megasphaera, Veillonella,  Escherichia More Details-Shigella, Anaerostipes, and Haemophilus could be regarded as new potential biomarkers to provide a new strategy for DKD therapy.[38]

Through digging deeper to elaborate the interaction between gut microbiota and renal function in nephropathy patients, we found that gut microbiota or its metabolites play an essential role in nephropathy. The recent studies demonstrated that two short-chain fatty acids (SCFAs)-producing bacteria, Succinivibrio and Anaerostipes, were dramatically reduced in death patients with chronic kidney disease,[42] while the expansion of Bifidobacterium and Prevotella could enhance the concentration of SCFAs so as to prevent acute kidney injury.[43] Further, the IgA nephropathy rat model possessed higher abundance of Lactobacillus reuteri, Rikenellaceae RC9, Ruminiclostridium 9, Actinobacteria, and Bifidobacterium, which is positively or negatively correlated with adipocytokine signaling pathway, caprolactam degradation, and so on.[44] These results indicated that the gut microbiota could affect the progress of IgA nephropathy through altering metabolites.

The further exploration was performed to elaborate the molecular mechanism about how gut microbiota or its metabolites play a role in alleviating nephropathy. The study showed that lack of Myd88 in the intestinal epithelial cells could modulate inflammation in the kidney, which exhibiting the vital effect of gut–kidney axis in chronic kidney disease.[45] The gut microbiota dysbiosis can also lead to immune activation and chronic inflammation, and this effect may be mediated by nuclear factor erythroid 2-related factor 2/NF-κB signaling pathway in M1 cells, the monocyte-derived macrophage.[46] Furthermore, gut microbiota metabolizes tryptophan and produces a series of related metabolites, such as 5-hydroxytryptamine and kynurenine. Then, these tryptophan metabolites activate aryl hydrocarbon receptor signaling and lead to the occurrence of inflammation, oxidative stress injury, and chronic kidney diseases.[47]

In summary, all these researches revealed that there is a potential connection between gut microbiota disorder and kidney dysfunction. Therefore, TCM may alleviate the symptoms of DKD via modulating gut microbiota dysbiosis and changing their metabolites.


  Traditional Chinese Medicine Alleviates the Progress of Diabetic Kidney Disease Via Regulating Gut Microbiota Composition Top


The typical microbes in DKD mice are Escherichia-Shigella, Tyzzerella 3, Proteus, Marvinbryantia, and Ruminiclostridium 6. Magnesium lithospermate B, the water extracts from Salvia miltiorrhiza, can alter these compositions and form new structure of gut microbiota which consists of Odoribacter, Peptococcaceae, Bilophila, Enterorhabdus, Rhodococcus, and Candidatus saccharimonas.[48] This implied that the causal relationship between DKD and this type of microbes should be further explored so as to understand the reason of occurrence of DKD.

Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria are four dominant phyla in the human gut microbiota. One study[32] uncovered that Bacteroidetes-to-Firmicutes ratio increased in DKD mice. Tangshen formula decreases Bacteroidetes-to-Actinobacteria ratio without influencing Bacteroidetes-to-Firmicutes ratio. Further, it enhances the relative abundance of Bifidobacteriaceae family but reduces Proteobacteria phylum, Enterobacteriaceae family, and Ruminococcus genus.[32] It is known that Bacteroidetes is positively correlated with NF-κB, TNF-α and IL-1β protein expression. Shenyan Kangfu tablet increases the relative abundance of Firmicutes and decreased Bacteroidetes.[33] These results suggest that Shenyan Kangfu tablet relieves inflammation by regulating gut microbiota. Resveratrol, a nature component, can reverse the disorder of gut microbiota characterized by lower abundance of Bacteroides, Alistipes, Rikenella, Odoribacter, Parabacteroides, and Alloprevotella genera in db/db mice, indicating the potential role of the microbiota in DKD treatment with resveratrol.[49]

Moreover, 16S rRNA sequencing revealed that Cordyceps cicadae polysaccharides increased the relative abundance of probiotics, such as Desulfovibrionaceae, Oscillospira, Prevotellaceae, Paraprevotella, Ruminococcus, and Roseburia and decreased abundance of lipopolysaccharide-producing bacteria, thus recovered the disorder of gut microbiota in DKD mice.[27] Jowiseungki decoction treatment can change the relative abundance of Alphaproteobacteria class, Atopobiaceae family, Acetatifactor, Butyricicoccus, Kerstersia, Peptococcus, and Coriobacteriaceae UCG-002 genus.[35] Furthermore, Allobaculum and Anaerosporobacter can deteriorate renal function, but Blautia is the potential protective factor for DKD.[50] In a word, gut microbiota is an effective mediator involved in alleviating symptoms of DKD by TCM [Table 3].
Table 3: Traditional Chinese medicine and its active component modulate gut microbiota in diabetic kidney disease

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  Gut–Microbiota–Metabolite Axis is Closely Related to the Progress of Diabetic Kidney Disease Top


The gut–microbiota–metabolite axis based on metabolomics is useful to find biomarker for diagnosis and treatment of disease. Many of the studies revealed that microbiota-derived metabolites mediate the occurrence and development of DKD mainly through two pathways.

SCFA, produced by gut microbiota, is an important source of nutrients for host intestinal cells and contributes to the regulation of the host immune system. On the one hand, Lactobacillaceae, Prevotellaceae, and Akkermansia can produce butyrate and lactic acid, regulate butyric acid and tryptophan metabolism, and lead to remission of renal metabolism.[8],[51] In DKD patients, some of these probiotics are decreased and their beneficial effects are weakened. On the other hand, excessive acetic acid due to the gut microbiota disorder may be involved in early DKD by activating the renin-angiotensin system. Specifically, the relative abundance of Blautia, Roseburia, and Paraprevotella increased, whereas Bacteroides decreased. These changes result in the increasing of plasma acetic acid and proteinuria, the thickening of glomerular basement membrane, and the disappearing of podocyte foot processes.[52] In addition, acetic acid can activate G protein-coupled receptor 43 and increase the expression of TGF-β and CTGF proteins in HK-2 cells, which mediate fibrosis of renal tubulointerstitial in DKD.[53]

Another aspect of effect of microbiota-derived metabolites on DKD is toxins such as IS, PCS, phenyl acetyl glutamine, indole-3 acetic acid, and TMAO. Destruction of the intestinal barrier in patients with DKD leads to the transfer of these toxins into the systemic circulation, causing inflammation and kidney injury.[54] IS, PCS, and phenyl acetyl glutamine are negatively correlated with Ruminococcaceae, Lachnospiraceae, and Christensenellaceae, which can be regarded as early symbols of recession of kidney functions.[55] The generation of phenyl sulfate relies on the gut microbiota-specific tyrosine phenol-lyase (TPL), which only expresses in Enterobacteriaceae. The TPL led dietary L-tyrosine synthesizes into phenol and further metabolizes into phenyl sulfate in the liver.[56] Therefore, phenyl sulfate is a marker and a therapeutic target in DKD patients. Prebiotics or fiber-rich foods supplementation can decrease the serum PCS production.[57] In addition, the level of TMAO has elevated in patients with chronic kidney disease, so the targeted inhibition of TMAO production will attenuate the development of chronic kidney disease.


  Conclusion and Prospect Top


In summary, the composition and structure changes of gut microbiota obviously contribute to the process of DKD. The microbiota-derived metabolites including SCFAs, IS, PCS, and TMAO are involved in the diagnosis and treatment of DKD [Figure 1]. The increasing abundance of butyrate-produce bacteria, such as Lactobacillaceae, Prevotellaceae, and Akkermansia, may benefit the DKD patients, whereas the acetic acid-produce bacteria (Blautia, Roseburia, and Paraprevotella) and toxins-produce bacteria are harmful for DKD patients. Therefore, how to promote the colonization of butyrate-produce bacteria but inhibit acetic acid-produce bacteria is the effective approach to treat DKD.

There is no doubt that changes of gut microbiota and its metabolites may serve as clinical biomarkers for DKD diagnostics, prognostics, and monitoring. The study showed that the relative abundance of Escherichia-Shigella and Prevotella 9 was obviously different among diabetic patients and DKD patients and thus can be used to distinguish these two diseases in the process of diagnosis. Although such study already focused on finding differential microbiota to diagnose and treat diseases, most of the studies remain at the genus level. In the future, the specific species or strains should be further explored so as to find the more accurate biomarkers to promote the diagnosis and treatment of DKD.
Figure 1: Traditional Chinese medicine in ameliorating diabetic nephropathy via modulating gut microbiota. Traditional Chinese medicine modulates the structure and composition of gut microbiota and then affects the production of microbiota-derived metabolites, such as short chain fatty acids, indoxyl-sulfate and so on. Some of these metabolites can improve renal function, while others can lead to renal injury. This regulation process is called “gut-kidney axis”. DKD is often accompanied by podocyte injury and inflammation. Some pathway such as TGF-β/ EMT, p38 MAPK/NF-κB, TLR4/NF-κB and TGF-β1/Smad often involved in the development of DKD. Traditional Chinese medicine can alleviate the symptoms of DKD by modulating gut microbiota and its metabolites. DKD: Diabetic kidney disease; EMT: Epithelial mesenchymal transition; MAPK: Mitogen-activated protein kinases; NF-κB: Nuclear transcription factor-κB; TCM: Traditional Chinese medicine; TGF-β: Transforming growth factor-β; TLR4: Toll-like receptor 4; Smad: Small mothers against decapentaplegic

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Moreover, the metabolites from gut microbiota also play a crucial role in the development of DKD. Current studies proved that uremic toxin, such as IS, PCS, and TMAO, were produced by proteolytic fermentation in nephropathy patients with typical gut microbiota disorders. These metabolites are regarded as markers and mediators of renal injury in DKD disease. In addition to paying attention to these harmful metabolites, it should also seek metabolites that can promote the amelioration of DKD. Next step is to associate the metabolites with specific species to increase the accuracy of DKD diagnosis and provide prospective approaches for targeted treatment of DKD.

The most difficult problem in clinical application of TCM is its multicomponent and complex mechanism. It may be the feasible direction to interpret the efficacy of TCM through associating gut microbiota or its metabolites with some disease-related factors. For instance, Kruppel-like factor-2 (KLF2) may play a role in glomerular endothelial cell injury in early DKD.[58] Whether the expression of KLF2 is affected by the gut microbiota will be the promising direction in the future study.

Financial support and sponsorship

Nil.

Conflicts of interest

Chongming Wu is an Editorial Board Member of the journal. The article was subject to the journal's standard procedures, with peer review handled independently of this editor and his research groups.



 
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