World Journal of

WJ D Diabetes
Submit a Manuscript: https://www.f6publishing.com World J Diabetes 2022 April 15; 13(4): 308-318

DOI: 10.4239/wjd.v13.i4.308 ISSN 1948-9358 (online)

MINIREVIEWS

Gut microbiota and diabetic kidney diseases: Pathogenesis and

therapeutic perspectives

Jia-Ran Lin, Zi-Ting Wang, Jiao-Jiao Sun, Ying-Ying Yang, Xue-Xin Li, Xin-Ru Wang, Yue Shi, Yuan-Yuan Zhu,
Rui-Ting Wang, Mi-Na Wang, Fei-Yu Xie, Peng Wei, Ze-Huan Liao

Specialty type: Endocrinology and Jia-Ran Lin, Mi-Na Wang, Graduate School, Beijing University of Chinese Medicine, Beijing
metabolism 100029, China

Provenance and peer review: Jia-Ran Lin, Department of Nephrology and Endocrinology, Dongzhimen Hospital Affiliated to
Invited article; Externally peer Beijing University of Chinese Medicine, Beijing 100700, China
reviewed.
Zi-Ting Wang, Department of Environmental Medicine, Karolinska Institutet, Stockholm 17165,
Peer-review model: Single blind Sweden

Peer-review report’s scientific Jiao-Jiao Sun, Yuan-Yuan Zhu, First Clinical Medical College, Beijing University of Chinese
quality classification Medicine, Beijing 100029, China
Grade A (Excellent): 0 Ying-Ying Yang, Clinical Research Center, Shanghai First Maternity and Infant Hospital, School
Grade B (Very good): B of Medicine, Tongji University, Shanghai 201204, China
Grade C (Good): C, C
Grade D (Fair): 0 Ying-Ying Yang, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet,
Grade E (Poor): 0 Solna 17165, Sweden

P-Reviewer: Qi R, China; Wen XL, Xue-Xin Li, Department of Medical Biochemistry and Biophysics, Karolinska Institutet,
China; Xiu Dong, China Stockholm 17121, Sweden

Received: May 9, 2021 Xin-Ru Wang, Department of Acupuncture and Moxibustion, First Clinical Medical College,
Peer-review started: May 9, 2021 Beijing University of Chinese Medicine, Beijing 100029, China
First decision: July 3, 2021
Yue Shi, Second Clinical Medical College, Beijing University of Chinese Medicine, Beijing
Revised: August 9, 2021
100029, China
Accepted: April 2, 2022
Article in press: April 2, 2022 Rui-Ting Wang, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100029,
Published online: April 15, 2022 China

Mi-Na Wang, Department of Acupuncture and Moxibustion, Beijing Hospital of Traditional

Chinese Medicine, Capital Medical University, Beijing Key Laboratory of Acupuncture
Neuromodulation, Beijing 100010, China

Fei-Yu Xie, Peng Wei, School of Traditional Chinese Medicine, Beijing University of Chinese
Medicine, Beijing 100029, China

Fei-Yu Xie, Department of Oncology, Wangjing Hospital of China Academy of Chinese Medical
Sciences, Beijing 100102, China

Ze-Huan Liao, School of Biological Sciences, Nanyang Technological University, Singapore

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 Lin JR et al. Gut microbiota and diabetic kidney diseases

637551, Singapore

Ze-Huan Liao, Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm
17177, Sweden

Corresponding author: Ze-Huan Liao, BSc, Teaching Assistant, School of Biological Sciences, Nanyang
Technological University, 60 Nanyang Drive, Singapore 637551, Singapore. [email protected]

Abstract
Diabetic kidney disease (DKD) is one of the major chronic complications of diabetes mellitus (DM),
as well as a main cause of end-stage renal disease. Over the last few years, substantial research
studies have revealed a contributory role of gut microbiota in the process of DM and DKD.
Metabolites of gut microbiota like lipopolysaccharide, short-chain fatty acids, and trimethylamine
N-oxide are key mediators of microbial–host crosstalk. However, the underlying mechanisms of
how gut microbiota influences the onset and progression of DKD are relatively unknown. Besides,
strategies to remodel the composition of gut microbiota or to reduce the metabolites of microbiota
have been found recently, representing a new potential remedial target for DKD. In this mini-
review, we will address the possible contribution of the gut microbiota in the pathogenesis of DKD
and its role as a therapeutic target.

Key Words: Diabetes; Gut microbiota; Insulin resistance; Diabetic kidney disease; Pathogenesis; Therapeutic
targets

©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.

Core Tip: This minireview consolidates the potential role of gut microbiota in the pathogenesis and as a
therapeutic target of diabetic kidney disease. It is known that metabolites of gut microbiota such as
trimethylamine N-oxide, short-chain fatty acids, and lipopolysaccharides are important mediators of
microbial-host crosstalk. However, the main mechanism of how the gut microbiota specifically affects the
occurrence and progress of diabetic kidney disease has not yet been fully explored.

Citation: Lin JR, Wang ZT, Sun JJ, Yang YY, Li XX, Wang XR, Shi Y, Zhu YY, Wang RT, Wang MN, Xie FY,
Wei P, Liao ZH. Gut microbiota and diabetic kidney diseases: Pathogenesis and therapeutic perspectives. World J
Diabetes 2022; 13(4): 308-318
URL: https://www.wjgnet.com/1948-9358/full/v13/i4/308.htm
DOI: https://dx.doi.org/10.4239/wjd.v13.i4.308

INTRODUCTION
Diabetes mellitus (DM) continues to be one of the most challenging and economically costly diseases in
the world, with its prevalence and incidence increasing[1]. About 20%-40% of the affected population
will develop into diabetic kidney disease (DKD)[2], which is the primary contributor of end-stage renal
disease (ESRD). The global incidence rate of diabetes in 2019 was expected to be 9.3% (463 million
people) and may rise to 10.2% (578 million) by 2030 and 10.9% (700 million) by 2045[3-5]. The direct
health expenses worldwide on diabetes in 2019 were predicted to be USD 760 billion and are projected
to increase to 825 billion dollars by 2030 and 845 billion dollars by 2045[6]. The concern is that the
prevalence of diabetes might continue to build up due to significantly expanded incidence of childhood
obesity.
DKD can occur in type 1 diabetes, type 2 diabetes, and other secondary diabetes. The development of
moderately increased albuminuria in patients with type 1 diabetes typically occurs 5 to 15 years after
diabetes initiation and progresses through time[7,8]. In a systematic review encompassing nine longit-
udinal studies of 7938 patients with type 1 diabetes and moderately increased albuminuria, the total
incidence rate of moderately increased albuminuria was 28% over the mean 15-year duration of diabetes
[9]. In comparison to patients with normoalbuminuria, the relative risk for all-cause mortality was 1.8
(95% confidence interval: 1.5-2.1), with a suggestion of a similar relative risk for cardiovascular
mortality[9,10]. Among nearly 5100 patients with type 2 diabetes included in the United Kingdom
prospective diabetes study[11], regarding the occurrence and progression of nephropathy, the results
are reported as follows: Ten years after the diagnosis of diabetes, the percentages of cases with

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Lin JR et al. Gut microbiota and diabetic kidney diseases

moderately elevated, those with severely elevated urine albumin, and those with plasma creatinine
concentrations elevated to > 175 μmol/L (2.0 mg/dL) or requiring kidney substitution treatment were
25%, 5%, and 0.8%, respectively.
The human gut nurtures more than 100 trillion microbial cells. The functional gut microbiota serves
particular roles in many metabolic aspects of the host, including nutritional metabolism, alloantigen and
medicinal metabolism, maintaining the integrity of the intestinal mucosal barricade structure, immune
regulation, as well as resistance to pathogens[12]. Microbial cells are susceptibility factors for the
development of nephropathy in individuals with a predisposition to nephropathy, such as patients with
DM[13,14]. The intestinal flora may influence the development and progression process of DKD by
modifying the endocrine functions of the gut and the components of microbial metabolism products,
and vice versa. Besides, hyperglycemia and progressive kidney disease determine alterations of the gut
microbiota[15,16].
In this article, we review the quantitative and qualitative changes in the gut microbiota of DKD
patients that lead to this symbiotic disorder and how it contributes to the progression of DKD, and
review well-targeted interferences that can reconstruct the symbiotic relationship.

DKD: PATHOGENESIS
DKD is a complicated and miscellaneous disease with numerous interrelated etiologic pathways.
Patients with DKD have four main glomerular histopathological changes: Mesangial expansion,
glomerular basement membrane (GBM) thickening, podocyte effacement, and glomerular sclerosis. It
was believed that these histopathological changes were mainly due to the metabolic and hemodynamic
disorders found in diabetes. Hemodynamic derangements are defined as the hyperfiltration which is
due to vasoconstriction of efferent arterioles following the activation of renin-angiotensin-aldosterone
system (RAAS) under the stimulation of hyperglycemia. Nevertheless, in recent years it has become
more and more apparent that despite the irrefutable central role of hyperglycemia in the development
of DKD, it is not the only contributor to DKD. In general, the development of DKD involves several
pathophysiological pathways including hemodynamic pathways, metabolic pathways, inflammatory
pathways, and autophagy pathways.
The changes in renal hemodynamics are partially regulated by vasoactive hormones, especially
angiotensin II (Ang II) and endothelin (ET). In cultured rat mesangial cells, glucose increases Ang II
production in a concentration-dependent manner, which results in stimulation of transforming growth
factor-β1 (TGF-β1) secretion, decreased matrix degradation, and increased matrix accumulation[17].
Temporarily blocking the prediabetic rats’ renin–angiotensin system for 7 wk resulted in a sustained
reduction in collagen accumulation and gene expression of connective tissue growth factor (CTGF),
which mediates downstream events of TGF-β and stimulates fibroblast proliferation and extracellular
matrix (ECM) protein synthesis[18,19]. In response to various factors, mesangial cells can release ET-1
and ET receptors, activation of which leads to a complex signaling cascade with resultant stimulation of
mesangial cell hypertrophy, proliferation, contraction, and ECM accumulations[20].
The metabolic pathways including four different entities: The polyol pathway, hexosamine pathway,
production of advanced glycation end products (AGEs), and activation of protein kinase C (PKC)[21].
Aldose reductase is the first enzyme in the polyol pathway. Studies have shown that the hemodynamic
changes caused by early diabetes and the increase in vascular albumin infiltration and urinary albumin
excretion (UAE) are phenomena associated with aldose reductase[22]. The hexosamine pathway
originates in the third phase of glycolysis, where fructose-6-phosphate is transformed into glucosamine-
6-phosphate. Glucosamine-6-phosphate later is utilized as a substrate which augments the transcription
of the inflammatory cytokines tumor necrosis factor-α (TNF-α) and TGF-β1[23], which we will discuss in
the inflammatory pathways later. Tissue protein glycosylation is also one of the causes of diabetic
nephropathy and other microvascular complications. In a long-term hyperglycemia state, part of the
excess glucose will bind to free amino acids in the circulation or tissue proteins. The non-enzymatic
reaction initially forms reversible early glycosylation products, and then forms irreversible AGEs. Long-
term infusion of AGE-albumin to non-diabetic animals led to glomerular enlargement, GBM
hyperplasia, mesangial ECM swelling, and albuminuria, which are all consistent with the glomer-
ulopathy analogous to DKD[24]. Hyperglycemia-induced PKC activation in cultured mesangial cells or
diabetic glomeruli is associated with a number of aberrations, namely, elevated arachidonic acid
secretion and prostaglandins synthesis, elevated expression of fibronectin, α1(IV) collagen, and TGF-β1,
and depressed Na+K+-ATPase action[25].
Various growth factors and cytokines may affect renal function directly or indirectly and perform
their actions by stimulating other factors. As mentioned before, in cultured mesangial cells, high glucose
or Ang-stimulated production of matrix proteins is partially regulated by TGF-β. The mechanisms
involve suppression of matrix metalloproteinase synthesis, incentive of metalloproteinase inhibitor
production, enhanced CTGF expression, etc.[19,26]. The expression of vascular endothelial growth factor
(VEGF) is pronounced in quite few cells including glomerular visceral epithelial cells and tubular
epithelial cells, where VEGF is able to induce a proliferative and an antiapoptotic response[27]. The

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direct evidence that VEGF is a mediator of DKD was collected from research, in which the weight of the
kidney, the glomerular volume, the thickness of basement membrane rose while UAE descended in
VEGF antibody-treated db/db mice. VEGF antibody administration tended to reduce expansion in total
mesangial volume[28]. Each cytokine has several different effects. IL-1 takes a part in the progression of
intra-glomerular hemodynamic aberrations associated with prostaglandin production by mesangial
cells and can directly increase vascular endothelial cell permeability[29,30]. The expression of renal IL-6
positively correlates with mesangial hyperplasia and tubular atrophy in various kidney disease models
[31]. IL-18 triggers the secretion of interferon gamma and results in producing additional inflammatory
cytokines including IL-1 and TNF, over-expression of adhesion molecules, as well as inducing
endothelial cell apoptosis[32]. TNF is recognized to play a crucial part in the pathogenesis of DKD. TNF
is not only cytotoxic to kidney cells, which can induce direct kidney damage, but also involved in
processes such as the induction of apoptosis and necrotic cell death[33]. Studies have shown that TNF
plays an important part in the progression of kidney hypertrophy and hypofunction, which are the two
major changes in the preliminary stages of DKD, indicating that renal level of TNF may even have the
potential to be used as a marker for early stage of DKD[34].
Autophagy (originating from the Greek word meaning "self-eating") is a basic cellular process
sending intracellular components to lysosomes to be degraded in order to sustain homeostasis and
cellular integrality[35]. Podocytes had a high basal level of autophagy. However, diabetic condition in
vivo and high glucose conditions in vitro impaired autophagy, resulting in lysosome dysfunction and
apoptosis, as well as autophagy defects leading to podocyte damage[36]. Because the dynamics of the
endoplasmic reticulum (ER) appeared to have a crucial function in modulating autophagic fluxes, the
cytoprotective capacity of the ER might fail under high glucose-induced unrelieved stress, which causes
autophagy disruption, speeding up the deterioration of DKD[37].
The components and activeness of the intestinal flora are symbiotic with the host since birth and are
contingent on complex interactions which depend on the host genome, nutrition, and lifestyle. The gut
microbiota plays an important role in maintaining the gut in normal individuals and human health as a
whole, and its dysfunction is tightly correlated with the occurrence of DM and the progression to DKD.
Metabolome-based genome-wide association studies showed that patients with T2DM are distinguished
by moderate dysbiosis of the intestinal microflora, for example, by decreased abundance of some
prevalent butyrate-producing bacteria, including Clostridium difficile SS3/4, Escherichia coli, Prevotella,
Roscoidium intestinalis, and Roscoidium chrysogenum, as well as by an elevated number of diverse
potential pathogens, including Bacteroides caccae, Clostridium hathewayi, Clostridium ramosum, Clostridium
symbiosum, Eggerthella lenta, and Escherichia coli, on top of which, there is an enrichment of the identified
mucin-degrading species Akkermansia muciniphila and sulphate-reducing species Desulfovibrio sp.
3_1_syn3[38]. Several pieces of high quality data from the United States Human Microbiome Project
(HMP)[39], European Metagenomics of the Human Intestinal Tract (Meta HIT)[40], and several other
studies have proven the favorable effects of the balanced intestinal flora on health all the way to the
genetic layer, while Tao et al[41] revealed that the abundance of the intestinal microflora and the degree
of diversity of bacterial groups were significantly different in DM with respect to healthy controls, and
DKD with respect to DM. Interestingly, the variables of g_Prevotella_9 (AUC = 0.9) allowed precise
identification of DM from age- and sex-matched healthy controls, and the variables of g_Escherichia-
Shigella and g_Prevotella_9 (AUC = 0.86) allowed precise identification of DKD from age- and sex-
matched DM patients[41].
The gut microbiota participates in the regulation of various host metabolic pathways. Disorders of the
gut environment and associated variations in the makeup of the gut microflora, as well as the
metabolites produced, represent a condition referred to as “intestinal dysbiosis”[42,43], leading to
disorders of interactive host-microbiota metabolism, signal transduction, and immune-inflammatory
axes, influence the gut, liver, kidney, muscle, and brain through physiological connection, and thus may
trigger a systemic inflammatory response. Under normal circumstances, the gut barricade precludes the
transfer of substances and microorganisms from the intracavity to the bloodstream; the gut barricade is
composed of distinct constructions/systems: Tight junctions, intestinal epithelial cell membranes,
mucus secretion, and immune defensive mechanisms of the gut lining[42,44]. However, intestinal
dysbiosis may result in a “leaky gut syndrome”, with increased permeability that enables the leakage of
pro-inflammatory bacterial products [e.g., lipopolysaccharide (LPS)], contributing to insulin resistance
[45] as well as expediting the development of renal disorders in people with diabetes[14]. Microbial
metabolites are essential intermediaries of microbial host crosstalk, engaging in the regulation of host
metabolism and gut integrity.
Endotoxin, a phospholipid, is the hydrophobic anchor of LPS which comprises the external layer of
the majority of Gram-negative bacteria. Salguero et al[46] revealed a significant relevance between the
dysbiosis of Gram-negative bacteria which includes increasing relative abundance of Proteobacteria,
Verrucomicrobia, and Fusobacteria, raised LPS concentrations, and accumulated state of inflammatory
biomarkers consisting of C-reactive protein (CRP), TNF-α, and IL-6 in DKD patients in contrast to the
controls[46]. Also, as a result of the leaky gut syndrome, LPS translocation which leads to high
circulating levels of LPS, a condition known as “endotoxemia”, stimulates immune system cells,
especially macrophages and endothelial cells. In macrophages, LPS activates IL-1R-associated kinase
(IRAK) through TLR4-mediated MyD88 and MD2 signaling, with ensuing induction of TNF receptor-

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associated factor 6 (TRAF6) binding with IRAK and other proteins forming a large complex, catalyzing
the synthesis of a Lys 63-linked polyubiquitin chain of TRAF6 and finally resulting in the activated
transcription factor NF-κB and discharged pro-inflammatory cytokines[47], which is known to be
important in the pathogenesis of DKD[48].
The hallmark feature of gut dysbiosis is a decrease in the levels of short chain fatty acids (SCFAs)-
producing saccharolytic microbes. SCFAs are the end products of fermentation of dietary polysac-
charides by intestinal microbiota, including acetate, propionate, butyrate, pentanoic acid, and isobutyric
acid[49]. The functions of SCFAs are generally concerned with the activation of transmembrane G
protein-coupled receptors (GPR) and the repression of histone acetylation (HDAC)[50], and the increase
of glucagon-like peptide-1 (GLP-1) and GLP-2 production through GPR stimulation, along with
elevated insulin expression and ensuing augmented insulin sensitivity and proliferation of pancreatic
cells. Intriguingly, glucose homeostasis and feelings of satiety are both regulated by gut microbiota
components like Bifidobacterium and Lactobacillus that enhance GLP-1 secretion[51]. Besides, SCFAs can
inhibit oxidative stress and inflammation of glomerular mesangial cells induced by high glucose and
LPS[52], as well as improve intestinal barrier function[53]. Sodium butyrate treatment markedly
reduced the levels of glucose, creatinine, and urea in plasma, attenuated histological changes, involving
fibrosis and collagen deposition, and curbed the activity of HDACs, eNOS, iNOS, fibronectin, TGF-β1,
NF-κB, apoptosis, and DNA damage in diabetic kidneys[54]. However, not all the remedies of SCFAs
showed favorable effects. Lu et al[55] discovered aberrant intestinal flora, elevated plasma acetate levels,
raised proteinuria, thickened GBM, and loss of renal podocyte foot process in DM rats compared to
control rats[55]. In addition, the amount of angiotensin II, angiotensin-converting enzyme, and
angiotensin II type1 receptor boosted in DM rats’ kidneys, suggesting that redundant acetic acid
produced from gut flora disorders may cause kidney damage by activating RAAS in the kidney. It is
hypothesized that these differences of SCFAs studies may result from disparate animal models in
disparate diseases as well as from the group, concentration, and timing of application of SCFAs.
Imbalance of the gut microbiota is also a potential source of uremic toxins. Urea is derived in the liver
from the urea cycle and its origin is dietary/endogenous amino acids and their decomposition in the
peripheral tissues. The intestinal microbiota uses urease to convert urea into ammonia (NH3) and
carbon dioxide. A portion of the ammonia goes through the urea cycle in the liver and is transformed
back into urea, whereas the rest of the ammonia is transformed into ammonium hydroxide (NH4OH)
and then excreted from the body with feces[13]. Changes in lifestyle and diet as well as reduced fiber
consumption can cause imbalance in the intestinal flora and production of an overload of the uremic
toxins [e.g., indoxyl sulfate (IS), phenyl sulfate (PS), p-cresyl sulfate (PCS), and trimethylamine-N-oxide
(TMAO)]. Normally, the amount of IS receptors [aryl hydrocarbon receptors (AhRs)] may modulate
podocyte functionality. Nevertheless, under conditions of imbalanced intestinal flora, AhRs are
prolonged activated by broad exposure to IS, which results in progressive damage of podocytes and
glomeruli including altered cell morphology, elevated levels of expression of pro-inflammatory
cytokines and chemokines, declined podocyte differentiation, and reduced expression of cytoskeletal
proteins[56]. Also, AhR was demonstrated to be able to interact with various signaling molecules such
as NF-κB, which is responsible for the upregulation of proinflammatory proteins in uremic conditions
[57]. Kikuchi et al[58] found that the amount of PS (an intestinal microflora-derived metabolite)
increased with advancing diabetes in rats in which the human uremic toxin transporter SLCO4C1 was
over-expressed in the kidney, whereas it declined in rats that showed limited proteinuria. In pilot
models of DM, the giving of PS triggers albuminuria and podocyte injury. In a cohort of DM patients,
PS levels were closely related to the baseline and forecasted advancement of albuminuria in patients
with microalbuminuria over 2 years[58]. Figure 1 illustrates the pathogenic associations between gut
dysbiotic microbiota and development of DKDs from the gut-kidney axis.

THERAPEUTICS AGAINST GUT MICROBIOTA IN DKD

Exercise is considered to be an important potential factor in modification of gut microbiota, which could
have both beneficial and harmful effects under some specific circumstances. Moderate levels of exercise
may be able to keep balance of gut microbiota and reduce harmful bacteria in the digestive tract to some
extent[59]. However, Cani et al[60] found that excessively intensive exercise may lead to increased
permeability in the digestive tract[60].
Obviously, the host genome is the main risk determinant for a number of different diseases.
Nonetheless, not alike the host genome, the genome of microorganisms in the host can be changed.
Through the administration of prebiotics (dietary foods that boost the growth or performance of
particular microorganisms), probiotics (live bacteria), synbiotics (mixtures of probiotics and prebiotics),
as well as antibiotics, people are able to alter the composition of the intestinal microbiota themselves
and thereby modify the resultant metabolites.
Animal studies found that high-fat-fed diabetic mice treated with prebiotics (fructo-oligosaccharides,
FOS) not only had higher levels of intestinal Bifidobacterial and colonic GLP-1 precursor and reduced
endotoxaemia, but also obtained improvement on their glucose tolerance and insulin resistance[61]. This

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Figure 1 Pathogenic associations between gut dysbiotic microbiota and development of diabetic kidney diseases from the gut-kidney
axis. On the one hand, endotoxins and uremic toxins accumulate because of gut microbiota dysbiosis and leak into the systemic circulation via a damaged gut
barrier, which effectuates inflammation and nephrotoxicity. On the other hand, the dysbiotic microbiota results in a decrease of short chain fatty acids (SCFAs)-
producing gut microbiota. SCFAs can activate transmembrane G protein-coupled receptors, which further stimulate secretion of glucagon-like peptide-1. In summary,
SCFAs production in normal condition stabilizes the blood sugar level and presents protective effects on kidney cells. LPS: Lipopolysaccharides; SCFA: Short chain
fatty acids; GPR: G protein-coupled receptors; GLP-1: Glucagon-like peptide-1; NF-κB: Nuclear factor kappa beta; TLR4: Toll-like receptor 4; GBM: Glomerular
basement membrane; A: Means inhibition; →: Means activation.

dietary shift method also worked in germ-free mice colonized with a synthetic community where at day
35 (7 d following the change to the FOS diet), there was a distinct decline in Bacteroides caccae enrichment
and a concurrent increment in B. caccae enrichment. Importantly, during the same period, there was a
significant reduction in the level of IS in the host, and this decrease remained unchanged after 1 wk,
suggesting a steady drop in the production of uremic toxins[62]. Li et al[63] reported that when feeding
diabetic rats with a high-fiber diet, and feeding diabetic control rats with a normal diet or a zero-fiber
diet, the former was less likely to fall into the DKD phase featured with albuminuria, glomerular
hypertrophy, podocyte injury, and interstitial fibrosis. Fiber can profitably reshape intestinal microbial
ecosystem and improve microecology dysbiosis. For example, fiber allowed growth in density of fecal
and systemic SCFAs through stimulating the colonization of SCFA-producing bacteria such as the
genera Prevotella and Bifidobacterium. Besides, fiber may intervene the progression of DKD by
diminishing the expression of genes which are responsible for the generation of inflammatory cytokines,
chemokines, and fibrosis-promoting proteins. SCFAs were nephroprotective in diabetic mice, providing
that GPR43 or GPR109A is present. In vitro cellular experiments revealed that SCFAs could regulate
hyperglycemia-induced inflammation in renal tubular cells and podocytes[63].
Bohlouli et al[64] analyzed data from 340 DKD patients by systematically reviewing and quantit-
atively synthesizing seven RCTs. They found that probiotics consumption beneficially impact the
inflammation and oxidative stress biomarkers by significantly reducing high-sensitivity C-reactive

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protein (hs-CRP) and malondialdehyde (MDA) plus increasing glutathione (GSH) and total antioxidant
capacity (TAC) in subjects. Yet, probiotics had no remarkable effect on concentrations of nitric oxide
(NO). Subgroup analysis indicated that when the probiotic dosage was greater 5 billion CFU per day, the
total impact of probiotics on serum TAC concentrations was more prominent[64]. Vlachou et al[65]
concluded that most studies showed the beneficial effects of supplementary probiotics in decreasing
inflammation and oxidative stress and improving biomarkers of kidney function in DKD patients, and
the majority of microbes applied in the studies were in the genera of Lactobacillus and Bifidobacterium.
Doses varied from 2 × 107 to 6 × 1010 CFU/g. The format of the probiotics differed among projects
(capsules, pouches, soy milk, yogurt, and honey)[65]. Probiotics use may also help to reinforce the
barrier function, through prevention of dysbiosis and regulation of cytoskeletal and tight junctional
protein phosphorylation. Guo et al[66] illustrated that Bifidobacterium infantis and Lactobacillus acidophilus
were able to safeguard the gut barrier from irritation by IL-1β and thereby preserve the intestinal
permeability to an extent. The mechanism may be that the levels of occluding and claudin-1 were
normalized and that the IL-1β-induced NF-κB activation was inhibited in Caco-2 cells[66]. Resta-Lenert
and Barrett[67] remarked that when the epithelial cell lines were under the exposure to enteroinvasive
Escherichia coli (EIEC), the application of S. thermophilus and L acidophilus could sustain and sometimes
even strengthen the structures of cytoskeleton and tight junction proteins[67].
There are relatively few studies on synbiotics in DKD. In a randomized, double-blind and placebo-
controlled trial encompassing 81 DM patients, the consumption of synbiotic bread containing Lactoba-
cillus sporogenes and inulin caused a marked increment in levels of NO in the blood plasma and a
remarkable drop in MDA concentrations compared to the probiotic and control breads. However,
probiotic bread intake had no significant influence on the levels of TAC, GSH, and catalase in plasma,
liver enzymes, calcium, iron, and magnesium in serum, and blood pressure in contrast to probiotic and
control breads[68]. There is another study where patients with ESRD who were undergoing
haemodialysis (HD) received synbiotic (Lactobacillus casei strain Shirota and Bifidobacterium breve strain
Yakult as probiotics and galacto-oligosaccharides as prebiotics) for 2 wk. The results of the study
demonstrated that p-cresol is a constipation-related uraemic toxin, and the three subjects with the
highest serum p-cresol level were diabetic HD patients. The synbiotic regimen regularized defecation
habits and reduced serum level of p-cresol in HD patients[69].
Hu et al[70] found that depletion of gut microbiota by antibiotics significantly alleviated tubulointer-
stitial injury, reduced IL-6 concentrations in the blood, and efficiently relieved glycemia in DM rats.
Meanwhile, it rescued the increased urine albumin/creatinine ratio and N-acetyl-β-D-glucosidase
/creatinine ratio. Intriguingly, in DM rats treated with antibiotics, the levels of acetate in the serum also
declined significantly and were positively correlated with kidney cholesterol concentrations[70]. Similar
results were found in diabetic rats by using broad-spectrum antibiotics, where not only the majority of
the intestinal microbiota was thoroughly killed, but also the concentrations of acetate in plasma were
reduced, intrarenal RAAS activation was effectively suppressed, and renal injury was mitigated[55].
Antibiotic therapy is unable to eliminate every microorganism that exists in the intestine of mice;
however, it is possible to maintain the microbiome in quite low levels, which is why antibiotic therapy is
commonly applied to acquire pseudo-germ-free mice in gut microbiota studies even if the requirement
of germ-free mouse maintenance is rigid and difficult to fulfil in most laboratories. Nevertheless, a large
amount of antibiotics may damage the kidneys of mice. Moreover, the use of antibiotics alone is not the
best solution, because of the possible consequences of microbiome abatement, for example, antibiotic-
related pathogen aggression[71]. The sensible application of antibiotics to achieve or enforce selection of
strains colonized with specific metabolic traits is likely to present a plan that can achieve shrinkage of
toxin production and preservation of many of the microbiota’s health benefits.
A more sustained and potent treatment to reconstruct a robust microbiome structure and
functionality might include contiguous fecal microbiota transplantation (FMT) originating in healthy
donors. Barba et al[72] found that FMT from healthy mice improved PCS accumulation, glucose
tolerance, and albuminuria[72]. Reconstructing a "healthy microbiota" in patients shows great promise
for rebuilding gut, immune, and metabolic homeostasis and it has been tested to be secure and well-
tolerated in previous clinical trials[73,74].

CONCLUSION
Gut microbiota serves as a central part as the regulator in metabolic and inflammatory homeostasis,
functioning as a link between the host and environmental influences. Constituent of the intestinal
microbiota in DKD patients varies from that of the healthy population. Both animal and human studies
have confirmed the correlation of gut dysregulation with DKD and associated metabolic disorders.
Several studies have shown budding therapeutics against gut microbiota on glucose tolerance, insulin
resistance, gut barrier integrity, endotoxaemia, uremic toxin, SCFA, TAC, and so forth, which may
breed new methods for the prevention and treatment of DKD and relevant metabolic diseases. Howbeit,
which gut microbiota constituents are the causes of renal injury and aberrant glucose metabolism, and
which are conservational factors against kidney damage and metabolic disorders, are still being

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 Lin JR et al. Gut microbiota and diabetic kidney diseases

scrutinized, so the systematic application is not currently recommended for DKD treatment and related
metabolic derangement. The dose, time length of treatment, and prolonged outcomes of the utilization
of various colonies still call for further investigation; extra searches are demanded before gut microbiota
therapies can be judiciously assigned for the treatment or prevention of DKD. Diet modification,
lifestyle modification, and control of environmental factors are still pivotal strategies to prevent DKD
progression. Our understanding of this gut-kidney crosstalk remains rudimentary, even though there is
rapidly accumulating information. Additional work is needed to describe the patho-physiological
elements of this interrelationship and to invent new treatments strategies to counteract a detrimental
loop of DKD-gut dysbiosis which drives renal disorders to ESRD.

FOOTNOTES
Author contributions: Lin JR generated the figure and wrote the first draft; Wang ZT, Sun JJ, Yang YY, Li XX, Wang
XR, Shi Y, Zhu YY, Wang RT, Wang MN, and Xie FY contributed to the writing and editing of the manuscript; Liao
ZH accepted the editor invitation, conceptualized the topic, and proofread the manuscript; both Wei P and Liao ZH
provided supervision and approved the submission of this minireview.

Conflict-of-interest statement: The authors declare no conflict of interest for this article.

Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by
external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-
NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license
their derivative works on different terms, provided the original work is properly cited and the use is non-
commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

Country/Territory of origin: Singapore

ORCID number: Jia-Ran Lin 0000-0001-8077-3895; Zi-Ting Wang 0000-0001-7206-9769; Jiao-Jiao Sun 0000-0002-8953-
7933; Ying-Ying Yang 0000-0001-5115-8375; Xue-Xin Li 0000-0001-5824-9720; Xin-Ru Wang 0000-0002-2724-9805; Yue
Shi 0000-0003-0225-0305; Yuan-Yuan Zhu 0000-0003-2141-5267; Rui-Ting Wang 0000-0002-8566-1101; Mi-Na Wang 0000-
0002-4029-5806; Fei-Yu Xie 0000-0002-1327-2852; Peng Wei 0000-0002-3721-7014; Ze-Huan Liao 0000-0002-7500-1521.

Corresponding Author's Membership in Professional Societies: American Association for Cancer Research, Associate
Member, No. 1075629.

S-Editor: Fan JR
L-Editor: Wang TQ
P-Editor: Fan JR

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