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MICROVASCULAR COMPLICATIONS—NEPHROPATHY (M AFKARIAN, SECTION EDITOR)
Intestinal Microbiota in Type 2 Diabetes and Chronic Kidney
Disease
Alice Sabatino
1
&Giuseppe Regolisti
1
&Carmela Cosola
2
&Loreto Gesualdo
2
&
Enrico Fiaccadori
1
#Springer Science+Business Media New York 2017
Abstract
Purpose of the Review Diabetes mellitus is a major cause
of kidney disease [chronic kidney disease (CKD) and end-
stage renal disease (ESRD)] and are both characterized by
an increased risk of cardiovascular events. Diabetes and
kidney disease are also commonly associated with a
chronic inflammatory state, which is now considered a
non-traditional risk factor for atherosclerosis. In the case
of type 2 diabetes mellitus (T2DM), inflammation is
mainly a consequence of visceral obesity, while in the
case of CKD or ESRD patients on dialysis, inflammation
is caused by multiple factors, classically grouped as
dialysis-related and non-dialysis-related. More recently, a
key role has been credited to the intestinal microbiota in
the pathogenesis of chronic inflammation present in both
disease states. While many recent data on the intestinal
microbiota and its relationship to chronic inflammation
are available for CKD patients, very little is known re-
garding T2DM and patients with diabetic nephropathy.
The aim of this review is to summarize and discuss the
main pathophysiological issues of intestinal microbiota in
patients with T2DM and CKD/ESRD.
Recent Findings The presence of intestinal dysbiosis, along
with increased intestinal permeability and high circulating
levels of lipopolysaccharides, a condition known as
“endotoxemia,”characterize T2DM, CKD, and ESRD on di-
alysis. The hallmark of intestinal dysbiosis is a reduction of
saccharolytic microbes mainly producing short-chain fatty
acids (SCFA) and, in the case of CKD/ESRD, an increase in
proteolytic microbes that produce different substances possi-
bly related to uremic toxicity.
Summary Dysbiosis is associated with endotoxemia and
chronic inflammation, with disruption of the intestinal barrier
and depletion of beneficial bacteria producing SCFAs. T2DM
and CKD/ESRD, whose coexistence is increasingly found in
clinical practice, share similar negative effects on both intes-
tinal microbiota and function. More studies are needed to
characterize specific alterations of the intestinal microbiota
in diabetic nephropathy and to assess possible effects of pro-
biotic and prebiotic treatments in this setting.
Keywords Chronic kidney disease .Diabetes mellitus .
Endotoxin .Inflammation .Intestinal microbiota .Uremia
Introduction
Type 2 diabetes mellitus (T2DM) accounts for at least 90% of all
diabetes cases in the adult population [1]. In the last two decades,
a true epidemic of T2DM has been observed, with more than
300 million people being affected globally [2]. It is estimated that
more than 80% of patients with T2DM are overweight or have
obesity, which is now considered the main cause of the disease
[3]. Diabetes mellitus is also the leading cause of chronic kidney
disease (CKD) and end-stage renal disease (ESRD), non-
traumatic limb amputation, and blindness among adults [1]. In
This article is part of the Topical Collection on Microvascular
Complications—Nephropathy
*Enrico Fiaccadori
enrico.fiaccadori@unipr.it
1
Unità di Fisiopatologia dell’Insufficienza Renale Acuta e Cronica,
Università degli Studi di Parma, Parma, Italy
2
Dipartimento dell’Emergenza e dei Trapianti di Organi—Sezione di
Nefrologia, Dialisi e Trapianti, Università degli Studi di Bari Aldo
Moro, Bari, Italy
Curr Diab Rep (2017) 17:16
DOI 10.1007/s11892-017-0841-z
the USA, T2DM is the primary cause of ESRD, being responsi-
ble for 44% of all new cases in 2011 [4].
CKD is a global health issue since 6–10% of the whole adult
population can be diagnosed with the disease according to the
most recent classification [5,6]. In this clinical setting, the most
frequent cause of death is cardiovascular disease (CVD), which
is attributable to the coexistence of traditional (e.g., hypertension,
diabetes, and dyslipidemia) and non-conventional risk factors
[7]. Among the latter, persistent low-grade inflammation has
received increasing attention, and it is now regarded as a major
catalyst for CVD in CKD [7]. Chronic inflammation is usually
defined as a persistent inflammatory response by a causative
stimulus. In the case of CKD, and especially ESRD on dialysis,
increased production and decreased renal clearance contribute to
the accumulation of cytokines [7]. The evidence concerning the
use of inflammatory markers to diagnose chronic inflammation
in the course of ESRD is vast [8] and suggests interleukin 6 (IL-
6) as an important marker of inflammation, also representing the
best outcome predictor in advanced CKD and ESRD [9].
However, since IL-6 measurement is not easily available in the
clinical practice, the assessment of C-reactive protein (CRP), a
marker of systemic inflammation and predictor of cardiovascular
risk, is now the standard of care in the clinical setting because of
its reliability, low cost, and wide availability [10].
Chronic inflammation is common in patients with T2DM,
CKD, and ESRD [7,11–19]. In the case of T2DM, inflamma-
tion is mainly considered a consequence of obesity, in partic-
ular visceral obesity [2,20,21]. As for CKD and ESRD, many
dialysis-related and non-dialysis-related factors are thought to
contribute to the chronic inflammatory state [10,22], and re-
cent research has also highlighted a key role of the intestinal
microbiota. Two main pathophysiological mechanisms are
likely to be involved. Firstly, the low-grade inflammation typ-
ical of T2DM and CKD and ESRD can be potentiated by
translocation, from the gut lumen to the blood, of bacteria
and bacterial products (e.g., lipopolysaccharides, LPS) caused
by an increase in intestinal permeability (“leaky gut syn-
drome”)[12,13,23–27]. Secondly, modifications in the intes-
tinal microbiota in terms of species richness, diversity, com-
position, and function may have a profound impact on host
physiology, through changes in nutrient utilization and syn-
thesis of bioactive metabolites [11,27]. While abundant evi-
dence has been accrued recently in patients with CKD or
ESRD, information on this issue in T2DM is scarce. Thus,
this review is aimed at summarizing and discussing the main
pathophysiology of the intestinal microbiota in the presence of
T2DM and CKD and ESRD.
Intestinal Microbiota in Healthy Subjects
In humans, microbial cells from different bacterial species out-
number human cells by 10-fold, with the gastrointestinal (GI)
tract being the habitat for greater than 70% of this microbial
population [28•]. The amount of microbes changes along the
intestine, being highest in its distal tract, where the environment
is poor in oxygen and rich in molecules that these micro-
organisms can utilize as nutrients [28•]. The intestinal microbiota
exerts important trophic and protective functions that are not
limited to the intestine but can affect the whole organism
(Table 1). The composition, function, and structure of the intes-
tinal microbiota is generally stable, but it is also very adaptive
depending on the biochemical environment of the GI tract and
changes in nutrient availability, which represents the most impor-
tant regulator of bacterial metabolism [28•]. Normal or “healthy”
intestinal microbiota consists of the bacterial phyla Firmicutes
and Bacteroidetes (>90%), followed by Actinobacteria and
Verrucomicrobia; usually few (0.1%) pathogenic and opportu-
nistic species are present [29–31].
The two main nutrients utilized by intestinal bacteria are
carbohydrates and proteins. The ratio between these two mac-
ronutrients significantly impacts on the predominance of dif-
ferent species. In the presence of adequate amounts of undi-
gested complex carbohydrates (especially dietary fibers),
saccharolytic bacteria are favored, and proteins are used for
bacterial growth, while carbohydrates are used for energy pro-
duction through bacterial anaerobic metabolism (fermenta-
tion). As a consequence of carbohydrate fermentation, meth-
ane, hydrogen, and short-chain fatty acids (SCFA) are pro-
duced as end-products [27]. However, in the absence of undi-
gested carbohydrates, also proteins and other nitrogen
Tabl e 1 Physiologic effects of gut microbiota
(A)Integrity and function of GI tract
–Maintenance of tight junction protein structure
–Induction of epithelial heat-shock proteins
–Upregulation of mucin genes
–Competition with pathogenic bacteria for binding to intestinal epithelial
cells
–Secretion of antimicrobial peptides
–Suppression of intestinal inflammation
(B)Immunologic effects
–Maturation of intestinal immune system
–Reduction of allergic response to food and environmental antigens
–Promotion of immunomodulation and cell differentiation
(C)Metabolic effects
–Breakdown of indigestible plant polysaccharides and resistant starch
–Facilitated absorption of complex carbohydrates
–Synthesis of vitamins (K and B groups)
–Synthesis of amino acids (threonine and lysine)
–Biotransformation of conjugated bile acids
–Degradation of dietary oxalates
From: Sabatino A et al. Nephrol Dial Transplant, 2015, 30:924–933, by
permission of Oxford University Press [32•]
GI gastrointestinal
16 Page 2 of 9 Curr Diab Rep (2017) 17:16
compounds can be fermented by proteolytic bacteria in order
to increase energy availability, with parallel production of po-
tentially toxic end-products, such as ammonia, amines, thiols,
phenols, and indoles [27].
Derangements of the intestinal milieu and related changes
in the composition of the intestinal microbiota represent a
condition referred to as “intestinal dysbiosis”that may trigger
a systemic inflammatory response [28•,32•]. Many external
(e.g., antibiotics and nutrient intake) and internal (e.g., host
genotype, extra-intestinal non-communicable diseases, and
inflammatory bowel diseases) factors may contribute to the
pathogenesis of intestinal dysbiosis and to the overgrowth of
pathobionts (microbes with pathogenic potential) [32•].
Normally, the intestinal barrier prevents the translocation of
substances and microbes from the lumen to the bloodstream. The
intestinal barrier is formed by different structures/systems: tight
junctions, enterocyte membranes, mucus secretion, and immu-
nologic defense mechanisms in the intestinal wall [28•,33••].
Particularly, tight junctions are a very efficient mechanical pro-
tection against the translocation of substances and bacteria along
para-cellular pathways from the gut to the bloodstream; in fact,
they bind together with epithelial cells and are capable of
adjusting their tightness according to physiological needs [34].
Intestinal Microbiota in Type 2 Diabetes
Obesity-induced insulin resistance is the dominant underlying
pathophysiological factor for the development of T2DM [3].
Obesity is a state of chronic low-grade systemic inflammation,
which is a well-known cause of insulin resistance [35].
In mouse models of obesity, dysbiosis is usually present
[17,36,37]. Specifically, a decrease in the Bacteroidetes/
Firmicutes ratio is associated with the obese state. Germ-free
mice are resistant to obesity induced by a high-fat diet [36],
and colonization of germ-free mice with the microbiota of
obese female humans caused obesity in the colonized mouse
[38], indicating that the composition of the microbiota can
predispose to the development of obesity. In addition, cohous-
ing the colonized mice with lean mice and giving them a low-
fat and high-fiber diet prevented further increase in adiposity,
while in lean animals no changes toward obesity were found,
suggesting that in the end, diet is responsible for phenotype
development [39].
A recent human study demonstrated that poor diversity of
intestinal microbiota (defined as low gene count, LGC) is also
associated with obesity, insulin resistance, hepatic steatosis,
and low-grade inflammation [11]. In this study, LGC subjects
had a more pro-inflammatory microbial profile, characterized
by a reduction of butyrate-producing bacteria and increased
mucus degradation and oxidative stress [11].
Similar results were found in the two largest metagenome
studies in T2DM [13,40]. A moderate dysbiosis was
demonstrated, characterized by a microbiota with decreased
butyrate synthesis capacity [13,40]. Dysbiosis promoted en-
richment in membrane transport of sugars and branched chain
amino acids, and increase in oxidative stress response and
sulfate reduction [13]. Table 2summarizes the major findings
from studies in T2DM patients. Earlier studies in humans and
in mice models of T2DM and obesity reported that obesity
and impaired glucose metabolism were associated with an
altered microbiota in comparison to healthy subjects [12,41,
42]. Particularly, a proliferation of Gram-negative bacteria
might explain the increase in serum LPS levels in obese and
T2DM patients, likely triggering the low-grade inflammation
state typical of these two conditions [12,13].
Indeed, endotoxemia is known to induce the secretion of
pro-inflammatory cytokines [14]. Studies on animal models
and humans have demonstrated that a high-fat diet is able to
modulate intestinal microbiota and to increase serum levels of
LPS. The mechanisms involved in this endotoxemia state are
probably related to an increased uptake of LPS in chylomi-
crons secreted from enterocytes and an increased intestinal
permeability, known as “leaky gut”[14–17]. Circulating
LPS are recognized by Toll-like receptors and activate the
innate immune system and pro-inflammatory pathways.
Glucose and energy metabolism are also influenced by the
microbial production of SCFA. Butyrate is the main source of
energy to the intestinal epithelium and also seems to have an
effect on insulin sensitivity and energy balance [43], while ace-
tate and propionate are mainly substrates for gluconeogenesis
and lipogenesis in the liver. In addition, butyrate has been dem-
onstrated to increase the secretion of GLP1 and PYY from L
cells in the colon [43,44] and to increase the intestinal transit
time [45]. Furthermore, GLP-1 and the activation of the complex
GLP-1/GLP-1 receptor have been demonstrated to ameliorate
the early effects of diabetes on the kidney in part by attenuating
proximal tubular hyper-reabsorption and growth [46].
To summarize, present evidence suggests that dysbiosis
may result in a “leaky gut syndrome,”with increased perme-
ability that might activate the innate immune system, altering
signaling pathways that affect lipid and glucose metabolism
and triggering low-grade inflammation, eventually leading to
insulin resistance and possibly T2DM. However, studies in
Tabl e 2 Major findings from studies in patients with T2DM
Reduced butyrate-producing bacteria (Roseburia intestinalis and
Faecalibacterium prausnitzii)
Moderate dysbiosis
Pro-inflammatory environment with increased expression of microbial
genes involved in oxidative stress
Reduced expression of genes involved in vitamin synthesis
Increased serum LPS concentration
Increased intestinal permeability
LPS lipopolysaccharides, T2DM type 2 diabetes mellitus
Curr Diab Rep (2017) 17:16 Page 3 of 9 16
human are yet to fully ascertain whether dysbiosis is a cause or
consequence of T2DM [47].
Intestinal Microbiota in CKD and ESRD
The cause–consequence relationship between the alterations of
intestinal microbiota and kidney disease is complex and diffi-
cult to dissect. Indeed, it is reasonable to hypothesize that both
factors may influence each other. A dysbiotic microbiota seems
to represent a susceptibility factor for the development of kid-
ney disease following injury or in predisposed individuals [48].
In addition, it is known that the progressive loss of kidney
function significantly contributes to worsen the intestinal
dysbiosis found in CKD/ESRD patients [49]. Different mech-
anisms are involved due to derangement of the intestinal barrier
and modifications of microbiota composition (Table 3).
In this context, specific associations have been recently
shown between certain intestinal [50] and salivary [51]micro-
bial phyla/families and the condition of IgA nephropathy in
comparison to healthy controls, with a further discrimination
between progressor and non-progressor patients. This evi-
dence suggests an active involvement of microbiota in the
etiology and/or progression of this particular kidney disease,
characterized by the key involvement of the immune system,
which is known to be importantly influenced and modulated
by the microbiota [21]. In this complicated framework, one
additional variable to be considered is the diet, known to sub-
stantially contribute to the modifications of intestinal microbi-
ota composition and metabolism [52]. It is by now ascertained
that typical dietary restrictions, used to be considered as man-
datory for the conservative treatment of CKD, are responsible
of the worsening of the intestinal dysbiosis already occurring
in this clinical setting. Dietary fiber is the primary substrate for
colonic bacterial fermentation; however, patients with CKD
often have a low intake ofdietary fibers, mainly because of the
need to control potassium intake. The main sources of potas-
sium and fiber in the diet are fruits and vegetables, which are
reportedly low in CKD patients’diet [53]. Reduced intake of
fibers, in addition to other factors related to CKD treatment
(dialysis modality, phosphate binders, low fluid intake), life-
style (inactivity), and comorbidities (diabetes, malnutrition,
heart failure, and cerebrovascular diseases), may prolong the
GI transit time. Prolonged transit time may lead to increased
CHO fermentation in the proximal segments of the intestine
[54], thus reducing CHO availability to the colonic bacteria. In
addition, protein digestion and absorption seem tobe impaired
in CKD patients [55] due to alterations in the GI tract motility,
hypochlorhydria, and bacterial overgrowth in the small bowel,
thus increasing the amount of intact protein available for pro-
teolytic bacteria in the colon [54,56,57].
Recent concepts about the nutritional management of CKD
are expanding the vision from the focus on a single nutrient to
the concept of “food matrices,”namely complex associations
of different food categories, often nutraceuticals (antioxidants,
fibers, proteins, vitamins, etc.) found together in the same
food. In particular, food matrices traditionally belonging to
the Mediterranean Diet are particularly rich in nutraceutical
components so that this dietary scheme is being reconsidered
as suitable for this category of patients [58].
As discussed earlier, the intestinal microbiota can be highly
adaptable to changes in the biochemical environment. That is
why relevant quantitative and qualitative changes in the bac-
terial population of CKD patients have been demonstrated,
also in earlier stages of the syndrome [59]. Recent studies
have demonstrated increased counts of aerobic and anaerobic
bacteria in the small bowel of CKD patients as well as over-
growth of Proteobacteria,Actinobacteria,andFirmicutes in
the colon [49]. In particular, an expansion of bacterial species
with urease, uricase, and indole- and p-cresol-forming en-
zymes has been documented [60]. Urea is now considered a
key factor in the pathogenesis of increased permeability of the
Tabl e 3 Effects of chronic
kidney disease on intestinal
bacteria metabolism
Effects Mechanism
1.Reduced intake of dietary fibers Prescribed potassium restriction leads to reduced intake of fruits
and vegetables
2.Prolonged colonic transit time
(constipation)
Multifactorial: dialysis modality, lifestyle, inactivity, phosphate
binders, dietary restrictions, low fluid intake, primary renal
disease, and comorbidities (diabetes, heart failure, malnutrition,
cerebrovascular disease)
3.Increased amounts of protein available
for proteolytic bacterial species
Protein assimilation is impaired in uremia, with increased amounts
of intact proteins reaching the colon
4.Changes of the colonic microbiota Increased blood ammonia concentrations may change intestinal
lumen pH; drug therapies (antibiotics, phosphate binders,
antimetabolites etc.) with local effect in the gut lumen
5.Increased permeability of the intestinal
barrier
Uremia; hypervolemia and intestinal ischemia caused by
aggressive ultrafiltration volumes or intradialytic hypotension
From: Sabatino A et al. Nephrol Dial Transplant, 2015, 30:924–933, by permission of Oxford University Press
[32•]
16 Page 4 of 9 Curr Diab Rep (2017) 17:16
intestinal barrier. The increased influx of urea into the intesti-
nal lumen as a consequence of uremia may foster bacterial
species that produce urease. These bacterial species hydrolyze
urea to ammonia and increase intestinal pH, leading to muco-
sal irritation and structural damage [61,62]. In addition, intes-
tinal excretion of both uric acid and oxalate is also increased in
CKD [63,64]. Because of the wide availability of nitrogen
waste products in the intestine, the overgrowth of microbes
capable of utilizing these substrates is thus favored [60].
CKD is characterized by the progressive accumulation of
many substances and solutes, such as electrolytes, hormones,
and other solutes. Some of these compounds, termed uremic
toxins, may interfere with many biological functions and may
have important effects on inflammatory status and CVD risk [7,
65,66]. The identity of such toxins remains an active area of study
[67,68]. Their precursors are formed in the GI tract during bac-
terial protein fermentation. The two most widely studied of these
compounds are p-cresol (the precursor of p-cresyl-sulfate and p-
cresyl-glucuronide) and indole (the precursor of indoxyl sulfate),
generated respectively from the fermentation of amino acids ty-
rosine and tryptophan. In healthy subjects, the kidney excretes
these molecules by active tubular secretion, while in CKD in-
creased blood concentration of p-cresyl-sulfate and indoxyl sul-
fate follows the reduction of renal function [69]. In ESRD patients
on dialysis, the clearance of p-cresyl-sulfate and indoxyl sulfate is
less than 10% of that of healthy subjects [70], and their increased
blood concentration correlates with poor outcomes [71–77].
These protein-bound compounds negatively affect endothelial
function and repair by several mechanisms, including inflamma-
tion, oxidative stress, impaired nitric oxide production, and inhi-
bition of endothelial proliferation and healing [73–78].
Targeting the Intestinal Microbiota to Modulate
Intestinal Barrier Dysfunction and Dysbiosis
in T2DM and CKD/ESRD
Probiotics and Prebiotics in T2DM
Probiotics are “viable organisms that, when ingested in sufficient
amounts, exert positive health effects”[79]. Among the many
claimed health benefits associated with probiotic bacteria, partic-
ularly important is the (transient) modulation of the intestinal
microbiota and the capability to interact with the immune system.
The term prebiotic refers to “a selectively fermented ingredient
that allows specific changes, both in the composition and/or ac-
tivity in the gastrointestinal microbiota that confer benefits”[80].
Prebiotics promote the growth of bacterial species that stabilize
the mucosal barrier function, reduce the abundance of pathogenic
bacteria by intestinal lumen acidification, overcome the compe-
tition for nutrients, and produce antimicrobial substances [81].
Some characteristics must be present in the food ingredient to be
classified as a prebiotic, such as resistance to digestion and
absorption in the upper gastrointestinal tract, easy fermentability
by the intestinal microbiota, and capability of selective stimula-
tion of growth and/or activity of beneficial bacteria potentially
associated with health and well-being [79,80]. Finally, when
probiotics are administered along with prebiotics, the combina-
tion is referred to as “synbiotics.”
It remains to be fully ascertained whether probiotic admin-
istration may represent an efficacious treatment for T2DM.
Recent literature has focused on targeting bacterial strains
and increased intestinal permeability by SCFAs. SCFAs have
been shown to modulate intestinal hormones and to have im-
portant effects in metabolic health since they affect intestinal
permeability, satiety, gastric emptying, and food intake [82,
83]. It appears that butyrate plays a pivotal role in the correc-
tion of endotoxemia, by improving intestinal wall barrier
function, with proliferation of colonic epithelial cells and
tight-junction tightness [84]. In a landmark study performed
in 18 obese subjects with metabolic syndrome and insulin
resistance, fecal transplantation from lean donors, but not au-
tologous transplantation, improved insulin sensitivity and in-
creased the microbiota diversity, in particular butyrate-
producing bacteria such as Roseburia intestinalis,
Faecalibacterium prausnitzii, and Eubacterium hallii [85].
There is also evidence that classical probiotics can stop weight
gain and improve glucose tolerance in mice with T2DM [86].
Research focusing on the intestinal barrier function demon-
strated that supplementation with 2 × 10
8
CFU/day of
Akkermansia muciniphila, a bacterium found in the mucus layer
of the intestinal wall, reduced serum LPS in mice fed a high-fat
diet [87]. However, data on A. muciniphila are still controversial
since some studies reported increased concentrations of this bac-
terial strain in some disease states or during high-fat diet [13,88].
Regarding the use of prebiotics, this approach was associ-
ated with favorable changes in the microbiota and improve-
ment of metabolic markers of obese mice [89]. In humans,
administration of prebiotics improved insulin sensitivity in
subjects without T2DM [90]. However, not all humans re-
spond to prebiotic treatment in the same manner, and lower
bacterial diversity is related to no response [91,92]. More
specifically, in a recent study, the Prevotella/Bacteroides ratio
of the intestinal microbiota of healthy subjects allowed the
identification of responders and non-responders [92]. In this
study, glucose metabolism of germ-free mice that received the
microbiota of responder subjects improved, while nothing
happened to germ-free mice that received the microbiota of
non-responders. More studies are needed to assess the role of
prebiotics and probiotics in the treatment of T2DM.
Probiotics and Prebiotics in CKD and ESRD
Currently, nutritional strategies aimed to modulate intestinal mi-
crobiota in CKD and to reduce the serum levels of uremic toxins
p-cresol and indoxyl sulfate are a promising area of research
Curr Diab Rep (2017) 17:16 Page 5 of 9 16
[93–102]. Preliminary data already demonstrated the ability of a
functional food rich in prebiotic fibers (barley beta-glucans) to
modulate intestinal microbiota composition and metabolome in a
clinical trial involving healthy volunteers [103]. Moreover, beta-
glucans were able to increase fecal SCFA levels [103]andto
reduce circulating p-cresyl sulfate levels [104], demonstrating
their ability to induce a shift toward an intestinal metabolism
driven by saccharolytic bacteria.
In the context of CKD, several studies tried to modulate the
intestinal environment and microbiota by using probiotics
(i.e., Lactobacillus,Streptococcus,Bifidobacteria)[93–96,
105], prebiotics (i.e., arabic gum, oligofructose) [97–99], or
synbiotics (i.e., Lactobacillus and Bifidobacterium combined
with oligosaccharides) [101,102]. In most cases, prebiotics
and probiotics were administered to explore their effects on
blood accumulation of blood urea nitrogen (BUN), p-cresyl
sulfate, and/or indoxyl sulfate, which are the metabolic
byproducts of nitrogen-containing compounds. In one study
on probiotics, the use of a mix of bacteria (Lactobacillus
acidophilus KB27, Bifidobacterium longum KB31, and
Streptococcus thermophilus KB19) for 6 months reduced
BUN and uric acid levels in stage 3–4 CKD patients [94]. In
amorerecentstudy[96], a 2-month treatment with a dairy
product containing 16 × 10
9
CFU of Lactobacillus casei
Shirota was able to reduce BUN concentration in CKD pa-
tients stages 3 and 4. Non-randomized studies on hemodialy-
sis (HD) patients [93,105] demonstrated a reduced excretion
of p-cresol and indican (i.e., a precursor of indoxyl sulfate)
and decreased serum levels of indoxyl sulfate [93,105], prob-
ably owing to reduced intestinal production of these toxins. In
CKD patients, the use of prebiotics also presented beneficial
effects, such as BUN decrease [98], improved eGFR [99],
higher fecal nitrogen excretion, and increased fecal
saccharolytic bacteria [89]. These data suggest that the pres-
ence of prebiotics provides enough energy substrates for the
intestinal microbiota, allowing saccharolytic bacteria to incor-
porate nitrogen for growth, thus reducing the production of
uremic compounds. Other studies have shown a reduction of
serum p-cresyl sulfate and p-cresyl sulfate generation rates in
ESRD patients on hemodialysis when patients received prebi-
otics [98] or fiber-enriched food [99]. The use of synbiotics
decreased serum p-cresol conjugate levels [100–102], normal-
ized the amount and consistency of stool in HD patients [100],
increased the counts of Bifidobacteria [101], and modified the
stool microbiome of HD patients [102]. However, studies in-
vestigating the impact of probiotics on clinical endpoints (i.e.,
CVD and mortality) are lacking.
Conclusion
There is increased interest in the complex and bidirectional
relationship between the host and its microbiota, especially
regarding the role on the development of non-communicable
disease such as obesity and diabetes. Since many studies are
cross-sectional, it is not possible at the present time to estab-
lish a clear-cut causal relationship between intestinal dysbiosis
and obesity or T2DM. However, we know that dysbiosis may
cause endotoxemia and chronic inflammation, both through
directly disrupting the intestinal barrier and by reducing the
number of beneficial bacteria that produce SCFAs. T2DM and
CKD, whose coexistence is increasingly found in clinical
practice, share similar negative effects on both intestinal mi-
crobiota and the intestine itself. Thus, prospective studies are
necessary to define causality, and further randomized con-
trolled trials are needed in both T2DM and CKD to fully
define the role of probiotic and prebiotic therapies.
Compliance with Ethical Standards
Conflict of Interest A.S., G.R., C.C., L.G., and E.F. declare that they
have no competing interests.
Human and Animal Rights and Informed Consent This article con-
tains studies with human subjects performed by one of the authors, L.G.
In this case, all procedures performed in studies involving human partic-
ipants were in accordance with the ethical standards of the institutional
research committee and with the Helsinki declaration. This article does
not contain any studies with animal subjects performed by any of the
authors.
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