Sampaio Maia2016
Sampaio Maia2016
Sampaio Maia2016
Contents
1. Introduction 66
2. Gut Dysbiosis in Chronic Kidney Disease 68
2.1 Bifidobacteriaceae and Lactobacillaceae 74
2.2 Enterobacteriaceae 75
3. Uremic Toxins and the Gut Microbiome 76
4. Intestinal Translocation, Inflammation, and Cardiovascular Risk in Chronic Kidney 80
Disease Patients
5. Prevention Strategies of Gut Dysbiosis in Chronic Kidney Disease 82
6. Conclusion 84
Acknowledgments 86
References 86
Abstract
Chronic kidney disease (CKD) is estimated to affect nearly 500 million people worldwide
and cardiovascular (CV) disease is a major cause of death in this population. However,
therapeutic interventions targeting traditional CV risks are not effective at lowering the
incidence of CV events or at delaying the progression of the disease in CKD patients. In
recent years, disturbances of normal gut microbiome were recognized in the patho-
genesis of diverse chronic diseases. Gut dysbiosis is being unraveled in CKD and
pointed as a nontraditional risk factor for CV risk and CKD progression. The most often
reported changes in gut microbiome in CKD are related to the lower levels of Bifido-
bacteriaceae and Lactobacillaceae and to higher levels of Enterobacteriaceae. Although
metagenomics brought us an amplified vision on the microbial world that inhabits the
human host, it still lacks the sensitivity to characterize the microbiome up to species
level, not revealing alterations that occur within specific genus. Here, we review the cur-
rent state-of-the-art concerning gut dysbiosis in CKD and its role in pathophysiological
mechanisms in CKD, particularly in relation with CV risk. Also, the strategies towards pre-
vention and treatment of gut dysbiosis in CKD progression will be discussed.
Advances in Applied Microbiology, Volume 96
© 2016 Elsevier Inc.
j
ISSN 0065-2164
http://dx.doi.org/10.1016/bs.aambs.2016.06.002 All rights reserved. 65
66 B. Sampaio-Maia et al.
1. INTRODUCTION
Chronic kidney disease (CKD) is a general term for heterogeneous
disorders affecting the structure and function of the kidney (Levey &
Coresh, 2012). The definition of CKD is based on the presence of kidney
damage (i.e., albuminuria) or decreased kidney function (i.e., glomerular
filtration rate [GFR] <60 mL/min/1.73 m2) for 3 months or more, irre-
spective of the clinical diagnosis (Bailie, Uhlig, & Levey, 2005). According
to the National Kidney Foundation Clinical Practice Guidelines for Chronic
Kidney Disease (Eknoyan & Levin, 2002), CKD is classified into five stages
on the basis of GFR, from normal kidney function (stage 1) to end-stage
kidney disease (stage 5).
CKD is a global health problem with high rates of morbidity and mor-
tality. A recent study indicated that in 2010 over 497 million adults in the
world had CKD from which, 236 million had moderate or severe decreases
in kidney function presenting CKD stages 3e5 (Mills, Xu, et al., 2015).
One potential outcome of CKD is end-stage renal disease (ESRD),
requiring costly renal replacement therapy. The number of patients
requiring renal replacement therapy in the form of hemodialysis (HD), peri-
toneal dialysis, or kidney transplant, increases 10e15% each year (Lozano
et al., 2012). The progressive loss of renal function leads to the accumulation
of organic waste products, in particular derivatives of nitrogen metabolism
normally cleared by the kidneys. It is under these circumstances that the
“uremic state” is established. Nonetheless, some adverse outcomes of
CKD can be prevented through early detection and treatment (Berns,
2014; Jha et al., 2013).
Diabetes and hypertension are the most common causes of CKD world-
wide. Other causes can include glomerulonephritis, pyelonephritis, and
polycystic kidney disease (Meyer & Hostetter, 2012). One of the major
causes of death in CKD patients is cardiovascular (CV) disease. Patients
with CKD carry a high CV burden by the time they commence renal
replacement therapy, as CV risk increases exponentially with disease
progression. CV-related mortality may be up to 500-fold higher in patients
with ESRD than in the general population (Sarnak et al., 2003). Therapeu-
tic interventions targeting traditional CV risk factors (e.g., hypertension,
diabetes, dyslipidemia) are not effective at lowering the incidence of CV
events or delaying the progression of the disease (Alani, Tamimi, & Tamimi,
2014). Therefore nontraditional CKD-related risk factors that increase in
CKD and Gut Microbiome 67
relationship that prevails between gut microbiome and the host under
normal conditions, leading to the production and absorption of pro-
inflammatory and otherwise harmful by-products, while simultaneously
limiting the beneficial functions and products conferred by the normal
and “healthy” microbiota. Such events can further contribute to uremic
toxicity, inflammation, and CV risk in CKD patients (Vaziri, Wong,
et al., 2013).
More than 80 uremic toxins are known (Meyer & Hostetter, 2012) and
probably most of them are secreted into the gut altering intestinal milieu,
inducing changes in the structure, composition, and function of the gut
microbiome. A clear example of uremic toxin mechanism is the increased
secretion of urea and uric acid into the gut. Once in the gut lumen, urea hy-
drolysis occurs resulting in the formation of large quantities of ammonia that
in turn are converted to ammonium hydroxide. This compound dynami-
cally alters the gut pH, inducing a change in the proportion of pH-sensitive
bacteria, causing mucosal damage, and irritation (Kang, 1993; Vaziri, Dure-
Smith, Miller, & Mirahmadi, 1985). Also, in the gut of ESRD patients,
secreted uremic toxins serve as alternative substrates for gut microbiota,
which normally utilize indigestible complex carbohydrates. Since, unlike
other mammals, humans lack the enzyme uricase that converts uric acid
to allantoin in the gut (Oda, Satta, Takenaka, & Takahata, 2002), bacterial
families possessing urease, uricase, p-cresol and indole-forming enzymes are
expanded, whereas short-chain fatty acid (SCFA)-forming bacteria are con-
tracted in ESRD patients (Wong et al., 2014).
Moreover, a study conducted by Wikoff et al. (2009) demonstrated that a
significantly large number of chemical species found in systemic circulation
arise due to the presence of the microbiome, revealing the role of the colonic
microbiota as a significant contributor to the metabolome (collection of small
molecule metabolites) in patients with CKD. Thus, uremic toxins have im-
plications not only at the intestinal level, but also in the human plasma metab-
olome, that ultimately results from a combination of endogenous metabolites
and metabolites originating from the colonic microbiota.
In ESRD patients, restricted consumption of fruits and vegetables, a rich
source of potassium, is invariably recommended to prevent hyperkalemia.
Since fruits and vegetables are also the main source of dietary fiber, their
limited consumption in CKD may have a direct impact on the composition,
function, and metabolism of the gut microbiome. For example, a daily diet
based on fibers, fruits, and vegetables (agrarian diet) in young children is
associated with an increase of Actinobacteria and Bacteroidetes in fecal
70 B. Sampaio-Maia et al.
samples, while a “Western” diet based in lower fiber and higher fat/sugar
content is associated with an increase of Proteobacteria (including the
most common enteric pathogens) (Simpson & Campbell, 2015). Some other
studies conducted with samples obtained from children living in Burkina
Faso, Malawi, Venezuela, and Bangladesh versus children living in Italy
and the United States suggested similar results and dynamics in the human
gut microbiome according to the diet regimen (De Filippo et al., 2010;
Lin et al., 2013; Yatsunenko et al., 2012). Moreover, the use of various
phosphate-binding products, i.e., anion-exchange resins, iron-based
products, calcium acetate, calcium carbonate, and aluminum hydroxide
which are commonly prescribed for patients with advanced CKD, will
certainly have yet unrecognized effects on the gut microbiome. Finally,
the frequent use of antibiotics can significantly affect the microbiome in
CKD patients.
The first studies describing gut dysbiosis in CKD patients with interme-
diary renal insufficiency stages (3e4) (Ranganathan et al., 2009) and ESRD
patients undergoing HD (stage 5) (Hida et al., 1996) employed traditional
microbiological methods, using nonselective and selective culture media.
These studies reported a decrease on the gut colonization by Bifidobacterium
spp. and an increase of colonization by Enterobacteriaceae. More recent
studies evaluated gut dysbiosis in CKD using molecular technologies,
namely the evaluation by next-generation sequencing of the DNA region
coding for the 16S rRNA (De Angelis et al., 2014; Wang, Jiang, et al.,
2012), microarray (Vaziri, Wong, et al., 2013; Wong et al., 2014), or Dena-
turing Gradient Gel Electrophoresis (DGGE) (Barros et al., 2015). Interest-
ingly, De Angelis et al. (2014) evaluated not only the DNA coding for the
16S rRNA, but also the RNA itself to explore both total and metabolically
active bacteria. The target population of these studies included CKD pa-
tients in stages 3e4 (Barros et al., 2015; De Angelis et al., 2014; Vaziri,
Wong, et al., 2013) and in stage 5 (Vaziri, Wong, et al., 2013; Wang, Jiang,
et al., 2012; Wong et al., 2014). The study of De Angelis et al. (2014) only
included patients with immunoglobulin A nephropathy. Each study pre-
sented a list of bacterial phyla, family, genera, or species altered in CKD
in comparison to a healthy control population. Fig. 1 depicts the studies
that reported increases (to the right in green) or decreases (to the left in
red) in each family or species of the gut microbiota in CKD. The studies
conducted by Vaziri and Wong (Vaziri, Wong, et al., 2013; Wong et al.,
2014) analyzed the same sample of patients, and, therefore, the results
from both studies were treated as a single study in Fig. 1.
CKD and Gut Microbiome 71
Bacteroidaceae
Bacteroides faecis
Bacteroides finegoldii
BACTEROIDETES
Bacteroides fragilis
Bacteroides salyersiae
Bacteroides thetaiotaomicron Alteromonadaceae
Bacteroides uniformis Alteromonas sp.
Bacteroides vulgatus Aquabacteriaceae
Pseudoflavonifractor capillosus Desulfovibrionaceae
Flavobacteriaceae Enterobacteriaceae
Porphyromonadaceae Enterobacter sp.
Butyricimonas virosa Escherichia coli
Prevotellaceae Escherichia sp.
Rikenellaceae Klebsiella sp.
Proteus sp.
Catabacteriaceae Shigella sp.
PROTEOBACTERIA
Clostridiaceae Halomonadaceae
Clostridium clostridioforme Methylococcaceae
Clostridium difficile Moraxellaceae
Clostridium herbivorans Acinetobacter sp.
Clostridium methylpentosum NOR5/OM60
Clostridium nexile Polyangiaceae
Clostridium symbiosum Pseudomonadaceae
Clostridium sp. Pseudomonas sp.
Clostridium xylanolyticum Rhodospirillaceae
Coprobacillaceae Rhodospirillum sp.
Catenibacterium sp. Thalassospira sp.
Enterococcaceae SUPO5
Enterococcus spp. Sutterellaceae
Erysipelotrichaceae Sutterella sp.
Holdemanella biformis Parasutterella
Turicibacter sp. excrementihominis
Eubacteriaceae Thiotrichaceae
Eubacterium desmolans
FIRMICUTES
Thiothrix sp.
Eubacterium eligens Xanthomonadaceae
Eubacterium oxidoreducens
Eubacterium siraeum Beutenbergiaceae
Eubacterium sp. Bifidobacteriaceae
ACTINOBACTERIA
TENERICUTES
Streptococcus sp. Erysipelotrichaceae
Ruminococcaceae TM7
Oscillospira sp. F 16
Papillibacter cinnamivorans VERRUCOMICROBIA
Ruminococcus flavefaciens Verrucomicrobiaceae
Ruminococcus gnavus
Ruminococcus obeum
Sporobacter termitidis
Veillonellaceae
Phascolarctobacterium sp.
Figure 1 Description and systematization of the quantity of studies that reported gut
dysbiosis in chronic kidney disease (CKD): increases (to the right in green (light gray in
print versions)) or decreases (to the left in red (gray in print versions)) for each family or
species of the gut microbiota (A e results obtained in animal models).
72 B. Sampaio-Maia et al.
Enterobacteriaceae
Escherichia spp. Bifidobacteriaceae
Enterobacter spp. Bifidobacterium spp.
Klebsiella spp. Lactobacillaceae
Proteus spp. CKD Lactobacillus spp.
Lachnospiraceae Bacteroidaceae
Ruminococcaceae Prevotellaceae
Figure 2 Overview of the relevant emerging results (in agreement in at least two studies)
regarding bacterial family or genera altered in chronic kidney disease (CKD) in compar-
ison to a healthy control population. CKD is associated with lower levels of the families
described in the downward red arrow (gray in print versions) and with higher levels of
the families described in the upward green arrow (light gray in print versions).
note that despite the results for bacteria taxonomic families as a whole, in-
dividual bacterial genera within a family may have a self-dynamic response
to milieu alterations. In fact, each taxonomic family may comprise numerous
genus and species, with specific characteristics. Thus, additional studies are
needed to fully characterize gut dysbiosis in CKD and to understand its
physiological impact. Also, it is important to conduct other studies where
the remaining members of the microbiome are evaluated, namely, fungi,
archaea, virus, and protozoa. Only then we will be able to fully characterize
the microbiome on CKD. Nevertheless, regarding the bacteriome some ma-
jor differences have been systematically described by multiple studies on
particular taxa such as Bifidobacteriaceae, Lactobacillaceae, or Enterobacter-
iaceae that strongly suggest a direct association to CKD (De Angelis et al.,
2014; Hida et al., 1996; Ranganathan et al., 2009; Vaziri, Wong, et al.,
2013; Wang, Zhang, et al., 2012).
Two types of microbial fermentation occur in the colon: saccharolytic
and proteolytic fermentation (Hamer, De Preter, Windey, & Verbeke,
2012; Leclercq et al., 2014). Saccharolytic fermentation is generally consid-
ered to be beneficial to the host, for example, the production of SCFAs,
whereas proteolytic fermentation is presumed to be detrimental and might
be involved in the etiology of some human pathologies, such as colon cancer
and ulcerative colitis (Nicholson et al., 2012; Windey, De Preter, &
Verbeke, 2012). Increased protein fermentation results in generation of
potentially toxic metabolites such as ammonia, phenols, amines, indoles,
74 B. Sampaio-Maia et al.
2.2 Enterobacteriaceae
The Enterobacteriaceae are Gram-negative, facultative anaerobic, rod-
shaped non-spore-forming bacteria. This family is characterized by
76 B. Sampaio-Maia et al.
The first publication in Pubmed related to uremic toxins is from the year
1960 (Desi, Feher, & Szold, 1960). Although only recently has the predom-
inant role of the intestine in the generation of some uremic solutes been
highlighted (Aronov et al., 2011; Fukuuchi et al., 2002; Lekawanvijit,
2015; Yatsunenko et al., 2012), back in 1966 Einheber and Carter (Einheber
& Carter, 1966) already reported that in mice with bilateral nephrectomy
the absence of microbiome prolonged the mice life expectancy. Also, in
1982, another group reported in weanling pigs with normal kidney function
the decreased fecal and urinary excretion of phenolic and aromatic bacterial
metabolites after depletion of gut microbiome by antibiotics (Yokoyama,
Tabori, Miller, & Hogberg, 1982). In 2009, Wikoff and colleagues showed
an association between gut microbiota and some protein-bound uremic
toxins, namely indoxyl sulfate, hippuric acid, and phenylacetic acid. Later
on, Aronov et al. (2011) analyzed the plasma from HD patients with and
without colons to identify and characterize colon-derived uremic solutes.
In this study, they identified by high-resolution mass spectrometry more
than 30 individual features in patients with colons that were either absent
or present in lower concentrations in patients without colons. These features
were also more prominent in the plasma of HD patients when compared to
control subjects, suggesting that they represent uremic solutes produced by
the colon in CKD. More recently, Poesen, Windey, et al. (2016) compared
the stool metabolome between HD patients, not related healthy subjects,
and related household contacts on the same diet as well as between sham
and 5/6th nephrectomized rats, 6 weeks after surgery. The conclusions of
this study were that CKD associates with a distinct colonic microbial meta-
bolism, although the effect of renal function loss per se in humans may be
inferior to the effects of dietary and other CKD-related factors. Thus,
although more studies are needed to exclude non-CKD factors, nowadays
it is well established that colonic microbes may produce an important
portion of uremic solutes, mostly still unidentified.
The most extensively studied colon-derived uremic toxins are indoxyl
sulfate and p-cresol sulfate (Meyer & Hostetter, 2012; Wing et al., 2015).
P-cresol is a protein-bound solute that results from the fermentation of
the amino acids tyrosine and phenylalanine (Cummings, 1983). Most of
the p-cresol generated is conjugated to p-cresyl sulfate in the intestine
and to p-cresyl glucuronide in the liver. Several studies reported the asso-
ciation between p-cresol and CV outcomes in CKD (Dou et al., 2004;
Liabeuf et al., 2010; Meijers, Claes, et al., 2010). P-cresol sulfate
CKD and Gut Microbiome 79
Figure 3 Mechanisms underlying the relation between gut dysbiosis and increased
cardiovascular (CV) risk in chronic kidney disease (CKD). Figure was produced using
Servier Medical Art, http://www.servier.com/Powerpoint-image-bank.
6. CONCLUSION
In the last few years a number of researchers are unraveling the role of
the gut and its microbiome on CKD progression and the associated increased
CV risk. However, a more interdisciplinary approach is needed to further
clarify the pathogenic role of the intestinal microbiota in kidney disease.
Gut dysbiosis is starting to be characterized in CKD. So far, lower
levels of Bifidobacteriaceae and Lactobacillaceae and higher levels of
CKD and Gut Microbiome 85
GLOSSARY
Chronic kidney disease CKD is characterized by abnormalities of kidney structure or
function for three or more months, irrespective of the cause. CKD may be detected by
decreased glomerular filtration rate (GFR, <60 mL/min/1.73 m2), by increased rates of
urinary albumin excretion or by abnormal kidney structure detected by imaging.
Endotoxemia Presence of endotoxins in the blood, which may result in shock. Endo-
toxins refer to the lipid component (lipid A) of the lipopolysaccharides (LPS) present in
the outer wall of most Gram-negative bacteria that may be released in the blood when
the bacterial cell wall is disrupted. Endotoxins may elicit strong immune responses.
End-stage renal disease Patients in stage 5 of CKD, who have severe loss of renal func-
tion (GFR <15 mL/min/1.73 m2) and require renal replacement therapy in the form of
hemodialysis, peritoneal dialysis, or renal transplantation.
Glomerular filtration rate GFR refers to the flow rate of filtered blood through renal
glomerulus. GFR is usually estimated (eGFR) using serum creatinine and one of several
available equations and is useful for staging CKD from normal kidney function to end-
stage kidney disease: >90 (stage 1); 60e89; 45e59; 30e44; 15e29; <15 mL/min/
1.73 m2 (stage 5).
Gut dysbiosis Imbalance of the intestinal microbiota that results in alterations of gastro-
intestinal tract activity producing deleterious effects.
Human microbiome The collection of all symbiotic, commensal, and pathogenic mi-
croorganisms living in association with the human body, composed of bacteria, archaea,
fungi, protozoa, and viruses.
Pathobionts Symbiotic microorganisms that present the potential to become pathogenic
to the host under specific circumstances.
Prebiotics Nondigestible fiber compounds used as substrate for selective gut microbiota.
Prebiotics induce specific changes, both in the composition and/or activity of the gastro-
intestinal microbiota, conferring benefit to the host.
Probiotics Live microorganisms that, when administered in adequate amounts, may
confer benefits to the host.
Synbiotics Mixture of pre- and probiotics.
Uremia Uremia or uremic state is a clinical state that occurs in patients with kidney failure
and cannot be explained by disturbances in extracellular volume, inorganic ion concentra-
tions (for example, hyperkalemia), or lack of known renal synthetic products (for example,
erythropoietin). It is presumed that uremia is established by the accumulation of uremic
toxins.
Uremic toxins Organic waste products that are normally cleared by the kidneys and
accumulated in the plasma and/or tissues of CKD patients. More than 80 uremic toxins
are known, including urea, D-amino acids, low molecular weight proteins, guanidines, ar-
omatic compounds, tryptophan metabolites, aliphatic amines, among others.
86 B. Sampaio-Maia et al.
ACKNOWLEDGMENTS
LSS and ISS are supported by the fellowships SFRH/BD/84837/2012 and SFRH/BPD/
101016/2014 from Fundaç~ao para a Ciência e Tecnologia/QREN e POPH. ISS is sup-
ported by a research grant in 2014 by the European Society of Clinical Microbiology and
Infectious Diseases (ESCMID). RA is supported by an Endeavour fellowship. This work
was financed by FEDERdFundo Europeu de Desenvolvimento Regional funds through
the COMPETE 2020dOperacional Programme for Competitiveness and Internationaliza-
tion (POCI), Portugal 2020, Norte 2020 (NORTE-45-2015-02) and by Portuguese funds
through FCTdFundaç~ao para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia
e Inovaç~ao in the framework of the project “Institute for Research and Innovation in Health
Sciences” (POCI-01-0145-FEDER-007274).
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