Environmental Pollution 235 (2018) 429e434

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Environmental Pollution
journal homepage: www.elsevier.com/locate/envpol

Gut as a target for cadmium toxicity*

Alexey A. Tinkov a, b, c, *, Viktor A. Gritsenko c, Margarita G. Skalnaya b,
Sergey V. Cherkasov c, Jan Aaseth d, e, Anatoly V. Skalny a, b, f
a
Yaroslavl State University, Sovetskaya St., 14, Yaroslavl 150000, Russia
b
Peoples' Friendship University of Russia (RUDN University), Miklukho-Maklay St., 10/2, Moscow 117198, Russia
c
Institute of Cellular and Intracellular Symbiosis, Russian Academy of Sciences, Orenburg, 460008, Russia
d
Innlandet Hospital Trust, 2226 Kongsvinger, Norway
e
Inland Norway University of Applied Sciences, Terningen Arena, 2411 Elverum, Norway
f
Orenburg State University, Pobedy Ave., 13, Orenburg 460018, Russia

a r t i c l e i n f o a b s t r a c t

Article history: The primary objective of the present study was to review the impact of Cd exposure on gut microbiota
Received 12 November 2017 and intestinal physiology, as well as to estimate whether gut may be considered as the target for Cd
Received in revised form toxicity. The review is based on literature search in available databases. The existing data demonstrate
26 December 2017
that the impact of Cd on gut physiology is two-sided. First, Cd exposure induces a significant alteration of
Accepted 28 December 2017
bacterial populations and their relative abundance in gut (increased Bacteroidetes-to-Firmicutes ratio),
accompanied by increased lipopolysaccharide (LPS) production, reflecting changed metabolic activity of
the intestinal microbiome. Second, in intestinal wall Cd exposure induces inflammatory response and cell
Keywords:
Cadmium
damage including disruption of tight junctions, ultimately leading to increased gut permeability.
Gut microbiota Together with increased LPS production, impaired barrier function causes endotoxinemia and systemic
Lipopolysaccharide inflammation. Hypothetically, Cd-induced increase gut permeability may also result in increased bac-
Bacteroides terial translocation. On the one hand, bacteriolysis may be associated with aggravation of endotoxemia.
Firmicutes At the same time, together with Cd-induced impairment of macrophage inflammatory response,
increased bacterial translocation may result in increased susceptibility to infections. Such a supposition is
generally in agreement with the finding of higher susceptibility of Cd-exposed mice to infections. The
changed microbiome metabolic activity and LPS-induced systemic inflammation may have a significant
impact on target organs. The efficiency of probiotics in at least partial prevention of the local (intestinal)
and systemic toxic effects of cadmium confirms the role of altered gut physiology in Cd toxicity.
Therefore, probiotic treatment may be considered as the one of the strategies for prevention of Cd
toxicity in parallel with chelation, antioxidant, and anti-inflammatory therapy.
© 2018 Elsevier Ltd. All rights reserved.

1. Introduction exposure is also found to be high in China (Zhang et al., 2016). At

Cadmium is an environmental pollutant possessing serious
health hazards (Satarug et al., 2011). In particular, Cd pollution is
widespread through Europe with the highest levels in sediments
and stream water being observed in Germany and Slovakia,
whereas topsoil Cd levels were maximal in Greece, Italy, France,
Austria, Ireland (Pan et al., 2010). The mean weekly intake of Cd in
European adults accounts for 2.5 mg/kg (Nawrot et al., 2010). Cd
*
This paper has been recommended for acceptance by David Carpenter.
* Corresponding author. Yaroslavl State University, Sovetskaya St., 14, Yaroslavl
150000, Russia.
E-mail address: tinkov.a.a@gmail.com (A.A. Tinkov).
the same time, the highest Cd content in rice was detected in
Bangladesh and Sri-Lanka (Meharg et al., 2013). Although some
studies demonstrate a significant reduction in Cd exposure (USA),
further reduction is required (Tellez-Plaza et al., 2012a,b).
High social costs of Cd exposure are related to its role in various
diseases. In particular, it has been demonstrated that Cd is associ-
ated with cancer (Adams et al., 2011; Hartwig, 2013), diabetes
mellitus (Tinkov et al., 2017), cardiovascular diseases (Tellez-Plaza
et al., 2012a,b), chronic kidney disease (Ferraro et al., 2010), oste-
oporosis (Kazantzis, 2004), liver disease (Hyder et al., 2013), neu-
rodegeneration (Min and Min, 2016), adverse neurodevelopmental
outcome (Wang et al., 2016), and other diseases (Satarug et al.,
2011). It has been estimated that high Cd exposure significantly

https://doi.org/10.1016/j.envpol.2017.12.114
0269-7491/© 2018 Elsevier Ltd. All rights reserved.
430 A.A. Tinkov et al. / Environmental Pollution 235 (2018) 429e434
increases mortality by 17% (Nawrot et al., 2010).
Traditionally, the variety of adverse health effects attributed to
Cd exposure has been explained by the general mechanisms of
metal toxicity. In particular, it has been reported that Cd is capable
of induction of oxidative stress (Liu et al., 2009), inflammation
(Olszowski et al., 2012), endoplasmic reticulum stress (Biagioli
et al., 2008), genomic instability (Rani et al., 2014), and essential
metal dyshomeostasis (Moulis, 2010). Certain effects of the metal
are associated with its effect as an endocrine disruptor (Takiguchi
and Yoshihara, 2006). However, further investigations of mecha-
nisms of Cd toxicity is highly required for assessment and pre-
vention of its harmful effects.
Gut microbiota is known to play a significant role in a number of
physiological functions (Tremaroli and Ba €ckhed, 2012), including
regulating immunity (Round and Mazmanian, 2009) and mineral
metabolism (Skrypnik and Suliburska, 2017). Qualitative, quanti-
tative, or functional (metabolic) disturbances of the gut microbiota
may mediate the development numerous diseases (Marchesi et al.,
2015; Scott et al., 2015). Microbiota has been considered as a target
for environmental pollutants including persistent organic pollut-
ants, antibiotics, pesticides, as well as heavy metals (Jin et al., 2017).
However, existing data and reviews on the possible role of gut
dysbiosis in mediating Cd toxicity are insufficient.
Therefore, the primary objective of the present study was to
review the impact of Cd exposure on gut microbiota and intestinal
physiology as well as estimate whether gut may be considered as
the target for Cd toxicity.
1.1. Cd and gut microbiota
Gut microbiota is considered to be an important target medi-
ating toxic effects of heavy metals including cadmium (Jin et al.,
2017). The role of gut microbiota as a protective factor of Cd
toxicity was indicated by Breton et al. (2013), who observed a sig-
nificant increase in blood, liver, kidney, and spleen Cd content, as
well as MT1 and MT2 expression in duodenum and colon in germ-
free mice treated with Cd (Breton et al., 2013a). Certain studies have
demonstrated the impact of chronic (and subchronic) and short-
term Cd exposure on gut microbiome physiology in laboratory
animals of different age.
Cd exposed (42 days) adult rats were characterized by a signif-
icant reduction in anaerobic, and also aerobic, and lactic bacteria in
the gut (Jafarpour et al., 2015). Moreover, Cd induced specific
changes in gut microbiota on family and genus levels. An earlier
study demonstrated a significant dose-dependent reduction in
B. cereus, Lactobacillus spp, Clostridium spp, E. coli intestinal pop-
ulations in mice exposed to Cd in drinking water for 45 days (Fazeli
et al., 2011). It has been also shown that Cd exposure for 8 weeks
resulted in a significant dose-dependent increase in the relative
abundance of Actinobacteria in caecum of mice, whereas the
changes in Bacteroidetes and Firmicutes were not significant. At the
family level, caecal flora was characterized by a dose-dependent
increase in the relative number of Coriobacteriaceae, Lactobacilla-
ceae, whereas the percent of Lachnospiraceae decreased. The
changes in fecal bacteria in Cd-exposed mice were less pronounced
(Breton et al., 2013). Zhai et al. (2017) have also demonstrated a
significant increase in relative abundance of Alistipes and Odor-
ibacter genera, whereas Mollicutes and unclassified Ruminococca-
ceae were characterized by a significant Cd-induced reduction in
adult male C57black/6 mice after the same period of metal expo-
sure (Zhai et al., 2017). It is notable that Cd-induced alterations in
microbiota are more pronounced in the first 4 weeks of exposure as
compared to the latter 4 weeks. Kim et al. (2015) also demonstrated
that oral Cd treatment reduces bacterial diversity of the gut as well
as alters Firmicutes to Bacteroidetes ratio. It is also notable that the
observed NF-kB activation and proinflammatory cytokine secretion
was at least partially dependent on Cd-induced alteration of gut
microbiome, as germ-free mice were less prone to proin-
flammatory response to Cd exposure (Kim et al., 2015). The
observed changes in the gut persisted for a long time after elimi-
nation of the agent. It is also notable, that transfer of gut micro-
biome to Cd-unexposed mice resulted in similar inflammatory and
allergic responses, whereas no changes were detected in germ-free
mice (Kim et al., 2017). These findings are generally in agreement
with the earlier observation of increased intestinal permeability to
macromolecules in Cd-exposed mice (28 days) (Kim et al., 2014).
Liu et al. (2014) demonstrated that administration of the increasing
doses of Cd significantly reduced intestinal bacterial populations as
well as decreased the Firmicutes to Bacteroidetes ratio starting
from 3 week of exposure. The number of Bifidobacteria also
decreased starting from the 1 week of Cd exposure, whereas the
significant dose-dependent reduction of lactobacilli population was
detected only after 3 weeks of exposure. These changes were also
accompanied by increased production of TNFa and alteration of
genes involved in the bacterial metabolism of short-chain fatty
acids (SCFAs). Correspondingly, incubation of the cultured fecal
microbiota with Cd in vitro resulted in a significant decrease in cell
viability (Liu et al., 2014). Oppositely, another study demonstrated a
significant decrease in Bacteroides abundance in response to Cd
treatment for 8 weeks. At the same time, Cd exposure was shown to
reduce SCFAs concentration in the fecal pellet (Li et al., 2016).
In parallel with altered intestinal biodiversity under chronic Cd
exposure, short term Cd treatment also affects gut microbiome
physiology. In particular, it has been demonstrated that Cd expo-
sure induces a significant shift in bacterial proteome starting from
15 min of exposure. Based on these findings the authors have
proposed the characteristic changes of protein expression in gut
microbiota may be related to three temporal response patterns to
Cd exposure: resistance, adaptation, sustained tolerance (Lacerda
et al., 2007). In an earlier in vitro study Wang and Crowly also
demonstrated Cd-induced alteration of global gene expression. Of
note, in line with the impact on energy metabolism, cell cycle,
transport and binding protein genes, Cd exposure for 0, 5, 15, and
25 min resulted in up-regulation of genes that may be related to
biosynthesis/transport of lipopolysaccharides (Wang and Crowley,
2005). These data are of great importance, being indicative of the
nearly immediate effects of Cd on gut microbiota.
Early life low-dose Cd exposure also significantly affected the
quantity and biodiversity of the gut microbiome. In particular, at 8-
week age Cd-exposed male (but not female) mice were character-
ized by a significant increase in Bacteroides and a concomitant
decrease in Firmicutes populations. At the genus levels, the most
significant decrease was detected in Bifidobacterium and Prevotella
populations. It is also notable that the population of Cd-
accumulating Sphingomonas was significantly higher in Cd-
exposed animals. Interestingly, the observed changes in gut
microbiome were associated with increased adiposity in Cd-treated
mice. This consequence of Cd-induced alteration of the microbiome
was confirmed by the observed increase in adipose tissue mass
accumulation after transfer of fecal flora from Cd-exposed to Cd-
unexposed mice. Moreover, pretreatment of mice with Gram-
negative targeting antibiotics prevented Cd-induced increase in
adiposity (Ba et al., 2017). Another study demonstrated a significant
decrease in caecal Firmicutes in response to Cd exposure in 5-week-
old C57BL/6 male mice, whereas Bacteroidetes and g-proteobacteria
were unaffected. These changes were associated with alteration of
energy homeostasis genes (fatty acids synthesis and transport,
triglyceride synthesis) in liver that may be related to LPS-induced
up-regulation of proinflammatory gene expression (Zhang et al.,
2015).
 A.A. Tinkov et al. / Environmental Pollution 235 (2018) 429e434
Therefore, the majority of studies demonstrate a significant in-
crease in Bacteroidetes-to-Firmicutes ratio due to increased Bacter-
oidetes abundance and/or reduced Firmicutes populations. The
existing contradictions on the effect of Cd exposure on particular
bacterial populations to Cd may be associated with different
exposure regimens (dose, duration, period of life) or particular Cd
species.
1.2. Gut permeability, inflammation and endotoxemia
It has been demonstrated that Cd exposure significantly affects
intestinal epithelial cells viability and affects paracellular perme-
ability through disruption of tight junction (Duizer et al., 1999).
Later studies indicated that Cd exposure induced an irregular dis-
tribution of tight junction proteins in HT-29 cell monolayers, as
well as significantly reduced mRNA expression of ZO-1, ZO-2,
occludin, and claudin-1 in jejunum and colon of Cd-exposed mice.
These changes were associated with increased gut permeability
resulting in elevated blood LPS levels (Zhai et al., 2016). In a culture
of Caco-2 cells Cd exposure resulted in a significant alteration of
tight junction permeability associated with intercellular junction
damage and increased expression of caspase 3, heat shock protein,
and oxidative stress-related genes (Rusanov et al., 2015). These data
are in agreement with the earlier findings of Boveri et al. (2004),
who detected a significant increase in paracellular permeability in
Caco-2 layer, being accompanied by a significant elevation of HSP70
levels and the presence of certain necrotic lesions (Boveri et al.,
2004). It has been also demonstrated that Cd exposure resulted
in a significant dose-dependent increase in serum LPS levels in
mice, being accompanied by induction of LPS target genes (Lbp,
lipopolysaccharide-binding protein; TLR4, toll-like receptor 4; MD-
2, myeloid differentiation factor 2; CD14) and pro-inflammatory
genes including IL-1b, TNFa, and IL-6 in liver (Zhang et al., 2015).
It has been suggested that an increased synthesis of the protein
zonulin, a prehaptoglobin (Fasano, 2011) mediates the changes of
tight junctions and accompanying disruptions in gut dysbiosis
(Sturgeon and Fasano, 2016.
Prolonged Cd exposure resulted in altered intestinal histology,
being characterized by short and thick villi with certain fusion and
necrotic areas. Altered gut morphology was also associated with
increased TNFa, IL-1b, IFN-y, and IL-17 levels in intestine, being
accompanied by reduced lactobacilli count. It is notable that Cd-
induced changes were also detected in mesenteric lymph nodes.
Cd exposure induced proliferation resulting in increased lymph
node cellularity. Moreover, the increase in lymph node IFN-y, IL-17,
and IL-10 at both protein and mRNA levels was detected in
response to Cd treatment (Ninkov et al., 2015). Later studies by the
authors have confirmed these findings and demonstrated strain-
specific changes, being more profound in Dark Agouti rats as
compared to Albino Oxford strain (Ninkov et al., 2016). In addition,
CdCl2 treatment resulted in a marked villi damage and infiltration
of inflammatory cells into the lamina propria of the proximal in-
testine of the mice, being associated with increased macrophage
inflammatory protein-2 (MIP-2) mRNA expression (Zhao et al.,
2006). The observed proinflammatory response in intestine may
be at least partially mediated by Cd-induced activation of NF-kB via
I-kBa degradation as observed in a Caco-2 cell model (Hyun et al.,
2007). However, a histological study of gastrointestinal tract in
Cd-treated animals did not reveal any significant lesions in intes-
tine (Nai et al., 2015).
Certain studies have demonstrated the interactive effects be-
tween Cd and LPS toxicity. In particular, it has been demonstrated
that Cd and LPS coexposure in rats resulted in a more significant
liver damage via oxidative (lipid peroxidation) and nitrosative
(nitrate, peroxynitrite) stress and inflammatory response (IL-1b) as
431
compared to control animals, as well as Cd and LPS-exposed only
(Srinivasan et al., 2011). In addition, Cd and LPS exposure may have
potentiating effect on Cd-induced displacement of essential metals
(Cu, Zn) and NO production (Satarug et al., 2000). It is also notable
that high Cd exposure as assessed by blood Cd levels significantly
improved the association between LPS levels and the prevalence of
metabolic syndrome (Han et al., 2015).
Other studies have indicated that Cd may interfere with normal
LPS signaling in cells. In particular, Cd perturbed inflammatory
response to LPS in macrophages via inhibition of NF-kB pathway,
thus reducing resistance to infectious agents (Cox et al., 2016), is in
agreement with the earlier study by Koropatnick and Zalups (1997).
It is proposed that Cd-induced oxidative stress may at least partially
mediate dysregulation of reactivity in murine macrophages (Jin
et al., 2016). Moreover, it has been demonstrated that Cd expo-
sure dose-dependently decreased proinflammatory cytokine
expression in colon of mice with dextran sodium sulfate or trini-
trobenzene sulfonic acid -induced colitis (Breton et al., 2016).
Generally, the existing studies demonstrate that in parallel with
increased LPS levels and endotoxemia due to Cd-induced increase
in gut permeability, Cd may also interfere with LPS signaling.
However, the interaction between LPS and Cd may have both
antagonistic and synergistic effects depending on the dose and
target processes.
1.3. Probiotics as a therapeutic strategy in Cd exposure
In agreement with the primary role of gut dysbiosis in Cd
toxicity, multiple studies have demonstrated that probiotics may
have a significant protective effect. It has been demonstrated that
the use of diets enriched with L. plantarum, B. coagulans, and inulin
prevented Cd-induced toxicity to liver and kidneys. In particular,
probiotic-rich diet significantly reduced Cd accumulation in liver
and kidney, as reflected by decreased serum values of ALT, AST,
creatinine and carbamide as compared to untreated Cd-exposed
rats (Jafarpour et al., 2017). The changes were accompanied by
improvement of the number of intestinal bacteria, especially lactic
bacteria, in Cd-exposed animals treated with the probiotics
(Jafarpour et al., 2015). Correspondingly, the prebiotic Lactobacillus
plantarum prevented significantly decreased Cd-induced inflam-
matory response in Cd-exposed colonic (HT-29) cells, reducing
TNFa, IL-1b, IL-6, and IL-8 expression. Moreover, L. plantarum
treatment alleviated tight junction alteration, gut permeability and
endotoxemia in Cd-exposed rats (Zhai et al., 2016). It has been also
demonstrated that the use of L. plantarum diminished Cd-induced
damage to liver and kidney and increased renal antioxidant
response. These findings allowed the authors to propose that the
use of probiotics may be a more effective tool in treatment of Cd
intoxication than antioxidant therapy (Zhai et al., 2013). It is also
notable that intraperitoneal administration of L. plantarum to Cd-
exposed animals did not reduce Cd accumulation in the organs,
although increasing antioxidant activity and protecting tissues
from damage (Zhai et al., 2014). Administration of a probiotic
containing L. rhamnosus, L. acidophilus and B. longum reversed Cd-
induced depression of lactobacilli and bifidobacilli populations,
being accompanied by a significant reduction in Cd genotoxicity, as
assessed by DNA damage in hepatocytes (Jama et al., 2012).
The protective effect of probiotics under Cd-exposure may be
related to direct binding of metal ions in the intestine (Ibrahim
et al., 2006) thus reducing their bioaccessibility (Kumar et al.,
2017). It has been demonstrated that the increase in fecal lacto-
bacilli content significantly correlates with fecal Cd levels and the
decrease in blood metal concentration (Djurasevic et al., 2017). In
an in vitro model, preincubation of Cd(NO3)2 with Lactobacillus kefir
significantly reduced its toxicity in HepG2 colony (Gerbino et al.,
432 A.A. Tinkov et al. / Environmental Pollution 235 (2018) 429e434
Fig. 1. The proposed targets and effects of Cd toxicity in the gut.
2014).
The scheme of the protective action of probiotics in Cd toxicity
was proposed by Zhai et al. (2016) who demonstrated that Cd-
induced intestinal inflammation and tight junction disruption
may be the key targets for probiotics (Zhai et al., 2016). The pro-
tective action of probiotics may be improved by supplementation
with zinc (Sturniolo et al., 2002).
1.4. Summary of the toxic effects of Cd exposure on gut physiology
The existing data demonstrate that the impact of Cd on gut
physiology is two-sided. In gut microbiota Cd exposure induces a
significant alteration of bacterial populations and their relative
abundance (increased Bacteroidetes-to-Firmicutes ratio, etc.),
resulting in increased LPS production. Moreover, starting from first
minutes of exposure Cd affects metabolic activity of the intestinal
microbiome. In intestinal wall Cd exposure induces inflammatory
response and cell damage. The one of the most important aspects is
disruption of tight junctions leading to increased gut permeability
to macromolecules. Together with increased LPS production,
impaired barrier function causes endotoxemia and systemic
inflammation. Moreover, Cd-induced alteration of gut lining may
itself be a factor of microbiota impairment, whereas direct effect of
Cd on intestinal microbiome may in turn mediate its effects on
intestinal wall.
Hypothetically, Cd-induced increase gut permeability may also
result in increased bacterial translocation into the tissues as
observed in a number of studies (Condette et al., 2014; Earley et al.,
2015). On the one hand, bacteriolysis may be associated with
aggravation of endotoxemia (Ginsburg, 2004). At the same time,
together with Cd-induced impairment of macrophage inflamma-
tory response, increased bacterial translocation may result in
increased susceptibility to infections. It is also notable that Cd
exposure decreases bacteriophage lytic activity (Dorozhko and
Rotshild, 1985), that may also decrease the rate of infectious
resistance. Such a supposition is generally in agreement with the
finding of higher susceptibility of Cd-exposed mice to infections
(Simonyte et al., 2003; Rager et al., 2014).
Therefore, both impaired microbiome metabolic activity and
LPS-induced systemic inflammation may have a significant impact
on target organs (Fig. 1).
In particular, it has been demonstrated that impaired gut
microbiota metabolism is associated with non-alcoholic fatty liver
disease and alcoholic steatohepatitis, inflammatory bowel diseases
(Goldsmith and Sartor, 2014), atherosclerosis (Koeth et al., 2013),
airway allergy, altered hemopoiesis (Trompette et al., 2014). In turn,
LPS is involved in numerous inflammatory diseases including
obesity and diabetes mellitus (Cani et al., 2007; We˛gielska and
Suliburska, 2016), neurodegenerative disorders (Qin et al., 2007)
including Parkinson's disease (Dutta et al., 2008), cardiovascular
diseases (Neves et al., 2013) including acute coronary syndromes
(Troseid, 2017), liver dysfunction (Fukui, 2015), kidney failure
(McIntyre et al., 2011). Taking into account the significant role of Cd
exposure in pathogenesis of these diseases, it is possible that
altered gut physiology may at least partially mediate the toxic ef-
fects of Cd. In addition, the efficiency of probiotics in at least partial
prevention of the local (intestinal) and systemic toxic effects of
cadmium confirms the role of altered gut physiology in Cd toxicity.
Therefore, probiotic treatment may be considered as the one of the
strategies for prevention of Cd toxicity in parallel with chelation,
antioxidant, and anti-inflammatory therapy. However, further
studies are strongly required to clarify the role of Cd exposure on
gut microbiota, its biodiversity, symbiotic interactions, and meta-
bolic activity, as well as on the intestinal wall in general and in-
testinal epithelium in particular.
Acknowledgements
This paper was financially supported by the Ministry of Educa-
tion and Science of the Russian Federation on the program to
improve the competitiveness of Peoples' Friendship University of
Russia (RUDN University) among the world's leading research and
education centers in 2016e2020.
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