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Endothelial Dysfunction in Mexican Obese
Children, is there A Role of the Gut Microbiota?
Khemlal Nirmalkar1,2, Selvasankar Murugesan1, María Luisa Pizano-Zárate3,
María delSocorro Romero-Figueroa4, Carlos Hoyo-Vadillo2 and Jaime Garcia-Mena1*
1Department of Genetics and Molecular Biology, Center for Research and Advanced Studies of the National
Polytechnic Institute. Av IPN 2508 Col Zacatenco, Mexico City, 07360
2Department of Pharmacology, Center for Research and Advanced Studies of the National Polytechnic Institute. Av
IPN 2508 Col Zacatenco, Mexico City, 07360
3Department of Nutrition, National Institute of Perinatology, Mexico
4Coordination of Health Research, Delegation Head of Medical Services IMSS Toluca
#Authors contributed equally to this article
Polytechnic Institute. Av IPN 2508 Col Zacatenco, Mexico City, 07360
2Department of Pharmacology, Center for Research and Advanced Studies of the National Polytechnic Institute. Av
IPN 2508 Col Zacatenco, Mexico City, 07360
3Department of Nutrition, National Institute of Perinatology, Mexico
4Coordination of Health Research, Delegation Head of Medical Services IMSS Toluca
#Authors contributed equally to this article
*Corresponding author: Jaime Garcia-Mena, Department of Genetics and Molecular Biology, Center for Research and Advanced Studies of the NationalPolytechnic Institute. Av IPN 2508 Col Zacatenco, Mexico City, 07360; E-mail:
@
Received: December 01, 2016; Accepted: December 24, 2016; Published: January 04, 2017
Citation: Nirmalkar K, Murugesan S, Pizano-Zárate ML, Romero-Figueroa MS, Garcia-Mena J, et al. (2017) Endothelial Dysfunction in Mexican Obese Children, is there A Role of the Gut Microbiota?. Obes Control Ther 4(1): 1-4. DOI: http://dx.doi.org/10.15226/2374-8354/2/2/00127
Abstract
Endothelial dysfunction is a predisposing factor for
atherosclerosis and other cardiovascular diseases; and at the same
time, endothelial dysfunction is associated to obesity. The prevalence
of endothelial dysfunction, atherosclerosis and obesity is quite high
among Mexican children; on the other hand, gut microbiota has
been associated to obesity in the same population. Atherosclerosis
is associated to gut microbiota in humans, and this association
raise the possibility that endothelial dysfunction is also related
with the gut microbiota in obese population. This review addresses
the current knowledge of association of endothelial dysfunction,
with obesity and atherosclerosis; however, there are no reports of
association of endothelial dysfunction with gut microbiota through
the measurement of adhesion molecules like ICAM-1, VCAM-1, and
selectins.
Keywords: Microbiota; Obesity; Endothelial Dysfunction; Children; SCFA
Keywords: Microbiota; Obesity; Endothelial Dysfunction; Children; SCFA
Endothelial Dysfunction
Endothelium is the thin layer of simple squamous cells that
lines the interior surface of blood vessels and lymphatic vessels,
forming an interface between circulating blood or lymph in the
lumen and the rest of the vessel wall. Endothelial Dysfunction
(EDF) is a state of imbalance of vasodilatation or vasoconstriction,
or diminished availability of (NO) Nitric oxide [Figure 1].
Here NO works as a vasodilator. This imbalance leads downregulation
of endothelial NO Synthase (eNOS), up-regulation of
Reactive Oxygen Species (ROS) [1], C - Reactive Protein (CRP) [2],
Vascular Cell Adhesion Molecule-1 (VCAM-1) [3] and it further
causes loss of endothelial dependent dilation, blood thickening
and formation of small plates. In addition, this imbalance causes
impairment of endothelium- dependent vasodilatation and it may cause further atherosclerosis and other cardiovascular diseases
[4]. Endothelial dysfunction can be diagnosed by the gold
standard method - angiography with acetylcholine injection, with
Flow Mediated Dilation (FMD) method, or by measurement of
endothelial dysfunction markers – VCAM-1,Intercellular
Adhesion Molecule-1 ICAM-1, E-selection
and CRP in blood [5,6].
Endothelial Dysfunction and Atherosclerosis
Atherosclerosis is a hardening process of the arteries, in
which plaque builds up inside the arteries. Plaque is made of
cholesterol, fatty substances, cellular waste products, calcium
and fibrin. It can block the blood’s flow through an artery in
the heart and that may lead a heart attack or stroke (American
Heart Association, 2014). Endothelial dysfunction is an early
marker for atherosclerosis. In Mexico, around 29.8% children are
suffering with endothelial dysfunction [7]. It has been reported
that atherosclerosis was observed in 53% in Mexico during
2005-2007.
Obesity
Obesity is a metabolic disease and a worldwide health issue.
In 2014, more than 600 million adults were obese and 41 million
children under the age of 5 were overweight or obese in 2014 [8].
Figure 1:(a) Structure of a blood vessel showing the endothelium, (b)
Normal function of a blood vessel
Initially, obesity was restricted to some developed country but
now it has become a global health problem and the prevalence
of obesity has also increased from few decades [9]. Obesity and
overweight are the fifth death cause with more than 3 million
deaths worldwide [10]. In Mexico, more than 70% adults are
overweight [11], 13.3% of children between the age of 5-11 years
old are obese [12], and 1 out of 3 children are overweight [13].
Gut Microbiota
The development of obesity has influence of human gut
microbiome [14]. A human gut is occupied by up to – 100 trillion
of microorganisms [15], these gut microorganisms help us to
balance the digestive system. Alterations in gut microbiome
are associated with obesity and with weight loss [16]. Human
gut microbial population is dominated by five bacterial phyla;
Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria and
Verrucomicrobia. On the other hand, obesity is associated with
changes in the relative abundance of phylum Firmicutes and
Bacteroidetes [15]. Recent studies showed that the relative
abundance of phylum Firmicutes was higher than Bacteroidetes
in a sample of United States obese population [17]. In addition,
it was reported that bacterial genera like Roseburia spp., Blautia
spp., Coprococcus spp., Faecalibacterium spp. and families like
Lachnospiraceae, Enterobacteriaceae relative abundance are
significantly higher in Mexican overweight and obese children
than normal children [18]. These bacteria are associated with
high capacity of energy harvest in obese population [19].
Anaerobic intestinal gut microbiota ferments the dietary fiber,
and produces Short-Chain Fatty Acids (SCFAs) such as acetic
acids, propionic acids and butyric acid [20] and regulates the host
energy metabolisms [21, 22]. In animal models, it has been found
that genetically obese ob/ ob mice shows high amount of SCFAs
in their caecum and less in their feces as comparative to their
lean littermates [19]. These SCFAs have many positively effect
on intestinal health such as, an energy source for the colonic
epithelium (butyrate), and for peripheral tissues (acetate and
propionate), an inflammation modulator, helps in the gut motility
and in wound healing, nurture the blood flow by vasodilating the
colonic vessels as well. In addition, propionate augments the
muscular activity, epithelial cell proliferation, and butyrate as a
main energy source for colonocytes [21].
Diet Alters the Gut Microbiota
Diet plays an important role in human health by modulating
the gut microbial composition. High fat diet is associated with
obesity whereas dietary fiber-rich diet can reduce the risk of
obesity. It was suggested that obese microbiota might produce
more SCFAs and extract more energy from provided diet than lean
microbiota [18]. A dietary fiber containing food enriches the gut
microbiota and protects the colonic mucus barrier and it reduces
the risk of colitis. Whereas, dietary fiber-free diet increases the
mucus-eroding microbiota which degrades the colonic mucus
barrier and allow mucosal pathogens like Citrobacter rodentium
bacteria to epithelial layer which can cause colitis [23]. A
recent study showed that dietary fiber-free diet and captivity
increases the intestinal colonization of bacteria Bacteroides spp. and Prevotella spp. in Non Human Primates (NHPs), which
reflects in parallel the converge of NHPs microbiota towards the
modern human microbiota, and suggests the recent loss of core
microbiota in humans [24]. These bacterial genera Bacteroides
spp., Prevotella spp. or Ruminococcus spp. are dominant in each
enterotype and are associated with the consumption of a diet and
not affected by gender, age or nationality [25].
Overview of a Molecular Mechanism Associating
Endothelial Dysfunction, Atherosclerosis and Obesity
Atherosclerosis can cause by any stress to the
endothelium like aging, systemic arterial high blood pressure,
hypercholesterolemia, Diabetes, smoking, hypertension and with
obesity as well. Any of these factors can damage the endothelium
and stimulate the secretion of primary proinflammatory
cytokines, such as Interleukin-1 (IL-1) and the Tumor Necrosis
Factor-α (TNF-α). These cytokines enhance the expression
of adhesion molecules such ICAM-1, VCAM-1 and P-, E-, and
L-selectins [Figure 2].
Obese children between the ages 5 to 17 years have more
risk of cardiovascular disease. Obesity is associated of high
levels of cholesterol, triglycerides in adipose tissues which
induces many proinflammatory molecules such as TNF-α, IL-6,
leptin, Plasminogen Activator Inhibitor -1(PAI-1), angiotensin-
II, resistin and CRP, Monocytes
Chemo Attractant Protein-1 (MCP-1) . These molecules can cause vascular
inflammations. Obese also associated with high levels plasma-CRP
which directly reflects the high body fat [26]. Angiotensin-II can
stimulate the production of ROS which
can oxidize the Low-Density Lipo Protein (LDL). These high-levels of
CRP, ROS and oxidized Low Density Lipo Protein (oxLDL) reduce the
availability of intracellular nitric oxide [1,2]. In addition, they
increase the expression of adhesion molecules as well. These
adhesion molecules - VCAM-1, ICAM-1 and E-selectins helps the
adhesion of blood leukocytes such as monocytes, T-cells, dendritic
cells and mast cells to the endothelium layer. Furthermore,
leukocytes trans-migrate into inner layer of endothelium called
tunica intima where monocytes convert into macrophages; along
with remaining leukocytes participates in inflammatory immune
reactions that’s make plaques. These reactions lead impairment
of endothelial function, which later can appear as atherosclerosis
[27].
Figure 2: Overview of a molecular mechanism associating with endothelial
dysfunction, atherosclerosis and obesity
Endothelial Dysfunction, Obesity and Gut Microbiota
Atherosclerosis and obesity are associated with endothelial
dysfunction and obesity with gut microbiota [17]. Recent studies
suggested that the gut metagenome is associated with the
symptomatic atherosclerosis [28]. As we know Atherosclerosis
is a deposition of lipid molecules and the gut microbiota causes
inflammation by LipoPolySaccharide (LPS) and peptidoglycan
that can lead metabolic disease. Pyrosequencing showed that
atherosclerotic plaque contains bacterial DNA [29]. Shotgun
sequencing of the gut metagenome revealed that the genus
Collinsella spp. was dominated in patients with symptomatic
atherosclerosis whereas Roseburia spp. and Eubacterium spp.
were observed more in healthy controls [28].
Obese children between the ages 5 to 17 years have more risk of cardiovascular disease. Recently, our group has reported the microbial diversity in Mexican obese children [18]. We found that the relative abundance of the phylum Firmicutes was more than the Bacteroidetes in obese children with high-level triglycerides and cholesterol. We also observed the SCFAs concentration in feces was lower in obese children feces than normal weight; it was attributed to an increase in the mucosal absorption of SCFAs. EDF and atherosclerosis prevalence is slightly higher in Mexican population. Although, there is no report up to our knowledge about association between EDF and gut Microbiota, even in the Mexican population. However, we believe SCFAs and gut microbiota play a role in endothelial dysfunction by inflammatory molecules in overweight and obese Mexican children population [Figure 3].
Obese children between the ages 5 to 17 years have more risk of cardiovascular disease. Recently, our group has reported the microbial diversity in Mexican obese children [18]. We found that the relative abundance of the phylum Firmicutes was more than the Bacteroidetes in obese children with high-level triglycerides and cholesterol. We also observed the SCFAs concentration in feces was lower in obese children feces than normal weight; it was attributed to an increase in the mucosal absorption of SCFAs. EDF and atherosclerosis prevalence is slightly higher in Mexican population. Although, there is no report up to our knowledge about association between EDF and gut Microbiota, even in the Mexican population. However, we believe SCFAs and gut microbiota play a role in endothelial dysfunction by inflammatory molecules in overweight and obese Mexican children population [Figure 3].
Conclusion
Endothelial dysfunction is a predisposing factor for
atherosclerosis and for other cardiovascular diseases, and
although there is a solid association of the gut microbiota with
obesity in Mexican children, it is necessary to investigate the
association between EDF and the gut microbial diversity or
function. Further studies are necessary to establish whether a
consequence of EDF is to alter the gut microbiota composition
or its function. A more appealing hypothesis is that a primary
gradual change occurs in the microbiota attributes before the
appearance of EDF in children. An altered gut microbiota could
contribute significantly to endothelial function by the production
of currently undescribed bioactive metabolites.
Figure 3: Association of gut microbiota with different factors (see text)
Acknowledgement
This work was funded by Cinvestav; CONACyT 163235
INFR-2011-01; and FONSEC SS/IMSS/ISSSTE-CONACYT-233361
granted to JGM. We thank a Postdoctoral Fellowship from FONSEC
SS/IMSS/ISSSTE-CONACYT-233361 granted to SM.
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