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Obesity and its associated complications like type 2 diabetes (T2D) are reaching epidemic stages. Increased food intake and lack of exercise are two main contributing factors. Recent work has been highlighting an increasingly more important role of gut microbiota in metabolic disorders. It's well known that gut microbiota plays a major role in the development of food absorption and low grade inflammation, two key processes in obesity and diabetes. This review summarizes key discoveries during the past decade that established the role of gut microbiota in the development of obesity and diabetes. It will look at the role of key metabolites mainly the short chain fatty acids (SCFA) that are produced by gut microbiota and how they impact key metabolic pathways such as insulin signalling, incretin production as well as inflammation. It will further look at the possible ways to harness the beneficial aspects of the gut microbiota to combat these metabolic disorders and reduce their impact.
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R E V I E W Open Access
The role of Gut Microbiota in the
development of obesity and Diabetes
Othman A. Baothman
1
, Mazin A. Zamzami
1
, Ibrahim Taher
2
, Jehad Abubaker
3*
and Mohamed Abu-Farha
3*
Abstract
Obesity and its associated complications like type 2 diabetes (T2D) are reaching epidemic stages. Increased food
intake and lack of exercise are two main contributing factors. Recent work has been highlighting an increasingly
more important role of gut microbiota in metabolic disorders. Its well known that gut microbiota plays a major role
in the development of food absorption and low grade inflammation, two key processes in obesity and diabetes.
This review summarizes key discoveries during the past decade that established the role of gut microbiota in the
development of obesity and diabetes. It will look at the role of key metabolites mainly the short chain fatty acids
(SCFA) that are produced by gut microbiota and how they impact key metabolic pathways such as insulin
signalling, incretin production as well as inflammation. It will further look at the possible ways to harness the
beneficial aspects of the gut microbiota to combat these metabolic disorders and reduce their impact.
Background
Obesity and its associated disorders have reached an
alarming stage worldwide. The last decades have experi-
enced an exponential increase in the number of people
suffering from obesity and its associated disorders such
as T2D [17]. Sedentary lifestyle and increased food
consumption has been considered the main underlying
causes for this obesity epidemic [810]. Environmental
and genetic factors have also been implicated including
changes in the gut microbiota to play a role in the devel-
opment of metabolic disorders [1117]. Gut microbiota
describes all organisms living in the gastrointestinal (GI)
tract. The majority of these organisms reside in the large
intestine. These bacteria play important physiological
role in vital processes such as digestion, vitamin synthe-
sis and metabolism amongst others. Even though the
exact mechanism linking gut microbiota to obesity is far
from being very well understood, its well established
that gut microbiota can increase energy production from
diet, contribute to low-grade inflammation and regulate
fatty acid tissue composition [11, 18, 19]. These pro-
cesses as well as others have been proposed as the link
between obesity and gut microbiota. However, the exact
contribution of gut microbiota to the development of
obesity and diabetes is not very clear due to many rea-
sons including the complexity and diversity of gut mi-
crobes, ethnic variation in studied populations and large
variations between individuals studied [14, 20]. Nonethe-
less, modulation of gut microbiota holds a tremendous
therapeutic potential to treat the growing obesity epi-
demic especially when combined with diet and exercise
[2123]. This review shed some light on the recent work
linking gut microbiota with obesity and diabetes and
looks at possible ways to modulate gut microbiota to
control the spread of obesity and diabetes.
Origin and composition of gut micribiota
The human body contains trillions of microorganisms
that inhabit our bodies during and after birth [2426].
During the pregnancy, infants intestinal tract is free of mi-
crobes until exposed to maternal vaginal microbes during
normal birth [27]. Infants born through Caesarian section
are exposed to maternal skin bacteria altering their bacter-
ial gut composition [27]. Feeding represents another
source of microorganisms where breast fed babies have
different gut microbiota composition than formula fed
babies [27]. Introduction of solid food represents another
shift in the composition of babies gut microbiota [28].
After that, gut microbiota remains relatively unchanged
until old age where the composition changes again. Adult
* Correspondence: jehad.abubakr@dasmaninstitute.org;
mohamed.abufarha@dasmaninstitute.org;mafarha@gmail.com
Equal contributors
3
Biochemistry and Molecular Biology Unit, Dasman Diabetes Institute,
Dasman, P.O. Box 118015462 Kuwait City, Kuwait
Full list of author information is available at the end of the article
© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Baothman et al. Lipids in Health and Disease (2016) 15:108
DOI 10.1186/s12944-016-0278-4
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
humans have more than 10 times the number of bacterial
cells than the cells constituting the human body. Majority
of microbiota in the GI tract are bacteria, nevertheless,
viruses fungi and other microorganisms are still present
[14]. Even though, individuals have unique microbiota
composition, gut microbiota is mainly members of four
phyla (Firmicutes,Bacteroidetes,Actinobacteria and
Proteobacteria)[19].AsshowninTable1,thelarge
intestine contains the highest number of bacteria con-
taining over 10
11
bacteria per gram of intestinal con-
tent. The mouth contains 10
12
followed by the Ileum
containing 10
8
10
9
bacteria [29]. On the other hand,
the jejunum harbors 10
5
10
6
while the stomach has
the least number of bacteria 10
3
10
4
[29]. Even though
we are still far from identifying, let alone characterizing
all bacteria in our system, advancing molecular biology
techniques such as next-generation sequencing has tre-
mendously contributed to our understanding of the gut
microbiota [30]. The use of gnotobiological methods to
breed mice in a sterile environment provided an
invaluable tool to understand the role of infecting con-
trolled bacterial cultures and defined bacterial strains
into animals. Studying their effect through various
genomic and proteomic tools [29].
Factors affecting gut microbiota composition
Composition of gut microbiota is affected by many fac-
tors such as diet, disease state, medications as well as
host genetics to name a few. As a result, the compos-
ition of the gut microbiota is constantly changing affect-
ing the health and well-being of the host such as disease
state as well as the use of various medicines such as an-
tibiotics (Fig. 1). The effect of antibiotics on gut micro-
biota is well documented showing a long term reduction
in bacterial diversity after use of antibiotics. Thuny et al
has shown that the use of intravenous treatment by
vancomycin plus gentamycin has been associated with a
major and significant weight gain [31]. Link between
antibiotics and weight gain is also well documented in
infants as well, for example, Saari et al has linked anti-
biotic exposure during the first 6 months of age to
weight gain in healthy children [32]. Furthermore, Stud-
ies have shown that the use of antibiotics will cause a
decline in the bacterial diversity, stereotypic declines as
well as increased abundances of certain taxa [3343].
On the other hand, recovery of normal microbiota from
certain antibiotic treatment can be long depending on
the type of antibiotic and its spectrum [44]. Strong and
broad spectrum antibiotics such as clindamycin can have
longer affects persisting up to 4 years as suggested by
some studies [45]. Moreover, the stress caused by the
disruption of normal flora after antibiotic treatment fa-
cilitates the transfer of antibiotic resistance genes to
virulent species leading to increased drug resistance
[44]. These studies highlight the importance of better
understanding of the role antibiotics play in modulating
gut microbiota and their contribution to weight gain and
potentially loss as well as other diseases.
Finally, the main contributor to the diversity of the gut
microbiota is diet [4652]. It has been suggested that
changes in the diet can account for 57 % of the varia-
tions in microbiota compared to genetic variations in
host that can only account for 12 % [53]. The effect of
diet on microbiota composition is prominently observed
as early as during breast and formula feeding as men-
tioned above. For example, level of Bifidobacteria spp. is
higher in breast-fed babies compared to formula fed ba-
bies [5459]. Formula-fed babies on the other hand have a
more diverse microbiota with higher levels of Bacteroids
spp. and Lactobacillus spp. [58]. Moreover, probiotics and
Table 1 Number of bacteria in different components of the
gastrointestinal tract
Digestive Tract Number of Bacteria
Mouth 10
12
Stomach 10
3
10
4
Jejunum 10
5
10
6
Terminal Ileum 108109
Large Intestine 10
11
Per gram of intestinal contents
Fig. 1 A diagram showing main factors affecting the gut microbiota
composition highlighting the great impact of diet on
this composition
Baothman et al. Lipids in Health and Disease (2016) 15:108 Page 2 of 8
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prebiotics are among the most dietary strategies estab-
lished for controlling the composition and metabolic
activity of gut microbiota. Probiotics are non-pathogenic
microorganisms used as food ingredients to benefit the
hostshealth. Jones et al investigated the effect of a bile
salt-hydrolyase Lactobacillus reuteri strain in hypercholes-
terolemic individuals. They found this strain can signifi-
cantly lower the low-density lipoprotein cholesterol
(LDL-C) [60]. Also they proposed the role of nuclear re-
ceptor farnesoid X receptor (FXR) as transactional factor
in reducing fat absorption from intestine. Furthermore,
prebiotics are fermented dietary fibers have been shown
to impact the host by specifically stimulating changes in
the composition and/or activity of bacteria in the colon,
and thus improving the hostshealth [61]. Lactulose,
resistant starch and inulin are the most prebiotic com-
pounds used by the food industry to modify the compos-
ition of gut microbiota to benefit human health. These
have been shown to mostly target bifidobacteria and
lactobacilli [62, 63]. Prebiotics are carbohydrate-like com-
pounds, such as lactulose and resistant starch, and have
been used in the food industry to modify the composition
of the microbiota species to benefit human health in re-
cent years [62]. Inulin is one type of prebiotics. These
prebiotics mostly target bifidobacteria and lactobacilli,
which are two kinds of probiotics [63]. Recent research
suggested that combining both prebiotics and probiotics,
namely synbiotics can also fight obesity [64].
A number of studies have shown tight connection
between diet and microbiota indicating how the compos-
ition of different diets will directly impact gut microbiota
[47, 49, 51, 52]. In an earlier study, Turnbaugh et al used
humanized mice that were generated by transplanting hu-
man feces into germ-free mice to study the effect of diet
on microbiota [65]. Switching mice from low-fat, plant
polysacchariderich diet to so call Western diet, a high-
fat and sugar diet, altered the composition of the micro-
biota within a single day [65]. Mice fed with the Western
diet had increased number of Erysipelotrichi class of
bacteria within the Firmicutes phylum and reduced
Bacteroides spp. Similarly mice fed a vegetarian diet,
rich in dietary fibers, had lower counts of Bacteroides
spp. E. Coli and other bacteria compared to the con-
trols. Table 2 gives a summary of recent studies looking
at changes in gut microbiota after consuming various
types of diets that have various levels of sugar, fat and
protein such as western diet, vegetarian and Calorie
restricted diet.
Obesity and gut microbiota
Due to the exponential increase in obesity rates and its
associated complications such as diabetes in the past few
decades, tremendous attention has been given to under-
standing underling mechanism. Albeit these tremendous
efforts and the identification of candidate genes and
mutations in studies like genome wide association stud-
ies (GWAS), full understanding is still lacking. During
the last decade new studies have emerged suggesting a
role for gut microbiota in the development of obesity
and diabetes [11, 6677]. More studies have been pub-
lished showing a wide range role of gut microbiota in
processes like energy homeostasis, blood circulation and
autoimmunity to list a few. Early studies showed that
obese mice as well as humans had different gut micro-
biota composition compared to lean. A number of stud-
ies showed an increase in bacteria from the Firmicutes
phyla and a decrease in the Bacteroidetes phyla that is
believed to be associated with increased energy absorp-
tion from food and increased low-grade inflammation
[15, 17]. However, other studies showed no difference
between these two phyla in lean and obese subjects,
highlighting the need for focusing further on specific
species within those groups rather than comparing them
at the phyla level. Another example for the role of
microbiota in obesity has been seen with patients under-
going Rouex-en-Y gastric bypass. After the surgery, pa-
tients observe dramatic metabolic improvement that
cannot be explained by the caloric restriction and the
weight loss alone. Changes in gut microbiota have been
shown to play a role in this improvement as a shift in
bacterial population has been observed in a number of
studies [1820, 76, 7886]. In order to demonstrate the
role of bariatric surgery in the changes of the gut micro-
biota, Liou et al showed that fecal transplantation from
RYGB-treated mice into germ-free mice lead to weight
loss and decreased fat mass in mice [87].
Table 2 The effect of various diets on the composition of gut
microbiota diversity
Diet Type Effect on bacteria
High Fat Diet Decrease of genera within the class Clostridia
in the ileum. Increase Bacteroidales in large
intestine [130]
Increase Lactobacillus spp., Bifidobacterium
spp., Bacteroides spp., and Enterococcus spp.
Decrease Clostridium leptum and
Enterobacter spp. [131]
Increase Firmicutes to Bacteriodetes ratio. And
increased Enterobecteriaceae [132]
increase Bacteroidales, Clostridiales and
Enterobacteriales [133]
Vegetarian Diet Decrease Acteroides spp., Bifidobacterium
spp., Escherichia coli and Enterobacteriaceae
spp. [134]
Decrease Enterobacteriaceae and increase
Bacteroides [135]
Increase Bacteroidetes, and decrease
Firmicutes and Enterobacteriaceae [136]
Calorie restricted Decrease Firmicutes to Bacteroidetes ratio [137]
Baothman et al. Lipids in Health and Disease (2016) 15:108 Page 3 of 8
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Gut microbiota contributes to energy metabolism
through the production of SCFA that are produced by
colonic fermentation which involves the anaerobic
breakdown of dietary fiber, protein and peptides. SCFA
are bacterial waste products that are produced by the
bacteria to balance the redox state in the gut. Most
abundant SCFA species are acetate, propionate, and bu-
tyrate. Acetate and propionate are mostly produced by
Bacteroidetes phylum, while butyrate is produced by the
Firmicutes phylum. They have been shown to exert
beneficial effects on body weight, glucose homeostasis
and insulin sensitivity. Gao et. al. showed that butyrate
dietary supplementation reduces diet-induced insulin re-
sistance in mice possibly through increasing energy ex-
penditure and mitochondria function [88]. Butyrate and
propionate were protective against diet-induced obesity
[89]. Oral administration of acetate also improved glu-
cose tolerance [90]. On the contrary to its proposed
beneficial effect in diet induced obesity, cecal and fecal
SCFA levels have been shown to be higher in genetically
obese ob/ob mice and obese human subjects [16, 91,
92]. It has been suggested that this increase in SCFA is
due to decreased colonic absorption with obesity [91].
SCFA can also act as signaling molecules and activate
various pathways such as the activation of the AMP-
activated protein kinase (AMPK) in liver and muscle tissues
that triggers the activation of key factors involved in
cholesterol, lipid, and glucose metabolism peroxisome
proliferator-activated receptor-gamma coactivator 1
alpha (PGC-1α), Peroxisome proliferator-activated re-
ceptor gamma (PPARγ), and Liver X receptors (LXR)
[93]. In addition SCFA have been also shown to activate
Glucagon-like peptide-1 (GLP-1) through G-protein
coupled receptor 43 (GPR43) which is also known as
free fatty acid receptor 2 (FFAR2) [94, 95]. FFAR2 is
one of the SCFA receptors and that has been shown to
be activated by acetate and propionate followed by bu-
tyrate [96, 97]. Mice lacking the FFAR2 receptor were
obese while its overexpression in adipose exhibited
leanness under normal conditions [98]. Itsbelievedthat
these phenotypes were mediated by gut microbiota pro-
duced SCFA since these mice strains did not show the
same phenotypes in mice grown under germ-free con-
ditions or when treated with antibiotics [99]. The sec-
ond SCFA receptor is GPR41, also called FFAR3 that
shares 33 % amino acid sequence identity with FFAR2
and is activated mainly by propionate and butyrate [89].
Similar to FFAR2, FFAR3 is capable of inducing the gut
hormone peptide YY (PYY) and GLP-1. It can also im-
prove insulin signaling through SCFA produced by gut
microbiota [100, 101].
Gut microbiota was also shown to play a role in the
regulation of bile acids and cholesterol metabolism in
both humans and animals [102]. Bile acids are synthesized
in the liver by a multistep pathway. It can also act as an
emulsifying agent in the intestine; helping to prepare diet-
ary triacylglycerol and other complex lipids for degrad-
ation by pancreatic digestive enzymes. Before bile acids
leave the liver, they convert into bile salts by conjugating
to either glycine or taurine then re-absorbed in the ileum.
A small amount of bile acids lost in fecal excretion via
the action of intestinal bacteria. It was suggested that
the possible role of gut microbiota in controlling bile
acid and cholesterol metabolism might be induced by
the up-regulation of transcription factors that link it to
nutritional-induced inflammation, lipid absorption and
de novo lipogenesis [102].
Low grade inflammation is a hallmark of obesity and
T2D. Productions of pro-inflammatory cytokines are co-
ordinated Via the Toll-like receptors (TLRs) and the
master regulator of key inflammatory cascades the nu-
clear factor kappa (NF-kB) [103106]. These pathways
have been shown to be activated by the production of li-
popolysaccharides (LPS) that are major component of
the outer membrane of Gram-negative bacteria that is
produced in the gut [106]. Higher LPS levels have been
associated with increased fat intake. It was also observed
in obese mice models. It has been proposed that dietary
fat mediated the absorption of LPS linking them to obes-
ity. In fact, it has been demonstrated that adding LPS to
normal-diet induced insulin-resistance and lead to
weight gain. It has been also shown that LPS binds to
TLR4 receptor on macrophages and activate the pro-
duction of inflammatory markers in a process that has
been linked to impairing pancreatic β-cell by suppress-
ing insulin secretion and decreasing gene expression of
Pancreatic And Duodenal Homeobox 1 (PDX1) [107].
Diabetes and gut microbiota
Its becoming increasingly evident that gut microbiota is
contributing to many human diseases including diabetes
both type 1 and type 2. Type 1 diabetes (T1D) is an
autoimmune disease that is caused by the destruction of
pancreatic β-cells by the immune system. Even though
T1D is mainly caused by genetic defect, epigenetic and
environmental factors have been shown to play an im-
portant role in this disease. Higher rates of T1D inci-
dence have been reported in recent years that are not
explained by genetic factors and have been attributed to
changes in our lifestyle such diet, hygiene, and antibiotic
usage that can directly affect microbiota [108]. It has
been shown that diabetes incidence in the germ free
non-obese diabetic subjects or patients (NOD) was
significantly increased which is in line with the observa-
tion that the rates of T1D is higher in countries with
stringent hygiene practices [108]. Similarly comparison
of the gut microbiota composition between children
with high genetic risk for T1D and their age matched
Baothman et al. Lipids in Health and Disease (2016) 15:108 Page 4 of 8
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healthy controls showed less diverse and less dynamic
microbiota in the risk group [109]. In the Diabetes Pre-
vention and Prediction (DIPP) study it was shown that
new-onset T1D subjects had different gut microbiota
composition than controls [110]. They showed that in
the control group, mucin synthesis was induced by
lactate- and butyrate-producing bacteria to maintain gut
integrity while mucin synthesis was prevented by the
non-butyrate-producing lactate-utilizing bacteria leading
to β-cell autoimmunity and T1D [110]. In another study
linking intestinal microbes with the innate immune sys-
tem Wen et al used Myd88 knockout to show that
specific-pathogen free (SPF) NOD mice lacking MyD88
protein do not develop T1D [111]. MyD88 is a mediator
for multiple innate immune receptors such as TLR4 that
recognize microbial stimuli [112]. Many other studies
confirmed the differences observed in gut microbiota
composition between T1D and their matched health
controls highlighting the need for better understanding
of the role that these bacteria may play in the develop-
ment of this disease [108, 109, 113122].
The link between T2D and gut microbiota is becoming
clearer with more studies showing the involvement of
microbiota in obesity and their role in insulin signaling
and low grade inflammation as discussed in the previous
section. The effect of microbiota on T2D has been pro-
posed to be mediated through mechanisms that involve
modifications in the secretion butyrate and incretins [94,
95, 101, 123, 124]. Qin et al showed that T2D patients
had moderate degree of gut microbial dysbiosis, a de-
crease in universal butyrate-producing bacteria and an
increase in opportunistic pathogens [125]. Similar data
were reported by other studies highlighting the role of
these bacteria in regulating important T2D pathways
such as insulin signaling, inflammation and glucose
homeostasis [13, 18, 99, 124129]. On the other hand,
gut microbiota has been shown to affect the production
of key insulin signaling molecules such as GLP-1 and
PYY through SCFA and its binding to FFAR2 [123].
These two molecules have favorable effects, decreasing
insulin resistance and the functionality of β-cells [123].
An increase in Bifidobacterium spp. in mice has been
linked to have anti-inflammatory effect through the pro-
duction of GLP2 and reducing intestinal permeability
[124]. These are just a few examples on the potential
impact of gut microbiota on the development of T2D.
Conclusions
In conclusion, overwhelming evidence is available
highlighting the important role of gut microbiota in key
metabolic diseases impacting key pathways like energy
homeostasis and inflammation. Changes in life style that
involves increased food consumption and reduced exer-
cise in addition to gut microbiota contribute more to
metabolic diseases. As a result, better understanding and
utilization of various prebiotic and probiotic bacteria
may prove to be beneficial in the treatment of metabolic
diseases in the future.
Authorscontributions
OB: Literature search and wrote manuscript. MZ: Literature search and wrote
manuscript. OB and MZ: These authors contributed equally to the paper. IT:
Critically revised the manuscript. KB: critically revised the manuscript, JA:
Critically revised the manuscript. MA: Literature search and wrote manuscript,
critically revised the manuscript. All authors read and approved the final
manuscript.
Competing interest
None of the authors have been paid to write this article by a pharmaceutical
company or other agency. None of the authors (OB, MZ, IT, JA and MA) have
any conflict of interest or anything to disclose.
Author details
1
Department of Biochemistry, King Abdul Aziz University, Jeddah, Saudi
Arabia.
2
Faculty of Medicine, Aljouf University, Aljouf, Saudi Arabia.
3
Biochemistry and Molecular Biology Unit, Dasman Diabetes Institute,
Dasman, P.O. Box 118015462 Kuwait City, Kuwait.
Received: 1 April 2016 Accepted: 15 June 2016
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... Level of SCFA, the diversity of microflora as well as their activities are interlinked. Bifidobacterium phyla are known to produce Acetate and propionate whereas Firmicutes are butyrate producers [20]. This fact is further confirmed in our current studies. ...
Article
Alteration of gut microflora results in a metabolic imbalance in the liver. In the present study, we investigate the reversal potential of alteration of the colonic microflora via improving metabolism balance and regulating the altered tight junction of the intestinal tract. Animals were fed with high sugar diet to mimic the onset of the pathophysiological conditions of diabetes. Following induction, animals were divided into two reversal groups i.e., crude cefdinir and colon-specific formulated cefdinir, to alter the gut microflora. In the present study, we have tried to quantify the microbial content via metagenome analysis to provide an actual picture of the alteration and subsequent reversal. Expression of mRNA of junctional protein and parameters involved in liver metabolism was determined using qPCR. Results indicated direct effect of altered composition of gut microflora on the gut perme-ability and metabolic alteration. Metagenomic analysis showed least evenness and richness in the HSD group whereas antibiotic-treated groups showed reversal of microflora towards control group with increased richness, evenness and decreased distance on PCoA plot. This changes in gut microflora composition changes expression of metabolic markers and thus insulin sensitivity. Targeting colonic microflora to have a reversal effect on T2D pathogenesis, found to have a positive impact on liver metabolic state with improved permeability markers of gut with SCFA alteration.
... In addition, NASH is associated with increased intestinal permeability, which indicates that an early phase of liver injury and inflammation contributes to the latter (Luther et al., 2015). Furthermore, changes in human gut microbiota have been reported to be associated with human body fat composition and gut permeability (Schneider et al., 2015;Baothman et al., 2016). This evidence indicates a "gutliver cross-talk" pattern in the pathogenesis of NAFLD and NASH. ...
Article
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Non-alcoholic steatohepatitis (NASH) is affecting people worldwide. Changes in the intestinal microbiome are crucial to NASH. A previous study showed that eradicating intestinal fungi ameliorates NASH; however, the role of intestinal fungi in the development of NASH remains unclear. Saccharomyces boulardii (SB) , a dietary supplement yeast, has been reported to restore the integrity of the intestine. Here, we tested the effect of SB in the treatment of NASH. For this study, we fed eight-week-old C57/BL6 male mice either a methionine-choline deficient (MCD) diet or a normal chow diet (NCD) for eight weeks. Half of the MCD diet-fed mice were gavaged with SB (5 mg/day) once daily. The remainder of the NCD–fed mice were gavaged with normal saline as a control. The MCD diet-fed mice on SB supplement showed better liver function, less hepatic steatosis, and decreased inflammation. Both hepatic inflammatory gene expression and fibrogenic gene expression were suppressed in mice with SB gavage. Intestinal damage caused by the MCD diet was tampered with, intestine inflammation decreased, and gut permeability improved in mice that had been given the SB supplement. Deep sequencing of the fecal microbiome showed a potentially increased beneficial gut microbiota and increased microbiota diversity in the SB -supplemented mice. The SB supplement maintains gut integrity, increases microbial diversity, and increases the number of potentially beneficial gut microbiota. Thus, the SB supplement attenuates gut leakage and exerts a protective effect against NASH. Our results provide new insight into the prevention of NASH.
... Researchers recently reported a strong correlation between the gut microbiome and cardiovascular risk factors such as obesity, type 2 diabetes, and hypertension, 5,46,47 . ...
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Background: Obesity changes gut microbial ecology and is related to endothelial dysfunction. Although the correlation between gut microbial ecology and endothelial dysfunction has been studied in obese persons, the underlying mechanisms by which exercise enhances endothelial function in this group remain unclear. This study investigated whether exercise improves endothelial function and alters gut microbiome composition in rats fed a high-fat diet (HFD). Methods: Obesity was induced by an HFD for 11 weeks. Whole-body composition and endothelium-dependent relaxation of mesenteric arteries were measured. Blood biochemical tests were performed, and gut microbiomes were characterized by 16S rRNA gene sequencing on an Illumina HiSeq platform. Results: Exercise training for 8 weeks improved body composition in HFD-fed rats. Furthermore, compared with the untrained/HFD group, aerobic exercise significantly increased acetylcholine-induced, endothelium-dependent relaxation in mesenteric arteries (P < 0.05) and circulating vascular endothelial growth factor levels (P < 0.01) and decreased circulating C-reactive protein levels (P < 0.05). In addition, exercise and HFD resulted in alterations in the composition of the gut microbiome; exercise reduced the relative abundance of Clostridiales and Romboutsia. Moreover, 12 species of bacteria, including Romboutsia, were significantly associated with parameters of endothelial function in the overall sample. Conclusions: These results suggest that aerobic exercise enhances endothelial function in HFD-fed rats by altering the composition of the gut microbiota. These findings provide new insights on the application of physical exercise for improving endothelial function in obese persons.
... The details of representative taxa are shown in Figure 6C. Furthermore, the important "signature" bacteria of dysbiosis in gut microbiota, including Proteobacteria and Escherichia-Shigella (47)(48)(49) were found to be significantly enriched in the Db-93M group. The results of the LEfSe analysis further validated the prebiotic characteristics of FG-FM cereal flour, including promoting the proliferation of probiotics and limiting the expansion of previously reported DKD-related bacteria in the gut microbiota of diabetic mouse model (15). ...
Article
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Diabetic kidney disease (DKD) is an important complication of diabetes. The prevention of DKD can effectively reduce the mortality rate of diabetic patients and improve their quality of life. The present study examined the effects of fermented and germinated foxtail millet whole grain (FG-FM) on kidney lesions in a diabetic mouse model (Db/Db mice). The results proved that the FG-FM consumption significantly alleviated the kidney tissue damage in the diabetic mouse model. The transcriptome analysis of kidney tissues demonstrated that the overactivation of signaling pathways related to inflammation and immunity in the diabetic mouse model was significantly inhibited with the FG-FM intake. Moreover, the consumption of the FG-FM diet effectively elevated the bacterial diversity, increased the relative abundance of probiotics and decreased the relative abundance of previously reported DKD-related bacteria in the gut microbiota of diabetic mice. Our study confirmed foxtail millet as a potential source of functional food for the non-pharmacological intervention of DKD.
... As such, scientists are only beginning to understand the depth and complexity of the HGM and its importance in human health. Mounting evidence points to the involvement of the HGM in a multitude of pathophysiological conditions, including asthma [5], colorectal cancer [6], diabetes [7], and obesity [8]. In African cohorts, the HGM has been implicated in playing a role in severe malnutrition in children [9] as well as the severity of neglected tropical diseases such as schistosomiasis [10,11]. ...
Article
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The gut microbiome of neonates, infants, and toddlers (NITs) is very dynamic, and only begins to stabilize towards the third year of life. Within this period, exposure to xenobiotics may perturb the gut environment, thereby driving or contributing to microbial dysbiosis, which may negatively impact health into adulthood. Despite exposure of NITs globally, but especially in Africa, to copious amounts and types of xenobiotics – such as mycotoxins, pesticide residues, and heavy metals – little is known about their influence on the early-life microbiome or their effects on acute or long-term health. Within the African context, the influence of fermented foods, herbal mixtures, and the delivery environment on the early-life microbiome are often neglected, despite being potentially important factors that influence the microbiome. Consequently, data on in-depth understanding of the microbiome–exposome interactions is lacking in African cohorts. Collecting and evaluating such data is important because exposome-induced gut dysbiosis could potentially favor disease progression.
... The intestine is the leading absorption site, which depends on the normal gut microbial composition and diversity [36]. Early investigations have indicated that the normal gut microbial composition and diversity were the prerequisite for performing its complex physiological functions, while gut microbial dysbiosis may be the central or driving factor of multiple diseases [37,38]. Previous research demonstrated that the gut microbial dysbiosis might be one of the reasons for the high mortality of diarrheic goats [16]. ...
Article
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Background Yak ( Bos grunniens ) mainly inhabiting Tibet Plateau, displayed a high incidence of diarrhea due to harsh living environment and nutritional deficit. Gut microbial community has been reported to be closely related to many diseases including diabetes, obesity and inflammatory bowel disease, but information regarding diarrheic influence on gut microbiota in yaks remains scarce. Here, this study was performed to investigate the gut bacterial and fungal alternations of diarrheic yaks. Results Results revealed that the gut bacterial and fungal communities of diarrheic yaks showed a distinct decline in alpha diversity, accompanied by significant shifts in taxonomic compositions. Specifically, diarrhea caused a distinct increase in the relative abundance of 1 phylum and 8 genera as well as a distinct decrease in 3 phyla and 30 genera. Fungal taxonomic analysis indicated that the relative richness of 1 phylum and 2 genera dramatically increased, whereas the relative richness of 2 phylum and 43 genera significantly decreased during diarrhea. Surprisingly, 2 bacterial genera and 5 fungal genera even cannot be detected in the gut microbiota of diarrheic yaks. Conclusions In summary, this study indicated that the gut bacterial and fungal compositions and diversities of yaks altered significantly during diarrhea. Moreover, these findings also contribute to understanding the gut microbial composition and diversity of yaks and developing strategies to alleviate and prevent diarrhea from gut microbial perspective.
... More research is needed to ascertain the type of food ingested and its contribution and impact on the sampled gut microbiome. Clostridiaceae has been observed in greater abundance in obesity-based animal models, in such cases, it was strongly correlated with a decrease in Enterobacteriaceae (Phylum Proteobacteria) (Baothman et al., 2016). However, in this instance, Clostridiaceae and Enterobacteriaceae were observed to be relatively higher in the PFAS exposed turtles. ...
Article
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Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent and pervasive. Understanding the toxicity of PFAS to wildlife is difficult, both due to the complexity of biotic and abiotic perturbations in the taxa under study and the practical and ethical problems associated with studying the impacts of environmental pollutants on free living wildlife. One avenue of inquiry into the effects of environmental pollutants, such as PFAS, is assessing the impact on the host gut microbiome. Here we show the microbial composition and biochemical functional outputs from the gut microbiome of sampled faeces from euthanised and necropsied wild-caught freshwater turtles (Emydura macquarii macquarii) exposed to elevated PFAS levels. The microbial community composition was profiled by 16S rRNA gene sequencing using a Nanopore MinION and the biochemical functional outputs of the gut microbiome were profiled using a combination of targeted central carbon metabolism metabolomics using liquid chromatography coupled to a triple quadrupole mass spectrometer (LC-QqQ-MS) and untargeted metabolomics using liquid chromatography coupled to a quadrupole time of flight mass spectrometer (LC-QToF-MS). Total PFAS was measured in the turtle serum using standard methods. These preliminary data demonstrated a 60-fold PFAS increase in impacted turtles compared to the sampled aquatic environment. The microbiome community was also impacted in the PFAS exposed turtles, with the ratio of Firmicutes-to-Bacteroidetes rising from 1.4 at the reference site to 5.5 at the PFAS impacted site. This ratio increase is indicative of host stress and dysfunction of the gut microbiome that was correlated with the biochemical metabolic function data, metabolites observed that are indications of stress and inflammation in the gut microbiome. Utilising the gut microbiome of sampled faeces collected from freshwater turtles provides a non-destructive avenue for investigating the impacts of PFAS in native wildlife, and provides an avenue to explore other contaminants in higher-order taxa within the environment.
... Intestinalmicrobial-derived sEVs can trigger powerful and durable anti-tumor immune responses, even in combination with CTLA-4 and anti-PD1 immunotherapies based on surface decoration with multiple heterologous tumor antigens and immunostimulatory bacterial DNA (CpG motifs) [112]. sEVs can prevent and treat inflammatory, autoimmune, and metabolic diseases associated with CRC development by transporting miRNAs and regulating the intestinal microbiota [113][114][115]. miR-1226-5p and miR-515-5p can reshape the intestinal microbiota by promoting the growth of Escherichia coli and Clostridium perfringens nuclei, respectively, thereby avoiding microbiota dysbiosis and CRC development [116]. ...
Article
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Colorectal cancer (CRC) is the third most common cancer worldwide, and its incidence and mortality rates have been increasing annually in recent years. A variety of different small extracellular vesicles (sEVs) are important mediators of intercellular communication and have an important role in tumor metastasis and progression. The development and metastasis of CRC are closely linked to tumor-cell-derived sEVs, non-tumor-cell-derived sEVs, and intestinal-microbiota-derived sEVs. Numerous studies have shown that the tumor microenvironment (TME) is a key component in the regulation of CRC proliferation, development, and metastasis. These sEVs can create a TME conducive to CRC growth and metastasis by forming an immunosuppressive microenvironment, remodeling the extracellular matrix, and promoting tumor cell metabolism. Therefore, in this paper, we review the role of different types of sEVs in colorectal cancer development and metastasis. Furthermore, based on the properties of sEVs, we further discuss the use of sEVs as early biomarkers for colorectal cancer diagnosis and the potential for their use in the treatment of CRC.
... Among the potential mechanisms that underlie poor anti-cancer drug response in obese cancer patients are adipose hypoxia, altered pharmacokinetics, increased ATP production, altered microbiota, the production of tumor-promoting growth factors and cytokines, and the generation of drug-resistant cancer stem cells [89,99]. The low-grade hypoxia which occurs in adipose tissues stimulates angiogenesis, inhibits macrophage migration and pre-adipocyte differentiation, increases fibrosis, and suppresses immune cell recruitment [100]. ...
Article
Cancer cells undergo alterations in lipid metabolism to support their high energy needs, tumorigenesis and evade an anti-tumor immune response. Alterations in fatty acid production are controlled by multiple enzymes, chiefly Acetyl CoA Carboxylase, ATP-Citrate Lyase, Fatty Acid Synthase, and Stearoyl CoA Desaturase 1. Ovarian cancer (OC) is a common gynecological malignancy with a high rate of aggressive carcinoma progression and drug resistance. The accumulation of unsaturated fatty acids in ovarian cancer supports cell growth, increased cancer cell migration, and worse patient outcomes. Ovarian cancer cells also expand their lipid stores via increased uptake of lipids using fatty acid translocases, fatty acid-binding proteins, and low-density lipoprotein receptors. Furthermore, increased lipogenesis and lipid uptake promote chemotherapy resistance and dampen the adaptive immune response needed to eliminate tumors. In this review, we discuss the role of lipid synthesis and metabolism in driving tumorigenesis and drug resistance in ovarian cancer conferring poor prognosis and outcomes in patients. We also cover some aspects of how lipids fuel ovarian cancer stem cells, and how these metabolic alterations in intracellular lipid content could potentially serve as biomarkers of ovarian cancer.
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Background and aims We aimed to describe and characterize the gut microbiota composition and diversity in children with obesity according to their metabolic health status. Methods Anthropometry, Triglycerides, HDL cholesterol, HOMA-IR, and systolic and diastolic blood pressure (SBP, DBP) were evaluated (and z-score calculated) and faecal samples were collected from 191 children with obesity aged from 8 to 14. All children were classified depending on their cardiometabolic status in either a “metabolically healthy” (MHO; n=106) or “metabolically unhealthy” (MUO; n=85) group. Differences in gut microbiota taxonomies and diversity between groups (MUO vs MHO) were analysed. Alpha diversity index was calculated as Chao1 and Simpson’s index, and β-diversity was calculated as Adonis Bray-Curtis index. Spearman’s correlations and logistic regressions were performed to study the association between cardiometabolic health and the microbiota. Results Children in the MUO presented significantly lower alpha diversity and richness than those in the MHO group (Chao1 index p=0.021, Simpson’s index p=0.045, respectively), whereas microbiota β-diversity did not differ by the cardiometabolic health status (Adonis Bray-Curtis, R² =0.006; p=0.155). The MUO group was characterized by lower relative abundances of the genera Christensenellaceae R7 group (MHO:1.42% [0.21-2.94]; MUO:0.47% [0.02-1.60], p<0.004), and Akkermansia (MHO:0.26% [0.01-2.19]; MUO:0.01% [0.00-0.36], p<0.001) and higher relative abundances of Bacteroides (MHO:10.6% [4.64-18.5]; MUO:17.0% [7.18-27.4], p=0.012) genus. After the adjustment by sex, age, and BMI, higher Akkermansia (OR: 0.86, CI: 0.75-0.97; p=0.033), Christensenellaceae R7 group (OR: 0.86, 95% CI: 075-0.98; p=0.031) and Chao1 index (OR: 0.86, CI: 0.96-1.00; p=0.023) represented a lower risk of the presence of one or more altered cardiovascular risk factors. Conclusion Lower proportions of Christensenellaceae and Akkermansia and lower diversity and richness seem to be indicators of a metabolic unhealthy status in children with obesity.
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Probiotics have been suggested to play an important role in the management of diabetes. We conducted a systematic review on the role of probiotics in modulating parameters related to diabetes in animal and human experiments. We searched Pubmed, Scopus and Cochrane central until June 2014, concerning the effects of probiotics on hyperglycemia, hyperinsulinemia and their anti-diabetic efficacies by modulating the activities of proinflammatory and antioxidant factors. Our initial search retrieved 1120 reports. After screening titles and abstracts, 72 full-text articles were reviewed for eligibility. Ultimately, 33 articles met our inclusion criteria consisting of five human and twenty eight animal reports. Lactobacillus strains were, in particular, used in all studies with or without other strains. We found that probiotics have beneficial effects on glycemic controls, as all human studies showed significant reductions in at least one of the primary outcome endpoints which were the levels of fasting plasma glucose, postprandial blood glucose, glycated haemoglobin, insulin, insulin resistance and onset of diabetes; similarly, all the animal reports, except for two, documented significant changes in these parameters. Regarding secondary outcome measures, that is, lipid profiles, pro-inflammatory and anti-oxidant factors, only one human and one animal study failed to show any significant changes in any of these parameters. This systematic review generally demonstrated beneficial effects of the probiotic administration, especially Lactobacillus sub-strains, on the management of diabetes-related blood parameters, although, more evidence, especially from human trials, is needed to confirm these effects and also to conduct a meta-analysis. Copyright © 2015 John Wiley & Sons, Ltd.
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Assessment and characterization of gut microbiota has become a major research area in human disease, including type 2 diabetes, the most prevalent endocrine disease worldwide. To carry out analysis on gut microbial content in patients with type 2 diabetes, we developed a protocol for a metagenome-wide association study (MGWAS) and undertook a two-stage MGWAS based on deep shotgun sequencing of the gut microbial DNA from 345 Chinese individuals. We identified and validated approximately 60,000 type-2-diabetes-associated markers and established the concept of a metagenomic linkage group, enabling taxonomic species-level analyses. MGWAS analysis showed that patients with type 2 diabetes were characterized by a moderate degree of gut microbial dysbiosis, a decrease in the abundance of some universal butyrate-producing bacteria and an increase in various opportunistic pathogens, as well as an enrichment of other microbial functions conferring sulphate reduction and oxidative stress resistance. An analysis of 23 additional individuals demonstrated that these gut microbial markers might be useful for classifying type 2 diabetes.
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Background: The microbiota of both humans and animals plays an important role in their health and the development of disease. Therefore, the bacterial flora of the conjunctiva may also be associated with some diseases. However, there are no reports on the alteration of bacterial flora in conjunctiva of diabetic rats in the literature. Therefore, we investigated the changes in bacterial flora in bulbar conjunctiva of rats with streptozotocin (STZ)-induced type I diabetes. Methods: A high dose of STZ (60 mg/kg, i.p.) was injected into Sprague-Dawley (SD) rats to induce type I diabetes mellitus (T1DM). The diabetic rats were raised in the animal laboratory and at 8 months post-injection of STZ swab samples were taken from the bulbar conjunctiva for cultivation of aerobic bacteria. The bacterial isolates were identified by Gram staining and biochemical features. The identified bacteria from both diabetic and healthy rats were then compared. Results: The diabetic and healthy rats had different bacterial flora present in their bulbar conjunctiva. In total, 10 and 8 bacterial species were found in the STZ and control groups, respectively, with only three species (Enterococcus faecium, Enterococcus gallinarum and Escherichia coli) shared between the two groups. Gram-positive bacteria were common in both groups and the most abundant was Enterococcus faecium. However, after the development of T1DM, the bacterial flora in the rat bulbar conjunctiva changed considerably, with a reduced complexity evident. Conclusions: STZ-induced diabetes caused alterations of bacterial flora in the bulbar conjunctiva in rats, with some bacterial species disappearing and others emerging. Our results indicate that the conjunctival bacterial flora in diabetic humans should be surveyed for potential diagnostic markers or countermeasures to prevent eye infections in T1DM patients.
Article
Obesity is a complex and multifactorial disorder that has become one of most prevalent health issues of the 21st century. Recent evidence suggests that an altered composition and functionality of the gut microbiota plays a key role in the increased prevalence of obesity. In this regard, gut microbiota modulation through the diet emerges as an efficient approach for the management of obesity. We provide an overview of the current evidence regarding the potential benefits of functional foods containing probiotics and prebiotics on reduction of weight and body fat and the use of these nutritional ingredients for the development of tailor-made solutions to fight against the epidemic of obesity.
Article
Bariatric surgery is currently the most effective procedure for the treatment of obesity. Given the role of the gut microbiota in regulating host metabolism and adiposity, we investigated the long-term effects of bariatric surgery on the microbiome of patients randomized to Roux-en-Y gastric bypass or vertical banded gastroplasty and matched for weight and fat mass loss. The two surgical procedures induced similar and durable changes on the gut microbiome that were not dependent on body mass index and resulted in altered levels of fecal and circulating metabolites compared with obese controls. By colonizing germ-free mice with stools from the patients, we demonstrated that the surgically altered microbiota promoted reduced fat deposition in recipient mice. These mice also had a lower respiratory quotient, indicating decreased utilization of carbohydrates as fuel. Our results suggest that the gut microbiota may play a direct role in the reduction of adiposity observed after bariatric surgery. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Article
Numerous studies of rodents suggest that the gut microbiota populations are sensitive to genetic and environmental influences, and can produce or influence afferent signals that directly or indirectly impinge on energy homeostatic systems affecting both energy balance (weight gain or loss) and energy stores. Fecal transplants from obese and lean human, and from mouse donors to gnotobiotic mice, result in adoption of the donor somatotype by the formerly germ-free rodents. Thus, the microbiota is certainly implicated in the development of obesity, adiposity-related comorbidities, and the response to interventions designed to achieve sustained weight reduction in mice. More studies are needed to determine whether the microbiota plays a similarly potent role in human body-weight regulation and obesity. Copyright © 2015. Published by Elsevier Ltd.