The role of Gut Microbiota in the development of obesity and Diabetes

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. 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.

Full text

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. 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.
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 [1–7]. Sedentary lifestyle and increased food
consumption has been considered the main underlying
causes for this obesity epidemic [8–10]. 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 [11–17]. 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, it’s 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
[21–23]. 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 [24–26].
During the pregnancy, infant’s 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 [33–43].
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 [46–52]. 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 [54–59]. 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 108–109
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
hosts’health. 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 hosts’health [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
polysaccharide–rich 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, 66–77]. 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 [18–20, 76, 78–86]. 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
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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]. It’sbelievedthat
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) [103–106]. 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
It’s 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, 113–122].
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, 124–129]. 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.
Authors’contributions
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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