SEMINAR PRESENTATION
ON
BCH 411
FRONTIERS IN BIOCHEMISTRY, MOLECULAR
BIOLOGY AND BIOTECHNOLOGY
TOPIC:THE ROLE OF GUT MICROBIOTA IN THE DEVELOPMENT
OF DIABETES AND OBESITY.
PRESENTED BY
OBINWA MARY-ANN UKAMAKA
REG NO: 2012474143
DEPARTMENT OF APPLIED BIOCHEMISTRY
FACULTY OF BIOSCIENCES
NNAMDI AZIKIWE UNIVERSITY,AWKA.
SUPERVISOR: MR.NWAJIOBI JIDE
DATE:DECEMBER, 2016 A
ABSTRACT
A recent growing number of
evidences show that the increased prevalence of obesity and diabetes cannot be
attributed to changes in the human genome, nutritional habits, or reduction in
physical activity in our daily lives Gut microbiota may play an even an more
important role in maintaining human health, as it function much like a
“metabolic organ” influencing nutrient aquisition, energy homeostasis and,
ultimately, the control of the body weight. Moreover, alterations in gut
microbiota can lead to increase intestinal permeability, and metabolic
endotoxemia which play a rolesss in the development of chronic low grade
inflammatory state in the host that contributes to the development of obesity
and diabetes. However the fact that gut microbiota can be modulated through
dietary components highlights the importance to study how fatty acid,
carbohydrates, probiotics, can influence gut microbiota composition and
management of obesity. Gut microbiota seems to be an important and promising
target in the prevention and treatment of obesity and its related metabolic
disturbances.
INTRODUCTION
The epidemics of obesity and type 2 diabetes mellitus in the
past 20 years have led to numerous investigations concerning the mechanisms
that are responsible for the development of these diseases.
The general view is that insulin resistance is an early
alteration of type 2 diabetes mellitus and obesity, and both diseases are
strongly influenced by genetics and environment. Moreover, studies in the past
ten years have shown that low-grade inflammation has an important role in the
molecular mechanism of insulin resistance in these diseases and more recently
(within the past five years) a new component that has both genetic and
environmental factors is also being studied: the gut microbiota.
This way, a paradigm has been dismantled: microorganisms
should no longer be associated with pathogenesis, since both bacteria and their
eukaryote hosts benefit from their cooperative relationships. In humans, there
are at least 100 trillion microbial cells, collectively called microbiota,
distributed in complex and site-specific communities. As the genome of these
bacteria—the microbiome—contains hundreds of genes that do not exist in the
human genome, we can consider our symbionts as an important extra organ.
This complex community—bacteria, eukaryotes, viruses and
Archeae—in its majority cannot be cultured. The reasons for this limitation are
unknown growth requirements of the bacteria, selectivity of the media that are
used, stress imposed by the cultivation procedures, necessity of strictly
anoxic conditions, and the difficulties on simulating the interactions of
bacteria with other microbes and host cells. Thus, a new approach was
introduced, culture-independent sequencing, which made detection of microbial genes
and disease-associated patterns in our gut microbiota possible. The bacterial component of the
microbiota has been intensively studied in the past few years, including
high-investment studies such as the Human Microbiome Project and MetaHIT.
Using this new approach made it possible to detect three
dominating bacterial phyla in the human gastrointestinal tract: the
gram-positive Firmicutes and Actinobacteria, and the gram-negative
Bacteroidetes. Firmicutes is known as the largest bacterial phylum, comprehending
200 genera, which includes Lactobacillus, Mycoplasma, Bacillus, and
Clostridium. In spite of Actinobacteria being also a dominant phylum, it is
usually missed by RNA gene sequencing and can only be detected by fluorescent
in situ hybridization.
Although gut microbiota has been described as relatively
stable concerning its composition until old age, this temporal consistency
considers that numerous variables are being held constant.
For example, dietary changes have been shown to have
significant effects on the microbiota. Shifting mice to a high-fat, high-sugar
―Western‖ diet, from a low-fat, plant polysaccharide-rich diet, changed the
microbiota within 24 hours . Likewise, shifting from a high-fat/low-fiber diet
caused notable changes in the gut microbiota within a day.
ORIGIN AND COMPOSITION OF GUT MICRIBIOTA
The human body contains
trillions of microorganisms that inhabit our bodies during and after birth.The
gastrointestinal tract starts to be colonized during the delivery of the baby.
During the first two years of life de microbiota is unstable and less diverse
than in the adulthood, when the complexity and diver-sity is higher. 5 Many
external factors influence the composition of the microbiota, especially the
diet, the hygiene conditions and the use of antibiotics. 6ing the pregnancy,
infant’s intestinal tract is free of mi-crobes until exposed to maternal
vaginal microbes during normal birth. Infants born through Caesarian section
are exposed to maternal skin bacteria altering their bacterial gut composition.
Feeding represents another source of microorganisms where breast fed babies
have different gut microbiota composition than formula fed babies(Tanaka et al.,2009). Introduction of solid
food represents another shift in the composition of babies gut microbiota.
After that, gut microbiota
remains relatively unchanged until old age where the composition changes again.
Adulthumans 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. Even though, individuals have unique microbiota composition, gut microbiota
is mainly members of four phyla (Firmicutes, Bacteroidetes, Actinobacteria and
Proteobacteria) ,The distribution of microorganisms throughout the
gastrointestinal tract is not homogenous. The stressful environment (gastric
juice, bile, pancreatic juice, peri-stalsis) in the stomach and small intestine
limits bacte-rial growth and the number of microorganisms.The large 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 bacterial. On the other hand, the jejunum harbors 10 5 –10 6 while
the stomach has the least number of bacteria 10 3 –10 4(Othman et al.,2016). The gut microbiota plays
different roles that are important for the host. They exert a trophic effect in
the intestinal epithelium, favoring the development of the microvilli, which in
turn favors the absorption of nutri-ents. The influence of microbiota in innate
and adaptive immune system maturation contributes to systemic and local immune
homeostasis and immune tolerance for a variety of antigens. The modulation of
the immune system activity can influence the intestinal barrier func-tion. The
capacity to break down non-digested dietary molecules into metabolites such as
short chain fatty acids (SCFS) and to synthesize vitamins demonstrates their
importance to human nutrition.
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
tremendously contributed to our understanding of the gut microbiota(Ji and
Nielsen.,2015). 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.
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. 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 (Guiden et
al.,2015). Similarly comparison of the gut microbiota composition between
children with high genetic risk for T1D and their age mhealthy controls showed
less diverse and less dynamic microbiota in the risk group. In the Diabetes
Pre-vention and Prediction (DIPP) study it was shown that new-onset T1D
subjects had different gut microbiota composition than controls(Murri et al., 2013).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 (Othman et al.,2016).
Recently, research has
pointed out that the intestinal microbiome might be an important contributor
for the development of type 2 diabetes (T2D). The use of genome-wide
association studies (GWAS) has achieved many elucidations in this matter(Qin et
al.,2013). characterized the gut microbiota of T2D patients and observed
increase in membrane transport of sugars, branched-chain aminoacids transport,
methane metabolism, xenobiotics degradation, and sulphate reduction. However,
they observed decrease in the levels of butyrate biosynthesis, bacterial
chemotaxis, flagellar assembly, vitamins and cofactors metabolism. This study
has also shown that the gut environment of T2D individuals is one that
stimulates bacterial defense mechanisms against oxidative stress and against
drugs.
(Andrea and Mario, 2013)
GUT MICROBIOTA AND ITS ROLE IN ENERGY HOMEOSTASIS AND THE DEVELOPMENT OF OBESITY
The metabolic activities of
the gut microbiota have the end results of extracting calories from ingested
dietary substances, helping to store those calories in host adipose tissue for
later use, and providing energy and nutrients for microbial growth and
proliferation. Bäckhed et al 1 dem-onstrated that conventionally raised mice
have a 40% higher body fat content and 47% higher gonadal fat con-tent than
germ-free (GF) mice, despite lower food intake (Frazier et al 2011).
However, it has been
suggested that the main routes under influence of gut microbiota that could
contribute to obesity develop-ment are provision of extra calories, increased
lipopro-tein lipase (LPL) activity, lipogenesis, increased intestinal
permeability, endotoxemia and endocannabi-noid (eCB) system (Blaut and Klaus,
2012).Gut microbiota contribute 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 . The most important SCFA
produced are acetate, propionate and butyrate. Acetate and propionate are
mostly produced by Bacteriodetes phylum while butyrate is produced by the
Firmicutes phylum (Othman et all 2016). These SCFA can provide additional
calories when they are oxidized by the host, favoring the higher weight and fat
gain observed in these animals. In addition, the binding of SCFA to G
protein-coupled receptor (GPR) in the intestine induces the secretion of the
hormone peptide YY (PYY). This hormone reduces intestinal transit time,
increasing the time for nutrient absorption from the intestinal lumen. In fact,
obese and overweight subjects presented higher concentration of SCFA in their
feces in comparison to lean individuals (Bodoni et al, 2014).
Low grade inflammation is a
hallmark of obesity. Production of pro- inflammatory cytokines are coordinated
via the Toll- like receptors and the master regulator of of key inflammation
cascades the nuclear factor kappa(NF-kB) (Kim et al, 2012).
The LPL (lipopolysaccharide)
activity influences the accumulation of triglycerides in the adipose tissue.
The microbiota can affect the activity of this enzyme by the influence on the
expression of the protein fasting-induced adipose factor (FIAF). In the absence
of microbiota (germ-free mice) it is observed higher expressin of FIAF. 16 On
the other hand, the conventionalization of the germ-free animal causes
inhibition of the expression of the FIAF and also stimulates body fat gain. It
is suggested that FIAF is a circulating inhibitor of LPL activity. Thus, the
inhibition of FIAF expression by the presence of microbiota allowus higher
activity of LPL and accumulation of triglycerides in adipocytes (Backhad et al,
2004).
Figure 2: Alteration in gut
microbiota composition due to obesity is accompanied by changes in activation
of enzymes and pathways which leads to and increased inflammatory state and
energy harvest.
AMPK: AMP- activated kinase, SCFA: Short chain fatty acids, LPL: Lipoprotein
lipase, ACC: acetyl- CoA carboxylase, CPT1: Carnitine palmitoyltransferase.
Source: Andrea and Mario., 2013
THE EFFECT OF GUT MICROBIOTA ON ENERGY
METABOLISM
The biological functions
controlled by the intestinal flora are related to the effectiveness of energy
harvest, by the bacteria, of the energy ingested but not digested by the host.
Among the dietary compound escaping to the digestion occurring in the upper
part of the human gastro-intestinal tract, the polysaccharides constitute the
major source of nutrient for the bacteria. Part of these polysaccharides could
be transformed into digestible substances such as sugars, or short chain
carboxylic acids, providing energy substrates which can be used by the bacteria
or the host. The control of body weight depends on mechanisms subtly controlled
over time and a small daily excess, as low as 1% of the daily energy needs, can
have important consequences in the long term on body weight and metabolism
(Hill, 2015). Consequently, the gut microbiota of obese subjects changed
according to the loss of body weight occurring after a hypocaloric diet. It was
demonstrated that two groups of bacteria are dominant in the intestinal tract,
Bacteroidetes and Firmicutes (Cani et al, 2008). The quantification and
characterization of each dominant group of bacteria were carried out by
measuring the concentration of the bacterial 16S rRNA. The number of
Bacteroidetes bacteria depended on the weight loss whereas the Firmicutes
bacteria group remained unchanged. Importantly, the bacterial lineage was
constant one year after the dietary intervention for a given body weight, validating
the bacterial signature of each individual. However, it could be related to the
diet and in particular to the presence of dietary fibres (Cani et al, 2008).
The gut bacteria from obese subjects are able
to specifically increase the energy harvested from the diet, which provide an
extra energy to the host. This conclusion was drawn from work showing that the
axenic mice colonized with a conventional gut flora gain weight rapidly. The
mechanisms of the apparent gain weight implied an increase in the intestinal
glucose absorption, energy extraction from non-digestible food component (short
chain fatty acids produced through the fermentation) and a concomitant higher
glycemia and insulinemia, two key metabolic factors promoting lipogenesis. Thus
an environmental factor such as gut microbiota regulates energy storage. The
results, obtained both in rodents and human, suggest that obesity is associated
with an altered composition of gut microbiota. However, this study did not
demonstrate that the relative change in bacterial strains profile leads to
different fates of body weight gain.
This particularly original idea that the bacteria can contribute to the
maintenance of the host body weight, is characterized by numerous paradoxes. It
is not clear, however, whether the small increased of energy extraction can
actually contribute to a meaningful body weight gain within a short period of
time, as suggested in the gut flora transplantation studies. Moreover, other
studies have clearly shown that a diet rich in non-digestible fibres decreases
body weight, fat mass and the severity of diabetes (Cani et al, 2014). However
these dietary fibres increase strains of bacteria able to digest these fibres and
provide extra-energy for the host as they thus increase the total amount of
bacteria in the colon (Kolida et al, 2013). This mechanism is not completely in
accordance with the ‘‘energy harvesting theory’’ according to which the
fermentation of non digestible polysaccharides would provide energy substrates
for the host.
In addition, it is difficult
to conclude that small changes in energy ingestion (1–2%) can induce sufficient
quick variation in weight (within two weeks) as observed in an American studies
( Backhed et aI, 2005). Importantly, the axenic mice colonized with the gut flora
from normal mice ate more than their conventional mice counterparts; therefore,
the body weight gain can also be dependent of the increased food intake. A last
crucial point, which cannot depend only on the role played by the bacteria to
harvest energy from nutrients escaping digestion in the upper part of the
intestine, concerns a study showing that axenic mice are more resistant to
diet-induced obesity. The authors maintained axenic or conventionalized mice on
a high-fat/high-carbohydrates diet (western diet) and found that
conventiona-lized animals fed the western diet gained significantly more weight
and fat mass and had higher glycemia and insulinemia than the axenic mice.
Strikingly, and opposite to the results previously observed in axenic mice fed
a normal chow diet, the amount of western diet taken up by an axenic or a
conventionalized mouse was similar and hence had similar fecal energy output.
All those data suggest that a bacterially related factor is responsible for the
development of diet-induced obesity and diabetes.
GUT MICROBIOTA AND INFLAMMATION
Obesity and type 2 diabetes
are metabolic diseased characterized by a low grade inflammation (Wellen and
Hotamisligil, 2011). In the models of high fat diet induced obesity, adipose
depots express several inflammatory factors IL-1(interleukin-1), TNF-a (tumor
necrosis factor-a) and IL-6 (interleukin-6) (Weisberg et al, 2010). These
cytokines impaired insulin action and induce insulin resistance. For example,
TNF-a phosphorylates serine residue substrate (IRS-1) from the insulin receptor
leading its inactivation and it has been proposed that nutritional fatty acids
trigger inflammatory response by acting via the toll-like receptor-4 (TLR4)
signalling in the adipocytes and macrophages. It was shown that the capacity of
fatty acids to induce inflammatory signalling following a high-fat diet feeding
is blunted in the TLR4 knock out mice (Shi et al, 2014). TLR4 is the co-receptor
for the lipopolysaccharides (LPS) constituent of the Gram negative
bacteria. A triggering factor of the
early development of metabolic diseases is the lipopolysaccharides, a molecule
involved early in the cascade of inflammation. Furthermore, LPS is a strong
inducer of inflammatory response and is involved in the release of several
cytokines that are key factors triggering insulin resistance. The concept of
dietary excess is more or less associated to high-fat feeding-induced
inflammation. Experiment has shown that mice fed a high-fat diet for a short
term period as two to four weeks exhibit a significant increase in plasma LPS.
An endotoxemia that is characterized as a ‘‘metabolic endotoxemia’’, since, the
LPS plasma concentrations were 10 to 50 times lower than those obtained during
a septic shock. LPS is absorbed into intestinal capillaries to be transported
by lipoproteins (i.e. chylomicrons). High-fat diet feeding changed gut
microbiota in favour of an increase in the Gram negative to Gram positive. CD14
is a key molecule involved in the innate immune system is a multifunctional
receptor constituted by a phosphatidyl inositol phosphate-anchored glycoprotein
of 55 kDa expressed on the surface of monocytes, macrophages and neutrophils.
CD14KO mice were hypersensitive
to insulin even when fed a normal diet, suggesting that CD14 could be modulator
of insulin sensitivity in physiological conditions. As a matter of fact, CD14KO
mice resist high-fat diet and chronic LPS-induced metabolic disorders.
Similarly hepatic steatosis, liver and adipose tissue inflammation and adipose
tissue macrophages infiltration was totally blunted in the CD14KO mice fed a
high-fat diet or bifidobacteria microflora
Therefore high-fat feeding
induced a low tone inflammation which originates from the intestinal absorption
of the LPS.
Thus data support the key
idea that the gut microbiota can contribute to the pathophysiology of obesity
and type 2 diabetes. High-fat feeding alters the intestinal microbiota
composition were Bifidobacterium spp were reduced. Several studies have shown
that this specific group of bacteria reduced the intestinal endotoxin levels and
improved mucosal barrier function (Cani
et al.,). The unique advantage of the prebiotic dietary fibres
(oligofructose, [OFS])was used to specifically increase the gut bifidobacteria
content of high fat diet treated mice. Among the different gut bacteria
analysed, plasma LPS concentrations correlated negatively with Bifidobacterium
spp. Together, these findings suggest that the gut microbiota contributes to the
pathophysiological regulation of endotoxemia, and sets the tone of inflammation
for the occurrence of diabetes/obesity. Thus, it would be useful to develop
specific strategies for modifying gut microbiota to favour bifidobacteria growth
and prevent the deleterious effect of high-fat diet-induced metabolic diseases
(Cani et al.,2013).
Figure 3: Signalling of LPs via
NF-B and MAPK. ERK: extracellular signal related kinase, IL: Interleukin, IKB:
Inhibitor of kappa B, IKK: IKB kinase, INOS: Inducible nitric oxide synthase,
IRAK: Interleukin-1 receptor-associated kinase, JNK : c-jun NH2 –terminal
kinase, LBP: Lipopolysaccharide binding protein, LPS: Lipopolysaccharide, MAPK:
mitogen-activated protein kinase, MCP-1: monocyte chemotatic protein-1, MD-2:
mycloid differentiation protein 2, MyD88: mycloid differentiation primary response gene 88, NF-KB: Nuclear factor Kappa
B, NIK: NF-KB inducing kinase, TLR: toll-like receptor, TNF: tumor necrosis
factor, TRAF6: TNF receptor-associated factor 6.
Source:
Boroni et al., 2014.
MODULATION
OF GUT MICROBIOTA
The importance of gut
microbiota in the mainte-nance of health has been receiving more attention
worldwide. The homeostasis of gut microbiota
depends on the characteristics of the host (age, gender, genetic
factors) and the environment (stress, drugs, toxic agents, infections,
diseases). However, the influ-ence of diet is also evident (Boroni Moreira et al., 2014). The conductance of future
studies aiming to understand how changes in diet modulate gut microbiota
composition is of great interest to help menu plannings that simulate the
achievement of a favorable microbiota.
Weight loss promotes changes
in gut microbiota composition. .(Fleissner et
al., 2015) The intake of specific dietary components (fatty acids,
carbohydrates, micronutri-ents, prebiotics, probiotics) can result in changes
in the composition of gut microbiota and modulate the expression of genes in
the host, especially in organs as intestine, muscle, liver and adipose tissue
(Boroni Moreira et al.2014,).
The relevance of the use of
prebiotics and probiotics in human’s obesity treatment is supported by few
results obtained in interventional studies. However, animal models show
potential beneficial effects. For example, genetically obese mice and mice fed
with high-fat diet were given the prebiotic oligofructose. After the
intervention it was observed a reduction in the circulatory levels of IL-18 and
IL-1β. These cytokines are considered as gut microbial related immunologic
factors that drive the obesity development.(Vijay-Kumar et al. 2014,).
Amongst probiotics,
Lactobacillus plantaraum shows a potential to modulate negative effects of
high-fat diets. High dietary fat intake increased body weight gain, white
adipose tissue weight, mean adipocyte size and serum total cholesterol and
leptin concentrations, and decreased serum adiponectin concentration in mice.
The administration of L. plantaraum to mice significantly reduced the mean
adipocyte size and tended to reduce the white adipose tissue weight and serum
total cholesterol and leptin concentrations as compared with the vehicle-administered
mice. Thus, it is suggested that gut
microbiota is an important
and promising target for the treatment of obesity (Takemura et al.,2014).
CONCLUSION
Conventional thoughts
regarding caloric intake,energy expenditure,and the development of
diabetes,obesity and obesity-related complication are being challenged by
recent revelation regarding the role of the gut microbiota, not only does this symbiotic relationship
result in vast differences in nutrient acquisition and energy homeostasis, but
it appears that diet composition can rapidly induce important changes in the
microbiota, which in turn, result in further metabolic consequences for the
host organism.
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