By Obinwa Maryann Ukamaka
Seminar presentation
INTRODUCTION
The epidemics of obesity and type 2 diabetes mellitus in the
past twenty (20) years have led to numerous investigations concerning the
mechanisms that are responsible for the development of these diseases (Rankinen
et al., 2014).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 (Cani et al., 2015).
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 (Lozupone et al., 2012). 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
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
Archea 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 in simulating the interactions of
bacteria with other microbes and host cells (Zoetenda et al.,2015). 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 extensively studied in the past few years, including
high-investment studies such as the Human Microbiome Project and MetaHIT
(Peterson et al., 2011).
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 (Qin et
al., 2010).
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 (Wu et al., 2015).
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 the microbiota is unstable and less diverse
than in the adulthood, when the complexity and diversity is higher. Many external
factors influence the composition of the microbiota, especially the diet, the
hygiene conditions and the use of antibiotics. During pregnancy, infant’s
intestinal tract is free of microbes 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
the infants stages, gut microbiota remains relatively unchanged until old age
where the composition changes again. Adult 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. 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, peristalsis) in
the stomach and small intestine limits bacterial growth and the number of
microorganisms. 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 nutrients.
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 function. 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 controlled bacterial cultures and defined bacterial strains into
animals.
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 important role in this disease.
Higher rates of T1D incidence 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 observation 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 healthy controls showed
less diverse and less dynamic microbiota in the risk group. In the Diabetes Prevention
and Prediction (DIPP) study it was shown that new-onset T1D subjects had
different gut microbiota composition than control (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 ofT2Dpatients 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. , 2005). Demonstrated
that conventionally raised mice have a 40% higher body fat content and 47%
higher gonadal fat content 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
lipoprotein lipase (LPL) activity, lipogenesis, increased intestinal permeability,
endotoxemiaand endocannabinoid (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 byBacteriodetes phylum while butyrate is
produced by theFirmicutesphylum
(Othman et al., 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 proinflammatory cytokines are coordinated
via the Toll- like receptors and the master regulator 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 [H1] by influencing the expression of the protein,
fasting-induced adipose factor (FIAF). In the absence of microbiota (germ-free
mice)there is an observed higher expression of FIAF. 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 allows higher activity of LPL and accumulation of
triglycerides in adipocytes (Backhadet
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: Carnitinepalmitoyltransferase.
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 digestion 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, BacteroidetesandFirmicutes(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, the study did not
demonstrate that the relative change in bacterial strains profile leads to
different fates of body weight gain.
The original idea that 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 fibers 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 study (Backhed
et al., 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 diseases 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.
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 Bifidobacteriumspp 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., 2013). 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 favourbifidobacteria growth
and prevent the deleterious effect of high-fat diet-induced metabolic diseases
(Cani et al.,2013).
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 orbifidobacteria
microflora.
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:
mycloiddifferentiation 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 maintenance of health has been receiving more attention
worldwide. The homeostasis of gut microbiotadepends on the characteristics of
the host (age, gender, genetic factors) and the environment (stress, drugs,
toxic agents, infections, diseases). However, the influence 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, micronutrients, 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
Changes in bacterial phyla
proportions during obesity have captured science attention worldwide,
especially because of their effects on metabolism. Increased proportion of firmicutes
and actinobacterial and decreased proportion of bacteriodetes have been
associated with increased serum LPS levels, insulin resistance, increased body
weight gain and other comorbidities of
the metabolic syndrome. The mechanisms that underlie this regulation are
unclear, but their
unrevealing [H2] brings potential interventions for the treament of
obesity and type 2 diabeties.
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