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Abstract
Overweight and obesity increase the risk for a number of diseases, namely, cardiovascular diseases, type 2 diabetes,
dyslipidemia, premature death, non-alcoholic fatty liver disease as well as different types of cancer. Approximately
1.7 billion people in the world suffer from being overweight, most notably in developed countries. Current research
efforts have focused on host and environmental factors that may affect energy balance. It was hypothesized that a
microbiota profile specific to an obese host with increased energy-yielding behavior may exist. Consequently, the
gut microbiota is becoming of significant research interest in relation to obesity in an attempt to better understand
the aetiology of obesity and to develop new methods of its prevention and treatment. Alteration of microbiota
composition may stimulate development of obesity and other metabolic diseases via several mechanisms:
increasing gut permeability with subsequent metabolic inflammation; increasing energy harvest from the diet;
impairing short-chain fatty acids synthesis; and altering bile acids metabolism and FXR/TGR5 signaling. Prebiotics
and probiotics have physiologic functions that contribute to the health of gut microbiota, maintenance of a healthy
body weight and control of factors associated with obesity through their effects on mechanisms that control food
intake, body weight, gut microbiota and inflammatory processes.
Keywords: Obesity, Gut microbiota, Intestinal permeability, Innate immunity, Metabolic inflammation,
Endocannabinoid system, Bile acid metabolism, FXR, Short-chain fatty acids, TLRs, FIAF
2016 Kobyliak et al. 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.
Kobyliak et al. Nutrition Journal (2016) 15:43 Page 2 of 12
transformation of microbiota into a kind of vital regula- of obesity. Prebiotics and probiotics are of interest because
tory body [6], consisting of a large number of microbial they have been shown to alter the composition of gut
cells, the number of which is 13 times higher than the microbiota and to affect food intake, appetite, body weight
number of own human cells [79]. This organ has a and composition as well as metabolic functions through
wide range of functions that are vital for whole body. gastrointestinal pathways and modulation of the gut bac-
Microorganisms that are routinely found in healthy terial community [16].
people considered to the normal microbiota, which is At present, the question of the probiotics influence
defined as a set of populations of microbes in individual on lipid metabolism and obesity is actively debated in
organs and systems in certain qualitative and quantita- the scientific literature [1719]. Backhed et al. were
tive ratios that support the host organisms biochemical, the pioneers in the study of the role of colon micro-
metabolic and immunological balance necessary for flora in regulation of metabolism [20]. Their findings
health maintenance. [10] were the catalyst for progress in this field. Further
Human microbiota includes hundreds of different spe- studies have shown that the composition of intestinal
cies with a total number of the cells over 10111013. microbiota is altered in overweight people. Thus, in-
Moreover, microorganism species composition depends testine microbiocenosis can be considered the envir-
on the organ inhabited [11]. The largest number of mi- onmental factor that modulates the development of
croorganisms is in the habitats of the digestive tract. obesity. It was demonstrated that prolonged exposure
Each part of the digestive system is characterized by dif- to a high fat diet (HFD) significantly changed the
ferent composition of microbial flora (Table 1) [12, 13]. composition of the colon microflora in mice, leading
However, the most simple method to count the bacteria to a reduction in the levels of Bifidobacterium and
number is the investigation of fecal samples and this Lactobacillus that are known to produce many posi-
does not fully reflect the microbiota content throughout tive physiological effects, e.g. improving the barrier
the digestive system. So, the true composition of micro- function of the intestinal mucosa as well as to an in-
flora and its functions may be misleading. Additionally, crease in the levels of Firmicutes and Proteobacteria
the data from different studies vary because of a great that include pathogenic species [19, 20]. Different
inter-individual difference in microflora [13]. studies have shown the decrease of abundance of Bac-
The most studied part of digestive tract regarding teroides (phylum Bacteroidetes) and increase of Bacil-
microflora is colon which characterized by the largest laceae, Clostridiaceae and other representatives of
variety of microorganisms [7, 14]. The dominant species phylum Firmicutes [21, 22]. Others speculate that not
of obligate microflora are asporogenous gram-positive the ratio of Firmicutes and Bacteroidetes is important
and gram-negative saccharolytic anaerobes: Bifidobacter- in obesity but emphasize on altered proportions of
ium, Lactobacillus, Propionibacterium, Bacteroides. Bifi- Actinobacteria in obese individuals [23]. It is also re-
dobacteria and Bacteroides comprise 8598 % of ported that gut of obese people is greatly inhabited
intestinal microflora (Table 1) [15]. with H2-oxidizing methanogenic Archaea [24]. It is
supposed that these microorganisms oxidize H2 pro-
Review duced by H2-producing bacteria from Prevotellaceae
Altered composition of gut microbiota in obesity family (phylum Bacteroidetes). Rapid H2-utilization ac-
Recent evidence suggests that gut microbiota is involved celerates fermentation of polysaccharides by Prevotella-
in the control of body weight, energy homeostasis and in- ceae and consequently results in the more considerable
flammation, and thus plays a role in the pathophysiology energy uptake by obese individuals [24].
Table 1 The content and composition of microflora in different parts of the human digestive tract in health
Habitats of the The number of microorganism Dominant microflora
digestive tract cells per 1 g of content
Lumen Surface
microflora microflora
Mouth 108109 10111012 Streptococcus (6090 %), Lactobacillus, Bifidobacterium, Propionibacterium, Bacteroides,
Actinomyces
Stomach 102103 105106 Acid resistant Lactobacillus, Streptococcus, Staphylococcus
Proximal small 10 10
3 5
10 10
10 11
Streptococcus, Lactobacillus, Enterococcus, Bifidobacterium, Escherichia,
intestine
Distal small intestine 1081010 10101012 Lactobacillus, Escherichia, Enterococcus, Bacteroides, Bifidobacterium
Colon 10 10
11 12
10 10
10 12
Bifidobacterium, Lactobacillus, Propionibacterium, Bacteroides 9095 %, Escherichia,
Enterococcus 510 %
Kobyliak et al. Nutrition Journal (2016) 15:43 Page 3 of 12
The importance of microbiota modification in the con- Fasting-induced adipose factor (FIAF)
ditions of obesity is confirmed by numerous studies of One of the key mechanisms by which germ-free animals
the probiotic interventions (Table 2). The analysis of are protected from diet-induced obesity is elevated levels
more than 20 articles from 2013 to July 2014 by Cani of fasting-induced adipose factor (FIAF), also known as
et al. showed that at least 15 different strains of Lactoba- angiopoietin-like protein 4. FIAF is a circulating lipopro-
cillus and two strains of Bifidobacterium do not equally tein lipase (Lpl) inhibitor produced by the intestine, liver
influence on body weight, fat mass, glucose metabolism, and adipose tissue [27]. Conventionalization of germ-
inflammatory markers, plasma and hepatic lipids and free mice suppresses expression of Fiaf in the gut epithe-
plasma cholesterol levels [25]. Furthermore, no single lial cells [20]. This leads to a higher adipocyte Lpl activ-
strain had all of these effects on different models of ity and results in increased cellular uptake of fatty acids,
obesity in rats. In our research the combination of adipocyte triglyceride accumulation and greater fat stor-
two Bifidobacterium and one Lactobacillus lyophilized age (Fig. 1). Germ-free Fiaf/ mice are obese similarly
strains did not influence body mass index and Lee to their conventionally reared counterparts. After con-
index. At the same time, they strongly reduced fat ventionalization, germ-free Fiaf/ mice had a 57 %
mass and serum lipids in rats and improved hormonal higher total body fat than their wild-type littermates
activity of adipose tissue, thus demonstrating the [20]. Consistently, germ-free Fiaf/ mice fed a high-fat
more pronounced combined effect on obesity as com- high-carbohydrate diet were not protected from diet-
pared to the effects of single strains described in the induced obesity, suggesting that FIAF is a mediator of
aforementioned article [25]. microbial regulation of energy storage [28].
In contrast, mice fed a high-fat diet complemented
with Lactobacillus paracasei exhibited significantly re-
Gut microbiota and obesity: pathways and mechanism of duced body fat, which was paralleled by increased circu-
interactions lating levels of FIAF [29]. Fleissner et al. showed that
The mechanisms of obesity development and microbiota germ-free mice on a high-fat diet showed increased in-
impact on it are under the close attention of scientists. testinal mRNA expression of Fiaf with no major changes
The most frequent cause leading to the obesity develop- in circulating FIAF, as compared to conventionalized
ment is a dysbalance between energy intake and energy mice, suggesting that FIAF mechanism is not universally
expenditure. In this complex process, genetic suscepti- associated with gut microbiota-related fat mass develop-
bility, environmental and lifestyle factors are involved. ment [30].
Recent advances in next generation sequencing technol-
ogy and mechanistic testing in gnotobiotic mice have AMP-activated protein kinase (AMPK)
identified the gut microbiota as an environmental factor Furthermore, Backhed and colleagues have also demon-
which influences whole-body metabolism [26]. Gut strated that germ-free mice exhibit increased levels of
microbiota affect energy balance, inflammation state and phosphorylated AMPK in muscle and liver. AMPK is a
gut barrier function, as well as integrate peripheral and key enzyme that controls cellular energy status, which in
central food intake regulatory signals leading to an in- turn activates key enzymes of mitochondrial fatty acid
crease in body weight. Underlying mechanisms of the oxidation, including acetyl-CoA carboxylase (ACC) and
gut microbiota contribution to host metabolism were re- carnitine-palmitoyltransferase I (CTP1) (Fig. 1). This en-
vealed from studies on germ-free mice which were pro- zyme activation is indicative of increased energy expend-
tected against developing diet-induced obesity. iture. The exact pathway through which the microbiota
signals to liver and skeletal muscle AMPK is unclear, but promoting fat accumulation in the liver and adipose tis-
appears to be independent from FIAF [28]. sue [28]. This reaction is controlled by carbohydrate re-
sponsive element binding protein (ChREBP) and sterol
Intestinal microbiota, short-chain fatty acids and energy responsive element binding protein (SREBP-1) [38]. Fur-
harvest from the diet thermore, monosaccharides that are produced by micro-
An important role of intestinal microbiota is synthesis of bial fermentation and absorbed and transferred to the
various biomolecules. For instance, microflora produces liver via portal vein, activate ChREBP which increases
wide range of vitamins (C, B, folate and niacin) and es- the transcription of several proteins involved in hepatic
sential amino acids and facilitates their absorption [31]. de novo lipogenesis [39]. This contributes to hepatic
Flora also promotes better absorption of calcium and steatosis.
vitamin D [32]. Anaerobic bacteria synthesize biologic- SCFAs act in the gut as signaling molecules and are
ally active substances: -alanine, 5-aminovaleri and - specific ligands for at least two G protein-coupled recep-
aminobutyric acid [33, 34]. Normal flora of the human tors, GPR41 and GPR43, mainly expressed in intestinal
body participates in the metabolism of proteins, carbo- epithelial cells [39, 40]. Samuel et al. have demonstrated
hydrates, lipids and nucleic acids; breaks down cellulose; that conventionally raised Gpr41/ mice and germ-free
provides epithelium with substrates of gluconeogenesis Gpr41/ mice colonized with only Bacteroides thetaio-
and lipogenesis; and stimulates intestinal motility [35]. taomicron and Methanobrevibacter smithii are signifi-
The gut microbiota that digests complex dietary car- cantly leaner than wild-type littermates, while there are
bohydrates produces many monosaccharides and short- no differences between wild-type or Gpr41/ germ-free
chain fatty acids (SCFAs) such as acetate, propionate, mice [41]. Gpr41, which is produced by enteroendocrine
and butyrate [28] which are an important energy source cells, may be a regulator of host energy balance through
and nutrition of the intestinal epithelium. Additionally, effects that are dependent on gut microbiota (Fig. 1). Ac-
gut microbes enhance the intestinal barrier and help tivation of GPR41 increases production of peptide YY
eliminate potential pathogens [36]. Conventionalization (PYY), an enteroendocrine cell hormone that normally
of germ-free mice doubles the density of small intestinal inhibits gut motility, increases intestinal transit rate and
villi capillaries [37] and enhances an uptake of these reduces extraction of energy from the diet, thus affecting
components from the gut into the portal blood and peripheral glucose utilization [41]. Recent study has
eventually participates in hepatic de novo lipogenesis shown that Gpr43/ mice are resistant to diet-induced
Kobyliak et al. Nutrition Journal (2016) 15:43 Page 5 of 12
obesity and insulin resistance, at least partly due to of TLR2 and TLR4 is a possible explanation for the in-
Gpr43-regulated energy expenditure [42]. sensitivity of intestinal cells to LPS of commensal bac-
teria, but the presence of TLR3 and TLR5 causes
Innate immunity and metabolic inflammation sensitivity of epithelium to infection through flagellated
Intestinal epithelium is the largest surface of cross-talks bacteria and components of enteropathogenic bacteria
with gut microbes. Innate immune system of the intes- [48, 49]. In support of this, Furrie et al. showed that
tine is one of the most important factors involved in the TLR2 and TLR4 expression was observed only in the
interaction between microflora and the host. This symbi- crypts. As epithelial cells mature and migrate to the villi
osis can on the one hand lead to the destruction of surface, expression of these receptors decreases [50]. In
pathogenic microorganisms, while at the same time pro- addition, intestinal epithelial cells express a large quan-
moting tolerance to commensal, thus creating ecological tity of TLR-inhibiting peptide (TOLLIP), which inhibits
niches for useful and consistently associated with the gut TLR2- and TLR4-mediated pathways and thus protects
microorganisms [43, 44]. host organism from a chronic inflammatory response to
The host symbiotic bacteria realize the effect on the commensal bacteria [51]. Another mechanism for main-
immune system through the interaction between their taining tolerance to symbiotic bacteria is the microbial
pathogen-associated microbial patterns (PAMP) (includ- ability to reduce ubiquitination of IB, which reduces its
ing lipopolysaccharide (LPS), lipoteichoic acids (LTK) of destruction and prevents NF-B translocation to the nu-
cell walls of bacteria, flagellin and double- or single- cleus and consequent activation of pro-inflammatory
stranded RNA and DNA) and specific toll-like receptors genes [52].
(TLRs) of epithelial and dendritic cells (DCs) of the di- Cani et al. demonstrated that bacterial LPS, which is
gestive tract [43, 45, 46]. TLRs are family of integral continuously produced in the gut through a lysis of
membrane pattern-recognition receptors that have a gram-negative bacteria, is a microbiota-related factor
crucial role in the innate immune system and are im- that can trigger an inflammatory process by binding to
portant for maintaining this balance [47]. Bacterial cells the CD14/TLR-4 complex at the surface of innate im-
are recognized by the host in three ways: 1) interaction mune cells [53]. Author mentioned that after 4 weeks of
with TLR on DC projection on the surface of the mu- high-fat feeding, mice exhibited an obese phenotype ac-
cosa; 2) interaction with TLR on DC in subepithelial companied by a change in gut microbiota composition
layer after the translocation of bacteria through M cells (reduction of Bifidobacteria and Eubacteria spp.) and a
in lymph plaques without degradation; and 3) binding to 23 fold increase in circulating LPS levels, which they
enterocyte receptor and subsequent PAMP presentation called metabolic endotoxemia since LPS plasma con-
to DC [45]. Binding of PAMP leads to connection of centrations were much lower than those observed dur-
adaptor protein myeloid differentiation primary response ing septic shock [54]. In fact, in this study, continuous
gene (MyD88) to TLR. Another domain of this protein subcutaneous low-rate infusion of LPS led to exces-
interacts with the interleukin 1 receptor associated ki- sive weight gain and insulin resistance in mice.
nases (IRAK): IRAK1 and IRAK4. IRAK4 phosphorylates Moreover, mice deficient in LPS receptor (Cd14-/-)
IRAK1, which allows joining of another adaptor protein tend to be resistant to this chronic inflammatory
TNF receptor associated factor 6 (TRAF6). TRAF6 is as- state and are hypersensitive to insulin even when
sociated with mitogen-activated protein kinase they are fed a normal diet, suggesting that CD14
(MAP2K), transforming growth factor (TGF) --acti- may modulate insulin sensitivity under physiological
vated kinase (TAK) 1, TAK-binding protein 1 (TAB1) or conditions [55]. Deletion of TLR-4 prevents the
NF-B-inducing kinase (NIK). As a result, the phosphor- HFDinduced insulin resistance [56]. Molecular links
ylation and activation of IB kinase (IKK) that phosphor- leading to TLR4-induced insulin resistance are not
ylates inhibitor of NF-B IB takes place. This provides fully elucidated, but some studies mention that
the release of NF-B, which migrates to the nucleus and TLR4 signaling interferes with insulin signaling. Fur-
triggers the transcription of various cytokines, chemo- thermore, a stimulation of TLR4 by fatty acids can
kines, adhesion molecules, and acute phase proteins, for lead to the recruitment of pro-inflammatory macro-
instance IL-1, IL-6, and IL-8. In most cells, the activa- phages to adipose tissue [57, 58] and cross-talk be-
tion of NF-B inhibits apoptosis [45]. tween macrophages and adipocytes in adipose tissue,
It should be noted that generally commensal bacteria which involves activation of NF-B and JNK by TLR
do not cause inflammation through hyperactivation of signaling and mediates insulin resistance by phos-
the immune system. This is due, firstly, to the lack of phorylation of IRS-1 [59, 60].
microflora-produced PAMP, and secondly, to normal ex- In recent study, Csak et al., demonstrated that
pression of TLR3 and TLR5 and poor expression of knockout of Tlr4 protected mice from fibrosis devel-
TLR2 and TLR4 by enterocytes in the normal state. Lack opment and lead to a significant attenuation of
Kobyliak et al. Nutrition Journal (2016) 15:43 Page 6 of 12
steatohepatitis and a decrease in serum alanine supporting the hypothesis that the deletion improves
transaminase levels and oxidative stress [61]. metabolic inflammation. Gut microbiota transplantation
Another member of pattern-recognition receptors from MyD88-KO HFD mice into germ-free recipient
family, TLR5, may be associated with an altered gut mice fed a HFD or into mice with intestinal MyD88 de-
microbiota metabolic changes development in the host. letion after the onset of obesity reduces body weight
Tlr5-deficient mice exhibit hyperphagia and develop gain, fat mass development and adipose tissue inflamma-
hallmark features of metabolic syndrome, including tion, indicating that targeting intestinal epithelial MyD88
hyperlipidemia, hypertension, insulin resistance, and in- constitutes a putative therapeutic approach for obesity
creased adiposity. All of these phenotypes are associated and associated disorders.
with altered gut microbiota composition. Furthermore Kleinridders et al. demonstrated that mice with
transplantation of microbiome from Tlr5-deficient mice MyD88 deletion in the central nervous system are pro-
to WT germ-free mice conferred many features of meta- tected from HFD-induced weight gain, leptin resistance
bolic syndrome to the recipients [62]. and from the induction of leptin resistance by acute cen-
TLR-2 recognizes components of gram-positive bac- tral application of palmitate [72]. Conversely, according
terial cell wall, such as peptidoglycan and lipoteichoic to Everard study, a key mechanism leading to protection
acid. In methionine-choline deficient (MCD) diet- against diet-induced obesity is change in food intake,
induced model of NASH the role of TLR-2 has been ex- which is independent from energy intake and energy ab-
amined. Tlr-2 deficient mice demonstrate significantly sorption. These data suggest that the impact of MyD88
higher steatosis, inflammation and necrosis histological deletion on energy intake is tissue-dependent: in the
score as compared with WT littermates. Furthermore, central nervous system MyD88 controls leptin sensitivity
they exhibite an increase in liver injury associated with and appetite via fatty acid signaling, whereas in the in-
approximately 3-fold elevation of TNF- mRNA expres- testine MyD88 controls energy metabolism via cross-talk
sion. Possibly, the TLR-2 deficiency exacerbates NASH with gut microbes [71].
by altering signaling via the TLR-4 pathway due to their Additionally, the activation of MyD88-independent
polymorphism [63, 64]. signaling pathway can lead to early induction of IFN-,
TLR-9 is a pattern recognition receptor that recog- as well as to activation of IFN-induced genes such as
nizes bacteria-derived cytosine phosphate guanine iNOS [45].
(CpG)-containing DNA and can be involved in the These findings directly demonstrate that modulation
pathogenesis of NAFLD. TLR9- and MyD88- (adaptor of the immune system is integrated with pathogen-
molecule for TLR9) deficient mice have significantly sensing systems (e.g. TLRs) and support the emerging
lower insulin resistance and show less steatohepatitis view that the gut microbiota contributes to the inflam-
and liver fibrosis histological pattern than WT mice. mation and metabolic disease (Fig. 2).
TLR9 signaling induces production of IL-1 by Kupffer
cells and therefore increases lipid accumulation in hepa- Increased intestinal permeability
tocytes, which leads to the NF-kB inactivation, resulting The result of the interaction of epithelial cells with sym-
in cell death [65]. biotic physiological microflora is formation of pre-
It has also been demonstrated that modulation of gut epithelial film that consists of a layer of molecules of
microbiota (e.g. by an antibiotic treatment and probio- mucus secretory IgA, immune cells, microcolonies of
tics or dietary intervention with oligofructoses) reduces obligate bacteria, enzymes and metabolites of microor-
metabolic endotoxemia and the cecal content of LPS, ganisms and the host [73]. This barrier closes the way to
improves glucose intolerance, insulin sensitivity and de- specific receptors on the epithelium for the living cells
creased body weight gain, and prevents development of of harmful microflora and its toxins.
obesity and NAFLD both in animal models of obesity There is also growing interest to gut microbiota and
and in human studies [6670]. intestinal mucus layer interlinks in the context of obesity
A recent study [71] examined the possibility that and associated diseases. Several studies have confirmed
MyD88, a central adaptor molecule for the majority of this interaction, including a recent one showing that
TLRs, acts as a sensor in the interaction between gut TM-IEC C1galt(-/-) mice with altered intestinal architec-
microbes and the host in obesity. Specific tamoxifen- ture have impaired gut microbiota composition with in-
induced MyD88 deletion in intestinal epithelial cells pro- verse shifts in the abundance of the phyla Bacteroidetes
tects against diet-induced obesity, is associated with in- and Firmicutes. These knockout mice due to the impair-
creased energy expenditure, improves glucose ment in mucus glycosylation have an elongated gastro-
homeostasis, and reduces hepatic steatosis and whole- intestinal tract with deeper ileal crypts, a small increase
body fat mass by 30 %. MyD88 deletion protects mice in the number of proliferative epithelial cells and thicker
against HFD-induced metabolic endotoxemia, thereby circular muscle layers in both the ileum and the colon
Kobyliak et al. Nutrition Journal (2016) 15:43 Page 7 of 12
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