# Insights into the Roles of Gut Microbes in Obesity

Authors: Yolanda Sanz; Arlette Santacruz; Giada De Palma
Journal: Interdisciplinary Perspectives on Infectious Diseases
 (2008)

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## Abstract

Obesity is a major public health issue as it enhances the risk of suffering several chronic diseases of increasing prevalence. Obesity results from an imbalance between energy intake and expenditure, associated with a chronic low-grade inflammation. Gut microbes are considered to contribute to body weight regulation and related disorders by influencing metabolic and immune host functions. The gut microbiota as a whole improves the host's ability to extract and store energy from the diet leading to body weight gain, while specific commensal microbes seem to exert beneficial effects on bile salt, lipoprotein, and cholesterol metabolism. The gut microbiota and some probiotics also regulate immune functions, protecting the host form infections and chronic inflammation. In contrast, dysbiosis and endotoxaemia may be inflammatory factors responsible for developing insulin resistance and body weight gain. In the light of the link between the gut microbiota, metabolism, and immunity, the use of dietary strategies to modulate microbiota composition is likely to be effective in controlling metabolic disorders. Although so far only a few preclinical and clinical trials have demonstrated the effects of specific gut microbes and prebiotics on biological markers of these disorders, the findings indicate that advances in this field could be of value in the struggle against obesity and its associated-metabolic disorders.


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## Body

## 1. Introduction

Obesity is a major public health concern
affecting both the developed and the developing world. The obesity epidemic started
to grow in US in the 1980s, with values rising from 22.9% obese adults in 1988–1994 to 30.5% in 1999–2000 [1]. In 1996, the World Health Organization (WHO) together with
national Ministries of Health agreed to tackle obesity worldwide, but since
then it has increased sharply, reaching values of at least 20% obese adults in
most US
states and European countries [2]. Obesity is detrimental to the quality of life and implies
high health costs as a consequence of its associated morbidities. Overweight
and obesity constitute risk factors for a number of chronic diseases
including diabetes, cardiovascular diseases,
nonalcoholic fatty liver disease, cancer, and other immune-related disorders
such as asthma and infections [3].Obesity results from a long-term positive
imbalance between energy intake and expenditure with excessive increase in body
fat. Obesity and the associated disorders are also characterized by a state of
chronic, low-grade inflammation with abnormal cytokine and adipokine production
[4]. Production of inflammatory immune mediators such as tumor-necrosis factor
(TNF)-α, interleukin (IL)-6, IL-1β, CC-chemokine ligand 2 (CCL2 or monocyte chemotactic protein 1), and the
proinflammatory adipokines leptin and resistin is usually high in these subjects,
whereas production of the anti-inflammatory and insulin-sensitizing adipokine
adiponectin is reduced [5]. Inflammation associated with obesity involves
diverse signal transduction cascades including the nuclear factor kappa B (NF-κB)/IKKβ system and the Jun N-terminal kinase (JNK) [4, 6]. Leptin is the dominant long-term signal informing the brain of energy
stores and, together with insulin, is secreted upon ingestion thus inhibiting
food intake. However, human obesity is not commonly associated with
leptin-deficiency but with leptin-resistance and increased levels of this
adipokine. Leptin seems to exert a proinflammatory effect by inducing the
production of CCL2, proinflammatory cytokines (TNF-α, IL-6, and IL-12), and also typical T helper (Th) 1-cytokines (IL-2 and IFNγ) involved in other chronic inflammatory and
autoimmune disorders such as Crohn’s disease [6, 7].Although susceptibility to definitive increases
in body weight is genetically determined, the environment also influences weight
gain considerably. It is currently believed that macrosocial changes associated
with regular intake of energy-dense foods and low-physical activity have
created an obesogenic environment worldwide,
constituting the cornerstone of the global obesity epidemic [8].
Traditional treatments based on calorie-restricted diets and increased physical
activity have succeeded in controlling obesity to some extent [9]. Nevertheless, these strategies usually yield limited
and short-lived weight reductions and most people regain some of their weight
loss [3]. Neither has pharmacological therapy fully succeeded in effectively
treating obesity for long-term periods and also has a number of side-effects [3, 10]. In this scenario, the identification of additional environmental factors
involved in energy regulation is critical with a view to develop more efficient
intervention strategies.The human gut is populated by an array of
bacterial species that coevolve with the host since birth and maintain dynamic
interactions with each other throughout life. The collective genome
(microbiome) of the gut microbiota contains at least 100 times as many genes as
the human genome, with most serving human physiological functions [11]. The metabolic role of the gut microbiota is
essential to the biochemical activity of the human body, resulting in salvage
of energy, generation of absorbable compounds, and production of vitamins and
other essential nutrients [12]. Thus, humans are considered superorganisms
whose metabolism represents the combination of both microbial and human
features [11]. The gut microbiota also regulates many aspects of innate and
acquired immunity, protecting the host from pathogen invasion and chronic
inflammation [13, 14]. In contrast, imbalances in the composition of gut
microbiota have been associated with susceptibility to infections, immune-based
disorders, and recently also with insulin resistance and body weight gain [15].
In the last decades, sound relationships between the composition of the gut
microbiota and human health have been established, leading to the design of
dietary strategies to favor the prevalence of beneficial bacteria to maintain a
healthy status. These strategies include the administration of prebiotic
oligosaccharides, which stimulate the growth and/or metabolic activity of
beneficial bacteria, and also of selected bacterial strains (probiotics) in the
form of functional foods and supplements [16]. Herein, the current knowledge of
the relationships between the composition and functions of the gut microbiota
and obesity is reviewed, including some studies intended to evaluate the
effects of probiotics and prebiotics in the management of metabolic disorders.


## 2. Gut Microbiota Composition, Diet, and Obesity

Obesity has been associated with increases in
the relative abundance ofFirmicutes and proportional reductions in Bacteroidetes by comparisons between the distal gut microbiota of genetically obese (leptin
deficient ob/ob mice) and lean mice, as well as of that of obese and lean human
subjects [17, 18]. In addition, obese human adults submitted to a hypocaloric
diet (either low carbohydrate- or low fat-containing diet) showed significant
increases in fecal proportions of Bacteroidetes paralleled to weight loss over a one-year-long intervention in a few subjects [18];
nonetheless, species diversity was reported to remain constant. Studies on the
cecal microbiota of genetically obese mice and their lean littermates also
related a higher proportion of Archaea to obesity [17]. These relationships between obesity and the gut microbiota
composition were first based on DNA sequence analysis of the total distal gut
microbiome of mice and humans obtained from genomic libraries or directly by
pyrosequencing. Of these microbial groups, Bacteroidetes and Firmicutes constitute the
dominant bacterial subdivision (>99%) among the 70 bacterial subdivisions identified
in distal gut, while Methanobrevibacterium
smithii constitutes the most prominent methanogenic archaeon among the 13 Archaea divisions reported to date based
on 16S ribosomal DNA sequencing data [11]. More recently, diet-induced obesity
in animal models has been associated with increases in the proportion of a
single-uncultured clade within the Mollicutes class of Firmicutes, which was also
diminished by subsequent dietary manipulations to limit weight gain, showing
more specific relationships between obesity and components of the gut
microbiota [19]. A study of a Chinese family, comprising 3 males and 4 females,
also related the lowest Bacteroidetes to Firmicutes ratio to the overweight
individual, and demonstrated a high degree of interpersonal variation in this
value, ranging from 0.26 to 1.36 [20].Differences in fecal microbiota composition
were shown to predict overweight in children early in life. Children maintaining
normal weight showed a greater number of bifidobacteria, while children
becoming overweight showed a greater number ofStaphylococcus aureus in feces during infancy [21]. Although the
selected population group included children prone to allergy, who may show the
described microbial aberrancies, the obtained results are also in accordance
with the protective role attributed to breast-milk against developing obesity
later in life [22], and the predominance of bifidobacteria in the
gut of breastfed babies [23]. Shifts in composition of animal and human gut
bacteria in response to dietary changes (a high protein/low carbohydrate or
high-fat intake) have also been shown to alter microbial composition and
activity in the large intestine that, in turn, could exert an impact on health [15, 24]. Obese humans submitted to a dietary intervention, based on reducing
carbohydrate intake and increasing protein intake, showed reductions in
populations of Bifidobacterium, and Roseburia spp. and Eubacterium rectale subgroups of clostridial cluster XIVa when
carbohydrate intake was decreased, while no differences were detected in Bacteroides or other clostridial
clusters [24]. The abundance of Roseburia spp. and E. rectale group
correlated well with the decline in fecal butyrate as carbohydrate intake was
reduced; however, relationships to body weight were not established. Recent
studies on the evolution of mammals and their gut microbes pointed out that the
acquisition of a new diet is a fundamental driver for changes in gut bacterial
diversity, which increases from carnivory to omnivory to herbivory [25]. Alterations
in gut microbiota composition associated with genetic or diet-induced obesity
have also been shown to be reversible by oral transfer of the gut microbiota
from lean mice to a germ-free recipient [19, 26] or by administration of
prebiotic substrates to animal models at least over short-term periods [27].
Therefore, it seems likely that a combination of environmental (e.g. diet) and genetic factors contributes to defining unique
combinations of bacteria within an individual, which could favor either an
obese or lean phenotype. In this context, some authors argue that both antibiotics
and probiotics have demonstrated to act as growth promoters when used in animal
feeding and, therefore, could contribute to current human obesity [28].
However, while antibiotics reduce gut microbiota populations, probiotics
restores their levels. Therefore, their common effect on animal weight gain can
be only a consequence of their common role in preventing infections. By
contrast, other scientists consider that the intentional manipulation of the
composition of gut microbiota via dietary strategies is a possible tool to
revert or prevent overweight and particularly metabolic-associated disorders
[19, 26, 27]. Although this line of research is still in its infancy, in the
following sections we summarize current evidence on the mechanisms of action of
gut microbiota on metabolic and immune aspects of obesity and the consequences
of its dietary manipulation by pro- and prebiotics.


## 3. Influence of the Gut Microbiota on Energy Metabolism

The gut microbiota is considered a critical
factor, together with lifestyle, involved in energy metabolism and obesity.
Germ-free mice colonized by the distal gut microbiota of conventionally raised
mice produced a remarkable increase (60%) in body fat within 10–14 days, although
feed consumption was reduced compared to the control germ-free mice [29]. This process also stimulated the synthesis of
leptin, and produced faster glycemia and insulinemia, paralleled to body-fat
increase [29]. The microbial colonization was demonstrated to increase the
host’s ability to both harvest energy from the diet and store this energy in
adypocites. This is thought to be achieved by diverse mechanisms including
improvement of diet macronutrient utilization, generation of metabolites
involved in energy balance and regulation of host gene expression. Commensal
bacteria have specialized sets of hydrolyses and transporters to digest
nutrients, like complex polysaccharides, that would, otherwise, be inaccessible
to humans. These are the main energy sources for bacteria colonizing the large
intestine and confer them a competitive advantage over transient bacteria. The
microbial fermentation of undigested dietary compounds can provide
approximately 10% of the daily energy supply in omnivores and up to 70% in
herbivores [30]. The degradation of matrix and other dietary polysaccharides
(xylans, manans, pectins, starch, and inulin) as well as host mucins lead  to
the generation of intermediate products (lactate, succinate, etc.) and finally
short-chain fatty acids (SCFA), including butyrate, acetate, and propionate,
which are almost completely absorbed along the gastrointestinal tract (Figure 1). The ability to degrade highly insoluble polymeric substrates, such as
cellulose and mucin, seems to be limited to a subset of primary microbe
degraders in the large intestine and requires the expression of specific
substrate attachment, degradation, and uptake systems like the so-called
cellulosome complex. In fact, cellulolytic species have been shown to form
biofilm associations with plant surfaces in
vitro, integrated by a higher fraction of Firmicutes and a smaller fraction of Bacteroides, which suggests
a more prominent role of the former bacterial group in energy harvest from the
diet by facilitating complex polysaccharide utilization [31]. Several
clostridial clusters of Firmicutes are important butyrate-producing bacteria in the distal gut, such as Roseburia, E. rectale, Eubacterium halli, and Anaerostipes caccae, most of
which are included in clostridial cluster XIVa [31]. Acetogenesis is another
metabolic attribute of relevance to obesity identified in this clostridial
cluster [31], which could partly explain the inverse relationship between Firrmicutes and body weight reductions
in previous human intervention studies [18]. Soluble and less complex
oligosaccharides such as starch and fructooligosaccharides can be utilized by
other gut microbes such as Bacteroides and Bifidobacterium, which could also
contribute to the generation of intermediary metabolites and finally to SCFA
(Figure 1).Figure 1
Schematic diagram of the
main metabolic pathways of dietary poly- and oligosaccharides in the gut
ecosystem.Although butyrate-producing bacteria would
appear to be related to higher gut metabolic  activity leading to overweight, butyrate is
extensively utilized by enterocytes and generally regarded as a healthy metabolite
[32]. The main role of butyrate is to fuel enterocytes, covering up to 70% of their energy needs and contributing to
epithelial cell growth regulation and differentiation (Figure 1). Butyrate also
exerts anti-inflammatory effects and seems to contribute to glucagon-like
peptide 1 (GLP-1) generation, which is involved in satiety, by promoting
differentiation of stem cells into positive GLP-1 L cells. Altogether, this may
have beneficial effects on obese-prone subjects [32, 33]. Unlike butyrate, acetate
and propionate generated in intestinal lumen can reach the blood stream and the
liver through the portal vein (Figure 1). Acetate can contribute to lipid and
cholesterol synthesis in the liver by activating the cytosolic acetyl S CoA
synthetase 2, while propionate may inhibit lipid synthesis from acetate at least in rat hepatocytes [34]. In fact, high-propionate production through
fermentation of starch or fructans has been associated with serum and liver
cholesterol reduction in rats and the acetate to propionate ratio in portal
blood, proposed as a possible maker of the effects of these dietary ingredients
on lipid metabolism [35, 36]. Nevertheless, acetate administered at a high dose
to rats and rat hepatocytes also induced AMP kinase and/or reduced SREBP-1c
expression related to lipogenesis inhibition, therefore further studies should
be carried out in humans to verify its positive or negative influences on lipid
metabolism [37].In addition to SCFA, hydrogen is produced by polysaccharide-degrading
species and its further utilization by methanogens, acetogens and sulfate-reducing
gut microbes also activates the metabolism and growth of
polysaccharide-degrading
bacteria  (Figure1). Archaea, which
are the main gut methanogenic microorganisms, were also overrepresented in
genetically obese mice as compared to their lean littermates and were related
to a greater capacity to promote adiposity when transferred to germ-free
recipients [38]. Eubacterium dolichum,
a human Mollicute, was also shown to
favor import and processing of simple sugars in subjects under a Western-style
diet, partly explaining its association and that of Firmicutes division with obesity [19]. In addition, cross-feeding
mechanisms between components of the gut microbiota have been identified at
different stages of the utilization of complex energy-rich polysaccharides.
Thus, B. adolescentis can degrade
starch, generating intermediate products (lactate and acetate) that can be
utilized by butyrate-forming bacteria such as E. hallii to generate butyrate [39] or by other intestinal
bacterial groups that convert lactate into propionate by the acrylate pathway [40].
Coinoculation of M. smithii and B. thetaiotaomicron into germ-free mice
showed that M. smithii directs B. thetaiotaomicron to focus on
fermentation of dietary fructans to acetate, whereas B. thetaiotaomicron-derived formate is used by M. smithii for methanogenesis. Moreover,
B. thetaiotaomicron-M. smithii cocolonization produced a
significant increase in host adiposity compared with monoassociated, or B. thetaiotaomicron-D. piger biassociated animals [41]. These studies emphasize the role of interactive sets
of microbes, rather than the role of individual microorganism within the gut
ecosystem in energy-metabolism and body weight regulation. This makes it far
more complex to identify those that are critical to obesity control through dietary
strategies.The gut microbiota may also influence energy
balance by modifying gene expression of host-related metabolic functions.
Angiogenesis, which is primarily involved in distributing nutrients to
peripheral tissues, was shown to depend on the gut microbial colonization
process.  Although capillary network
formation was arrested in adult germ-free mice, this developmental process
restarted and was completed within 10 days after colonization with a complete
microbiota harvested from conventionally raised
mice, or withBacteroides
thetaiotaomicron [42]. Commensal bacteria, such as B. thetaiotaomicron, have also been shown to induce expression of host
monosaccharide transporters in monocolonized mice [43]. This would lead to
increasing the absorption of monosaccharides and SCFA and, thereby, promote the novo synthesis of lipids in the
liver. In addition, the microbial colonization of germ-free mice increased
liver expression of two key enzymes involved in the de novo fatty acid
biosynthetic pathways, acetyl-CoA carboxylase  and fatty acid synthase, as well as
the transcriptional factors ChREBP and SREBP-1, which are involved in
hepatocyte lipogenic responses to insulin and glucose [29]. Unlike colonized mice, germ-free animals were
protected against the obesity that develops after consuming a Western-style,
high-fat, sugar-rich diet by increasing fatty acid metabolism via two
complementary mechanisms: (i) increasing levels of circulating fasting-induced
adipose factor (Fiaf), which inhibits lipoprotein lipase thereby limiting fat
storage in adipocytes and promoting fat oxidation in muscle; and (ii)
increasing skeletal muscle and liver levels of phosphorylated AMP-activated
protein kinase and its downstream targets, involved in fatty acid β  oxidation
[44].Commensal gut microbiota and probiotics could
also regulate serum lipids by taking part in bile acid metabolism. Bile salts
are highly effective detergents that promote solubilization and
absorption of dietary lipids throughout the intestine. The major
bile salt modifications of microbial origin in the human gut
include deconjugation,
oxidation of diverse hydroxyl groups and 7α/β-dehydroxylation [45]. Certain probiotics
have been shown to decrease serum cholesterol levels by means of
their bile salt hydrolytic activity [46]. Significant bile salt
hydrolysis occurring in the proximal and terminal ileum reduces bile salt
uptake through high-affinity transport system and lipid
solubilization. This also leads to an increase in bile-acid excretion in feces
and bile-acid synthesis from cholesterol [45]. For example, administration of L. acidophilus ATCC 43121 seemed to reduce
serum cholesterol levels by bile acid deconjugation and dehydroxylation
reactions during cholesterol metabolism in hypercholesterolemia-induced rats [46].
This intervention resulted in increased excretion of total fecal acid sterols
and secondary bile acids (deoxycholic and lithocholic acids), and a reduction
of primary bile acids (cholic and chenodeoxycholic acids). Particularly, the
reduction in blood cholesterol levels was related to the increase in the
insoluble bile acid, lithocholic acid. More recently, metabolomic studies have
indicated that supplementation of Lactobacillus
paracasei NCC2461 or Lactobacillus
rhamnosus NCC4007 probiotics to germ-free mice colonized with human baby
flora-induced changes in hepatic-lipid metabolism and enterohepatic
recirculation of bile acids that led to a decrease in the plasma concentrations
of lipoproteins VLDL and LDL, when compared to controls [47]. Lactobacillus supplementation also decreased fecal excretion of bile acids probably due to
their accumulation in Lactobacillus probiotic cells. Probiotic
administration also led to reductions of acetate in cecal content as well as of
the hepatic acetate to propionate ratio, which was related to a reduction in serum
lipids [47]. Furthermore, studies in vitro indicated that fecal commensal bacteria, but not probiotics, were
able to reduce cholesterol to coprostanol and thus increasing its excretion in
feces [48].Some probiotic strains of the genusLactobacillus and Bifidobacterium were also reported to synthesize conjugated
linolenic acid (CLA) from polyunsaturated fatty acids of soy oil, which reduces
serum lipids and cholesterol in liver. One example of these bacteria is Lactobacillus rhamnosus PL60, which is a
human isolate that produces t10, c12-conjugated linoleic acid and was found to exert
an antiobesity effect on diet-induced obese mice after 8 weeks of feeding. This
strain reduced body weight without reducing energy intake, and caused a
specific reduction of white adipose tissue without producing liver steatosis,
which is a common side effect of CLA [49].


## 4. Immune Role of the Gut Microbiota and Obesity

Obesity is considered an inflammatory disorder,
which affects both innate and adaptive immunity and favors the development of
other disorders such as type-2 diabetes and cardiovascular diseases [50]. In
fact, chronic activation of innate immunity is regarded as a risk factor as it
favors the development of these disorders, which could also be influenced by the
gut microbiota [27, 51]. The gut microbiota largely regulates innate and
adaptive immunity, influencing local and systemic responses (Figure 2). The recognition of
bacterial components through pattern-recognition receptors (PRRs), such as toll-like
receptors (TLRs) of innate immune cells, is considered to be the starting point
of immunity, informing the immunocompetent cells to respond properly to each
environmental stimulus (e.g., pathogens or harmless microbes) [13]. TLR-4
recognizes lipopolysaccharide (LPS) from Gram-negative bacteria, while TLR-2
recognizes lipopeptides and lipoproteins from various pathogens, and
peptidoglycan and lipoteichoic acid from Gram-positive bacteria (Figure 2) [52].
Upon ligand binding, TLR interacts with different adaptor proteins (MyD88,
TIRAP/Mal, TRIF, and TRAM) activating the transcription of different
downstream effector systems, such as the mitogen-activated kinases (MAPK), the
NF-κB/IKKβ system, and the activator protein-1 (AP-1) with
production of cytokines and diverse immune mediators [53]. Cytokines such as
TNF-α, IL-1β, and IL-6 are the major proinflammatory
mediators produced in response to TLR-4 stimulation by endotoxin (LPS) as well
as those increased in obese and insulin-resistant patients (Figure 2) [54]. Unlike
pathogenic microbes, commensal bacteria maintain a peaceful relationship with
their hosts by producing a transient activation of the NF-κB cascade or its suppression by diverse
mechanisms including (i) promotion of nuclear export of NF-κB subunit relA in complex with PPAR-γ [55], (ii) inhibition of IκB ubiquitination and degradation in epithelial
cells [56], (iii) regulation of TLR expression and upregulation of the negative
regulator Tollip protein [57], and (iv) induction of anti-inflammatory cytokines such as IL-10 [58]. TLRs and derived cytokines also play a pivotal
role in linking innate and adaptive immunity through exerting action on T-cells
and particularly on dedritic cells (DCs), keeping a physiological Th1/Th2
balance [13]. Th1-polarized responses characterized by overproduction of IFN-γ, IL-2, and IL-12 cytokines are associated with
clearance of intracellular pathogens as well as with chronic diseases including
diabetes and obesity. Most TLR-activated DCs induce differentiation of naïve
CD4+ T cells into Th1 cells, while TLR2-activated DCs promote the
differentiation of Th2-cells or regulatory T cells by producing high levels of anti-inflammatory cytokine
IL-10 which could help to counteract the inflammatory status associated with
obesity [58]. Interestingly, TLRs have been identified not only in innate and
adaptive immune cells but also in insulin-responsive tissues such as the adipose
tissue, muscle, and liver, suggesting a connection between immunity, microbial
stimulation, and metabolism [59]. Diet-induced and genetically obese mice (ob/ob or db/db) showed a
significant upregulation of expression of TLR-1 to -9 in adipocytes and
preadipocytes along with higher cytokine production upon stimulation [60]. In particular, it is
known that TLR-4 can be activated
by both lipopolysaccharide (LPS) and dietary-saturated fatty acids
inducing upregulation of common intracellular inflammatory pathways,
such as JNK and NF-κB in adipocytes and macrophages, related to the
induction of insulin resistance and increased adiposity (Figure 2) [51]. Conversely, adipocyte-specific
knockdown of TLR4 prevented cytokine expression induced either by LPS or
saturated fatty acids and similar effects were shown in macrophages. With some exceptions,
loss-of-functional mutation in TLR-4 also prevented diet-induced obesity and
insulin resistance in vivo mice
models [51]. Recently,
metabolic endotoxaemia, characterized by an
increase in serum LPS levels, has been demonstrated to be an inflammatory
factor, causative of body weight gain, insulin resistance, and diabetes in
high-fat fed animal models [27, 61]. In contrast, the
inhibition of the gut microbiota by antibiotic administration (norfloxacin and
ampicillin) in two different mouse models of insulin resistance resulted in
reduced serum LPS levels, low-grade inflammation, obesity, and type-2 diabetes,
demonstrating the link between the gut microbiota and certain metabolic
disorders [15]. LPS stimulation also produces a cytokine-mediated increase in
plasma lipid levels by increasing the synthesis of VLDL lipoproteins in the
liver and inhibiting lipoprotein lipase. In fact, mobilization of lipid stores
is considered a mechanism to fuel the host’s response against infections;
moreover, lipoproteins also seem to help fight against infection by binding and
neutralizing LPS [62].  Therefore, common
responses can be induced by “pathogenic lipid nutrients” and microorganisms
mainly related to TLR-4-signaling and proinflammatory cytokine and gene
transcription activation pathways. In this scenario, one can hypothesize that shifts
in gut microbiota composition caused by a high-saturated fatty acid-containing
diet [27],
together with dietary lipids,
could constitute synergic TLR signals, thus contributing to the amplification
of inflammation occurring in obesity. Consequently, it has been suggested that probiotics
and prebiotics with anti-inflammatory properties could be of help in the fight
against obesity and
associated disorders, as reported in other chronic inflammatory diseases [53]. Although few specific studies have proven such
a hypothesis so far, the administration of the probiotic VSL3# was demonstrated
to exert a preventive effect against type-1 diabetes in a nonobese diabetic
mice model by immunomodulatory mechanisms, inducing IL-10 production in Peyer patches,
and spleen and its expression in the pancreas [63]. In addition, Lactobacillus culture-supernatants were
shown to reduce in vitro leptin
production by adipocytes, thereby reducing IFN-γ production by lymphocytes and exerting an
anti-inflammatory role [64]. Oral administration of a functional food product
containing L. plantarum 299v to heavy
smokers for six weeks led to a decrease in leptin, systolic blood pressure, and
fibrinogen, which was attributed to the anti-inflammatory effects of this
probiotic, suggesting it would be able to reduce cardiovascular risk [65]. In
contrast, oral administration of Lactobacillus
acidophilus and Bifidobacterium
longum strains to human subjects did not influence serum leptin levels [66].
The administration of a prebiotic (oligofructose) to high-fat-diet fed mice was
also shown to restore Bifidobacterium levels, which positively correlated with improved glucose tolerance,
glucose-induced insulin secretion, and normalization of inflammatory tone by
decreasing endotoxaemia in plasma and proinflammatory cytokines in adipose
tissue [27].Figure 2
Schematic diagram of
signaling pathways triggered by bacterial components, saturated fatty
acids, and adipokines in epithelial and innate immune cells leading to
either activation or negative regulation of proinflammatory pathways related to
obesity and insulin resistance. (1) Lipopolysaccharide (LPS) from Gram-negative
bacteria and saturated fatty acids (SFAs) is recognized by toll-like receptor
(TLR) 4 activating proinflammatory pathways involving the MyD88 (myeloid
differentiation primary-response protein 88)-dependent and -independent
pathways that may lead to activation of nuclear factor (NF)-κB and activator protein-1 (AP-1) with production
of pro-inflammatory cytokines. (2) Peptidoglycan (PGL) and lipoteichoic acid
from Gram-positive bacteria are recognized by TLR-2 triggering the activation of
the MyD88-dependent pathway. (3) Commensal bacteria and some probiotics may
suppress activation of NF-κB cascade by (i) promotion of nuclear export of
NF-κB subunit relA in complex with PPAR-γ; (ii) inhibition of IκB ubiquitination and degradation, (iii)
induction of anti-inflammatory (IL10) cytokine production. (4) Leptin interacts
with its receptors (OBR) activating the signal transducer and activator of
transcription (STAT), and induces production of CCL2, proinflammatory
cytokines, and reactive oxygen species (ROS) causing endoplasmic reticulum (ER)
stress.


## 5. Conclusions and Future Challenges

Gut microbes are viewed as novel factors
involved in host physiology and body weight regulation by driving a number of
metabolic and immune functions. The initial association of the microbial
colonization process of the germ-free intestine with body weight gain conferred
a negative role to gut microbes with respect to obesity. Further, relationships
established between a specific microbiota structure and a lean or obese
phenotype have suggested that different microbes may influence body weight
differently, and species- and stain-specific functions are being defined. In
addition, endotoxaemia and dysbiosis have been identified as inflammatory
factors responsible for insulin resistance and body weight, thereby returning
to the concept that a healthy microbiota may be beneficial in preventing these
disorders. Although the cause-effect relationships of the gut microbiota with
obesity remain unclear and a limited number of in vivo trials have been done to assess the effects of specific
microbial strains (commensals and probiotics), and prebiotics on metabolic
disorders, the knowledge provided by these studies constitutes a breakthrough
in the identification of their etiology. Further work based on systems biology
coupled with “omic” technologies (metagenomics, trancriptomics, and
metabolomics) will be critical to shed light on the roles of specific sets of
microbes on metabolic disorders, with a view to
design more efficient
dietary-based strategies to reduce their risk.



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