ArticlePDF AvailableLiterature Review

Abstract

The human intestine harbors a complex bacterial community called the gut microbiota. This microbiota is specific to each individual despite the existence of several bacterial species shared by the majority of adults. The influence of the gut microbiota in human health and disease has been revealed in the recent years. Particularly, the use of germ-free animals and microbiota transplant showed that the gut microbiota may play a causal role in the development of obesity and associated metabolic disorders, and lead to identification of several mechanisms. In humans, differences in microbiota composition, functional genes and metabolic activities are observed between obese and lean individuals suggesting a contribution of the gut microbiota to these phenotypes. Finally, the evidence linking gut bacteria to host metabolism could allow the development of new therapeutic strategies based on gut microbiota modulation to treat or prevent obesity.
REVIEW
Gut microbiota and obesity
Philippe Ge
´rard
1,2
Received: 11 August 2015 / Revised: 29 September 2015 / Accepted: 5 October 2015 / Published online: 12 October 2015
Springer Basel 2015
Abstract The human intestine harbors a complex bacte-
rial community called the gut microbiota. This microbiota
is specific to each individual despite the existence of sev-
eral bacterial species shared by the majority of adults. The
influence of the gut microbiota in human health and disease
has been revealed in the recent years. Particularly, the use
of germ-free animals and microbiota transplant showed
that the gut microbiota may play a causal role in the
development of obesity and associated metabolic disorders,
and lead to identification of several mechanisms. In
humans, differences in microbiota composition, functional
genes and metabolic activities are observed between obese
and lean individuals suggesting a contribution of the gut
microbiota to these phenotypes. Finally, the evidence
linking gut bacteria to host metabolism could allow the
development of new therapeutic strategies based on gut
microbiota modulation to treat or prevent obesity.
Keywords Microbiome Gnotobiotic models
Metabolic syndrome Intestinal permeability Antibiotics
Probiotics Prebiotics Fecal transplant
Abbreviations
AMPK AMP-activated protein kinase
ANGPTL4 Angiopoietin-like 4
BSH Bile salt hydrolase
DIO Diet-induced obesity
eCB Endocannabinoı
¨d
FFAR Free fatty acid receptor
FMT Fecal microbiota transplant
GF Germ-free
GI Gastro-intestinal
GLP Glucagon-like peptide
HFD High-fat diet
HGC High gene count
IBD Inflammatory bowel disease
LGC Low gene count
LPL Lipoprotein lipase
LPS Lipopolysaccharides
PYY Peptide YY
SCFA Short chain fatty acid
TLR Toll-like receptor
TMA Trimethylamine
Introduction
Obesity is a major health concern, whose incidence is
increasing dramatically in both industrialized and devel-
oping countries [1]. Nowadays, more than 500 million
people are obese worldwide leading to considerable eco-
nomical costs as well as public health challenge [2].
Indeed, obesity predisposes individuals to a number of
diseases including diabetes, cardiovascular diseases, non-
alcoholic fatty liver disease, cancer, and some immune-
related disorders. Several genes have been implicated in
the determination of body weight, but this genetic sus-
ceptibility may only explain a small fraction of obesity, and
cannot explain the rise in incidence of this pathology.
Therefore, obesity arises from complex interactions
between genes and environmental factors such as diet, food
&Philippe Ge
´rard
philippe.gerard@jouy.inra.fr
1
INRA, UMR1319 MICALIS, Equipe AMIPEM, Building
442, Domaine de Vilvert, 78350 Jouy-en-Josas, France
2
AgroParisTech, UMR MICALIS, 78350 Jouy-en-Josas,
France
Cell. Mol. Life Sci. (2016) 73:147–162
DOI 10.1007/s00018-015-2061-5 Cellular and Molecular Life Sciences
123
components and/or way of life, and results from a long-
term positive imbalance between energy intake and
expenditure with excessive increase in body fat [3].
Overall, the complex pathways that lead to development of
overweight and its consequences are not thoroughly
understood and recent studies have suggested that the gut
microbiota (the trillions of bacteria that normally reside
within the human gastrointestinal (GI) tract) should be
factored into this equation [4]. Indeed, there is growing
evidence that the gut microbiota and its bacterial genome
(the microbiome) affect nutrient acquisition, energy regu-
lation and fat storage [5]. These findings raise the
possibility that the gut microbiota plays a role in regulating
host energy metabolism and may contribute towards the
development of obesity and associated metabolic diseases.
The objective of this review is to provide an overview of
this emerging field related to the role of the gut microbiota
in obesity and metabolic disorders.
The gut microbiota
Development and stability of the gut microbiota
Foetuses are thought to be sterile in uteri although low
levels of bacterial translocation through the placental cir-
culation may provide an elementary microbiota before
birth [6]. During birth, bacteria from the mother and the
surrounding environment colonize the infant’s gut rapidly.
The composition of this microbiota depends on various
factors including mode of birth (cesarean section or vaginal
delivery), antibiotic treatment, feeding (breastfeeding or
formula) or sanitation of the environment [7]. This
microbiota changes during the first years of life, under the
control of different factors including developmental chan-
ges in the gut environment, the host genotype, and the
introduction of solid foods, and a more complex and
stable community, close to the adult microbiota, is estab-
lished at approximately 3 years of age [7,8]. In adults, the
gut microbiota remains remarkably constant slightly fluc-
tuating around an individual core of stable colonisers.
Then, alterations occur at old age when digestive physi-
ology and diet changes [9]. Nevertheless, dietary factors or
antibiotic treatments can lead to transient changes. For
example, short-term treatment in humans with a single dose
of oral antibiotics alters the gut microbiota for as long as
4 weeks before it tends to recover its original composition
[10]. Moreover, some bacterial species are not recovered
even several months after treatment leading to a reduced
diversity following repeated antibiotic exposures [11].
Similarly, changes in diet lead to modification of the gut
microbiota composition. Diet provides nutrients for both
the host and the microbiota whose bacterial species can be
favoured or disadvantaged by dietary substrates. Therefore,
a study showed that diet changes in mice could explain
57 % of the total structural variation in gut microbiota,
whereas genetic mutation accounted for no more than 12 %
[12]. In humans, the gut microbiota in twin pairs and their
mothers has been characterized to assess the impact of
genotype and environmental exposures. It revealed that
family members share more similar microbiotas than
unrelated individuals, but that monozygotic twins have a
similar degree of variance than dizygotic twins, indicating
that early environmental exposures are key determinants of
adult gut bacterial community [13]. Interestingly, this study
also showed that if each microbiota is different in terms of
bacterial composition (no bacterial species shared by all
154 individuals), there was a wide array of shared micro-
bial genes named the ‘‘core microbiome’’, reflecting
evolutionary convergence of unrelated bacterial species.
The final composition of the microbiota is, therefore,
unique and specific to each individual [14] and a recent
study demonstrated that individuals could be uniquely
identified based on their microbiomes alone [15].
Nonetheless, the factors guiding this feature are still a
matter of debate.
Composition of the gut microbiota
In humans, the gut microbiota is a complex and dynamic
ecosystem that has coevolved with its host [16] and rep-
resents approximately 1 kg of our body weight. It is now
recognized that the communities of microbes in our gut
function as an organ with many metabolic, immunologic
and endocrine-like actions that influence human health
[17]. A large fraction of the gut bacteria still remains
impossible to culture so that our understanding of this
microbiota has been a long time limited by technical issues.
In the 1980s, Pace and co-workers introduced a new cul-
ture-independent method to identify bacteria, based on the
sequencing of the 16S rRNA gene [18]. The development
of these molecular techniques makes now possible a reli-
able assessment of the gut microbiota. Although Eukaryota
and Archaea domains are also present in the intestine,
Bacteria clearly predominate. Adult humans are colonized
by microbes from nine divisions (deep evolutionary lin-
eages) of Bacteria and at least one division of Archaea
[19]. This represents only a small fraction of the more than
70 bacterial and 13 archaeal divisions known in the bio-
sphere. Moreover, three bacterial divisions, the Firmicutes
(Gram-positive), Bacteroidetes (Gram-negative) and Acti-
nobacteria (Gram-positive), dominate the adult human gut
microbiota and account for more than 90 % of all bacteria,
whereas Methanobrevibacter smithii, a hydrogen-consum-
ing methanogen, dominates the Archaea domain [20].
These results were obtained from fecal samples which
148 P. Ge
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123
correspond to the colonic population. However, the specific
density and type of bacteria in the GI tract are influenced
by environmental variations through the gut, such as pH,
oxygen, and nutrient availability. Hence, the bacterial
concentration is higher in the lower portion of the GI tract,
and if this gut section is largely populated by anaerobic
bacteria, aerobic bacteria dominate in the proximal gut.
Nevertheless, molecular analyses revealed that the same
bacteria are present in the different sections of the gut and
that only the relative abundance of the different species
varies [21].
Increased sequencing and bioinformatics capacities have
allowed entering into a new era, through the Human
Microbiome Project [22,23], not only giving access to the
type of bacterial species present but also to their gene
content [24]. Using these techniques, it is now estimated
that the human GI tract harbors approximately 10
14
microorganisms (ten times more cells than the whole
human body) and that each gut microbiota is composed of
500–1000 distinct bacterial species [20,25]. Moreover, the
MetaHit consortium has published a catalog of nearly
10 million non-redundant genes obtained from sequencing
fecal samples from 1267 individuals [26] indicating that
the human microbiome contains at least 100 times as many
genes as the human genome [2628]. Each individual hosts
on average 500–600,000 bacterial genes, about half of
which is shared by most individuals (functional core).
However, many functions are worn by the intestinal
microbiota in a fraction of humans only and could con-
tribute greatly to the metabolic diversity observed in the
human population. It was further observed that the human
population may be grouped into three distinct clusters,
based on gut microbiota composition [29]. This concept of
enterotypes is based on co-occurring of bacterial species,
with enterotypes being dominated by Bacteroides,Pre-
votella, and Ruminococcus, respectively. Although
divergences in enterotypes were first found to be inde-
pendent of geography, age, gender, or body mass index,
differences in long-term diet pattern have been associated
with these enterotypes [30]. Finally, although the concept
of enterotypes is still debated [31], it can be important for
making associations between gut microbiota and health and
defining what constitutes healthy and dysbiotic bacterial
community.
Gut microbiota functions
The gut microbiota performs essential functions that the
human body cannot carry out, resulting in a symbiotic
relationship. The gut microbiota is, therefore, critical for
maintaining normal GI and immune functions, and efficient
digestion of nutrients [32,33]. For example, the microbiota
ferments otherwise indigestible food components,
synthesizes vitamins and other essential micronutrients,
metabolizes dietary toxins and carcinogens, converts
cholesterol and bile acids, assures the maturation of the
immune system, affects the growth and differentiation of
enterocytes, regulates intestinal angiogenesis, and protects
against enteric pathogens [34]. In the last decades, rela-
tionships between the gut microbiota and human health
have been established. Moreover, imbalances in its com-
position (i.e., dysbiosis) have been associated with immune
disorders, susceptibility to infections, and more recently to
several non-intestinal pathologies including cardiovascular
diseases, obesity, diabetes, liver or even brain diseases [35
38]. The current knowledge of the relationship between the
gut microbiota, obesity and associated diseases is presented
in the next parts of this review.
Gut microbiota and obesity
Evidences from germ-free animal models
The first evidence on the role of the gut microbiota on host
adiposity came from studies in germ-free (GF) animals,
i.e., animals devoid of bacteria and bred in sterile isolators.
In 1983, Wostmann and colleagues observed that GF
rodents require 30 % more calories to maintain their body
mass than conventional ones (possessing their own
microbiota) [39]. The potential mechanisms accounting for
this observation remained unclear until recent landmark
studies, preeminently originating from Jeffrey Gordon’s
laboratory at Washington University, Saint-Louis, MO,
USA. Indeed, they pioneered the investigation of gut
microbiota as a factor influencing fat storage and obesity.
They first found that conventionally raised mice have 42 %
more total body fat and 47 % more gonadal fat than GF
mice, although GF mice consumed more food [40]. They
next demonstrated that colonization of GF mice with a
cecum-derived microbiota from conventional mice pro-
duces a 60 % increase in body fat mass within 2 weeks.
The increase in body fat was accompanied by insulin
resistance, adipocyte hypertrophy, and increased levels of
circulating leptin and glucose [40]. This was partly
explained by the capacity of the gut microbiota to degrade
undigestible polysaccharides into monosaccharides which
could be absorbed leading to increased hepatic lipogenesis
in the host. Moreover, inoculation of a gut microbiota
suppresses the intestinal expression of angiopoietin-like 4
(ANGPTL4), a circulating inhibitor of lipoprotein lipase
(LPL). Conventionalization leads, therefore, to increased
adipocyte LPL activity and then to increased cellular
uptake of fatty acids and adipocyte triglycerides accumu-
lation [40]. The physiologic importance of ANGPTL4 was
further established by the demonstration that GF
Gut microbiota and obesity 149
123
ANGPTL4
-/-
mice have the same degree of adiposity as
their conventional counterparts. Finally, in contrast to
conventional mice, GF mice fed a high-fat, sugar-rich diet
are protected from diet-induced obesity (DIO) [41]. This
lean phenotype was associated with increased skeletal
muscle and liver levels of phosphorylated AMP-activated
protein kinase (AMPK) [41]. AMPK is an enzyme that is
conserved from yeast to humans and functions as a fuel
gauge that monitors cellular energy status and stimulated
fatty acid oxidation in peripheral tissue. Hence, the gut
microbiota may suppress skeletal muscle fatty acid oxida-
tion through a metabolic pathway involving
phosphorylation of AMPK. It was further observed that GF
mice receiving a high-fat diet (HFD) showed enhanced
insulin sensitivity with improved glucose tolerance and
reduced insulinemia in comparison to conventional mice.
This was associated with a reduced hypercholesterolemia, a
moderate accretion of hepatic cholesterol and an increase
in fecal cholesterol excretion suggesting an altered
cholesterol metabolism in GF mice [42]. Nevertheless, this
resistance to diet-induced obesity may depend on mice
genetic background and diet composition as C3H GF mice
were not found resistant to the obesogenic effect of a low-
sucrose, lard-based high-fat diet, while resistant to high
sucrose, palm oil-based high-fat diet [43]. Also, similar
body weights and adiposity were observed in GF and
conventional Fischer 344 rats [44]. In these rats, GF status
was associated with increased intestinal ANGPTL4 and
reduced hepatic lipogenesis as well as increased adipocyte
size suggesting that impact of a gut microbiota on fat
storage may be more complex than proposed by pioneer
papers.
Role of bacterial fermentation in host energy harvest
and appetite regulation
An important mechanism that can explain differences in
body fat between conventional and GF mice is the increase
in energy harvest from the food due to the fermentation of
the gut microbiota. Indeed, the gut microbiota is able to
process complex dietary plant polysaccharides, otherwise
inaccessible to humans, to monosaccharides and short-
chain fatty acids (SCFAs), principally acetate, propionate,
and butyrate. These SCFAs represent an important energy
source for our body as they can provide approximately
10 % of the daily energy supply in omnivores and up to
70 % in herbivores [45]. Butyrate is the preferred source of
energy for colonic epithelial cells and increases the density
of capillaries underlying the small intestine villus epithe-
lium [46]. Absorbed propionate and acetate are delivered to
hepatocytes where they can be used for gluconeogenesis
and lipogenesis, respectively. However, SCFAs act not
only as energy substrates for the host, but also as signaling
molecules, influencing energy intake and metabolism [47].
Therefore, they are ligands for at least two G-protein-
coupled receptors, free fatty acid receptor 2 (FFAR2 or
GPR43) and free fatty acid receptor 3 (FFAR3 or GPR41).
These GPCRs are mainly expressed by gut epithelial cells,
in particular enteroendocrine cells. FFAR2 is preferentially
activated by acetate, and FFAR3 by butyrate, whereas
propionate activates both receptors [48]. FFAR2
-/-
mice
were found to resist to diet-induced obesity indicating that
FFAR2 could promote fat storage [49]. Similarly, it has
been shown that GF FFAR3
-/-
mice colonized by a
microbiota gained less fat mass than their wild-type lit-
termates [50]. The authors proposed that in the absence of
FFAR3 signaling, the plasma level of peptide YY (PYY) is
reduced leading to an increased gut motility and reduced
energy harvest from the diet. Therefore, FFAR2 and
FFAR3 would be modulators of host energy balance
through effects dependent upon the gut microbiota. These
receptors may also control eating behavior as increased
production of SCFAs due to fiber administration leads to
increased satiety and reduced food intake [5153]. These
effects are mediated by increases in the satietogenic gut
peptides PYY and glucagon-like peptide (GLP) 1 together
with decrease in orexigenic ghrelin [54]. Moreover, buty-
rate and propionate may reduce appetite via induction of
leptin expression from adipocytes [55]. Other pathways
may be involved in SCFAs outcomes as butyrate and
propionate were also shown to protect mice against diet-
induced obesity via FFAR3-independent mechanism [56].
Finally, SCFAs produced by the microbiota may constitute
a fine tune of the host metabolism by the regulation of
energy harvest, fat storage and appetite.
The influence of antibiotics on obesity
If the gut microbiota plays a role in obesity, modulation of
this bacterial community should have an impact on obesity
development. Antibiotics are known to disrupt microbiota
composition and while a rapid recovery is observed fol-
lowing short-term antibiotic treatment, pervasive effects
may be obtained after repeated antibiotic perturbations [10,
11]. Seventy years ago, it was first shown that adminis-
tration of low doses of antibiotics resulted in promotion of
growth in chicks [57]. This effect was confirmed in
mammalian livestock (cows, pigs, and sheep), and antibi-
otics have been used to promote weight gain in farm
animals for over 60 years. Moreover, antibiotics have no
growth-promoting effects in GF chicken [58] indicating
that changes in the microbiota of treated animals are
responsible for these effects. Interestingly, increases in
body mass are obtained only when antibiotic exposure
occurs early in life [59] which has been confirmed in mice
more recently [60,61]. Indeed, mice that received low-dose
150 P. Ge
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penicillin treatment at birth had higher body weight gain
than their counterparts that were exposed at weaning [61].
Notably, these effects in mice lasted into adulthood weeks
after antibiotic treatment was stopped indicating that even
transient perturbations early in life can cause long-term
effects [62]. Finally, GF mice colonized with the micro-
biota from low-dose penicillin-treated mice gained more
fat mass than mice colonized with the microbiota from
control mice, demonstrating that the shifted microbiota
itself possesses the capacity to trigger obesity [61]. Nev-
ertheless, the effect of antibiotic exposure in obesity
development is dependent on the dose of antibiotics.
Indeed, high doses of antibiotics resulted in reduced fat
mass and insulin resistance in mice models of obesity [63].
It can be assumed that these high doses of antibiotics
reduce considerably the bacterial population and, therefore,
the capability of the gut microbiota to extract calories from
the diet, then mimicking the conditions observed in GF
animals. In humans, a growth-promoting effect of antibi-
otic treatments has been reported in the 1950s [64,65], but
these studies have been ignored until the recent demon-
stration of a link between the gut microbiota and obesity.
Therefore, epidemiological studies from different countries
have been recently launched to evaluate the impact of
antibiotic treatment in infancy on risk of obesity develop-
ment. The first published results seem to confirm that
exposure to antibiotics in early life is associated with an
increased body mass index [6669]. This suggests that the
massive use of antibiotics in the last decades could be
involved in the parallel increase in prevalence of obesity in
the western countries.
Gut microbiota and obesity: the dysbiosis concept
Dysbiosis is defined as the condition of having microbial
imbalances associated with a pathology. In accordance
with this definition, it has been shown, firstly in mice, that
obesity can be associated with an altered gut microbiota.
Ley et al. analyzed 5088 bacterial 16S rRNA gene
sequences from fat ob/ob, lean ob/?and wild-type mice
fed the same polysaccharide-rich diet [70]. They revealed
that obese animals have a 50 % reduction in the abundance
of Bacteroidetes and a proportional increase in Firmicutes
[70]. Ob/ob mice also harbored more methanogenic
Archaea, which may increase the efficiency of bacterial
fermentation via removal of H
2
. Similar differences in the
gut microbiota of lean versus obese humans were observed
in initial studies by the same team [71]. Indeed, it was
found that obese people had lower Bacteroidetes and more
Firmicutes than did lean control subjects. Moreover, the
Bacteroidetes to Firmicutes ratio approached a lean phe-
notype after 52 weeks of diet-induced weight loss.
Together, these results obtained in mice and humans
suggested that obesity alters the nature of the gut micro-
biota and raised the possibility that manipulation of the gut
microbiota towards a lower Firmicutes/Bacteroidetes ratio
could be a new strategy for treating obese people. How-
ever, if several studies confirmed an increased Firmicutes/
Bacteroidetes ratio in obese individuals [7274], others did
not report any differences in the abundance of Firmicutes
and Bacteroidetes in obese and lean subjects, or even found
an opposite relationship [7578]. Therefore, these phylum-
wide changes in the gut microbiota composition cannot be
currently considered as a biomarker for obesity. Changes in
microbiota composition at lower taxonomic levels have
also been associated with obesity and genera or even
specific bacterial species abundance may better define the
dysbiosis associated with obesity than Firmicutes/Bac-
teroidetes ratio. Moreover, if several bacterial genera have
been found increased or decreased in obese patients, bac-
terial species belonging to these genera may follow an
opposite trend suggesting a species or even strain-depen-
dent effect. As an example, if a higher level of
Lactobacillus has been found in obese patients than in
controls [72], some species belonging to this genus (L.
reuteri) have been indeed associated with obesity whereas
others (L. casei,L. plantarum) have been found associated
with weight loss in humans and animals [79]. Several
studies also reported an association between obesity and
lower populations of bifidobacteria [74,75,80], but only a
few bifidobacterial species have been proved to exert anti-
obesogenic effects in animal models [81]. Also, potential
opportunistic pathogens have been frequently associated
with obesity and a few bacterial strains have been proposed
as markers or even contributors to obesity. For instance,
Staphylococcus aureus was found more abundant in the gut
of overweight children and pregnant women [75,80,82].
Similarly, increased populations of Enterobacteriaceae
have been described in overweight pregnant women as
compared to normal weight [74]. Further, a bacterium
belonging to this family, Enterobacter cloacae strain B29,
has been isolated from the gut microbiota of an obese
human. B29 constituted almost 35 % of his gut microbiota
before dietary intervention, but became undetectable after
the volunteer lost 51.4 kg of his 174.8 kg initial weight.
Strikingly, this bacterium was shown to cause obesity when
introduced into high-fat diet-fed germ-free mice [83].
Conversely, Faecalibacterium prausnitzii, a butyrate pro-
ducer with known anti-inflammatory properties [84], has
been found decreased in morbidly obese subjects with
diabetes [73], similarly to its low abundance in patients
with inflammatory bowel disease (IBD) [85]. Moreover, it
was negatively associated with plasma levels of inflam-
matory cytokines. Similarly, Akkermansia muciniphila is
inversely related to fasting plasma glucose levels, visceral
fat accumulation, and adipocyte diameter in subcutaneous
Gut microbiota and obesity 151
123
adipose tissue in obese humans [86]. In addition, feeding
mice with A. muciniphila reduces body weight gain, fat
mass development, and low-grade inflammation and
restores gut barrier function [87]. Altogether these results
suggest that specific bacterial species, or a combination of
these species, may contribute directly to obesity develop-
ment or protection. However, it is still impossible to define
what an ‘‘obese’’ microbiota is due to a variety of co-
founding factors (including heterogeneity in genotype, diet,
lifestyle) that exist within the human population, and it is
likely that identical gut microbiota may have a different
influence on obesity development in the heterogeneous
human population. Also, we can hypothesize that the
contribution of the gut microbiota to obesity may rather
depend on the genes present in the microbiome and on the
metabolites produced than on taxonomic composition. The
development of high-throughput sequencing techniques
makes it now possible to get access to the whole gene
content of the gut microbiota. This could allow the iden-
tification of metabolic functions that can be
overrepresented in the microbiome of obese individuals.
Accordingly, it was first showed that the cecal microbiome
of genetically obese ob/ob mice contains more genes
involved in the hydrolysis of indigestible polysaccharides
leading to the hypothesis that the ob/ob microbiome has
increased capacity to harvest energy from the diet [88].
Consistently, fecal energy content was reduced and the
amounts of cecal SCFAs were increased in ob/ob vs wild-
type mice. In obese humans, genes involved in phospho-
transferase system, in carbohydrate metabolism and in
membrane transport, were found increased whereas genes
involved in transcription, nucleotide metabolism and
cofactors and vitamin metabolism were found depleted [13,
89]. Analysis of SCFAs also suggests that the fermentation
activity of the gut microbiota is higher in obese individuals,
propionate being the most increased SCFA [90]. Recently,
a bimodal distribution of microbial gene counts leading to
the stratification of the population as either ‘‘low gene
count’’ (LGC) or ‘‘high gene count’’ (HGC) has been
identified [91]. This microbial gene richness was associated
with body weight, fat mass, inflammation, glucose and
lipid metabolism. Strikingly, dietary restriction in over-
weight or obese patients was less efficient in LGC than in
HGC individuals in terms of body weight loss, improve-
ment of insulin sensitivity and decrease of inflammation
[92]. These results suggest that a decreased bacterial
diversity may be a feature of the ‘‘obese microbiota’’ as it
has been described for other disease states [93]. In con-
clusion, it appears that obesity is associated with a gut
microbiota differing from a lean microbiota in terms of
composition, diversity, metabolic activity, and gene con-
tents. However, the association studies described in this
paragraph do not inform whether this dysbiosis is a cause
or a consequence of obesity.
Causative role in obesity: evidences from gut
microbiota transplant experiments
If the gut microbiota plays a causal role in obesity devel-
opment, transplanting different gut microbiota to GF mice
should lead to different weight gain and adiposity. Con-
sistently, Turnbaugh et al. first transplanted cecal
microbiota from lean and ob/ob mice to GF wild-type
recipient. They found that after only 2 weeks, mice har-
boring the microbiota from obese mice gained more fat
compared to the mice inoculated with the gut microbiota
from lean donors [88], supporting a causal role of these
bacteria in the pathogenesis of obesity. They further raised
an important question. Are the differences in the compo-
sition of the gut microbiota a consequence of host genotype
or the hyperphagic state, as it is well known that ob/ob
mice consume more food than their wild-type littermates.
To further investigate this question, the same team devel-
oped a model of Western diet-induced obesity (DIO) to
study the interrelationship between gut microbiota, diet and
energy balance [94]. They showed that DIO produced a
bloom in a single uncultured clade within the Firmicutes,
named Erysipelotrichi. Moreover, this group of bacteria
was reduced following dietary manipulations that limit
weight. Similar to transplantation of the ob/ob microbiota,
transplantation of a DIO gut microbiota to GF recipients
promoted greater fat gain than transplants from lean
donors. Metagenomic sequencing also revealed that the
Western diet microbiome is enriched in pathways involved
in import and fermentation of simple sugars and host gly-
cans [94]. To determine whether human gut microbiota
may also be able to cause obesity in mice, transplantations
of adult human fecal microbiota to GF mice have been
performed. In a first study, these humanized gnotobiotic
mice were then fed a low fat or a high-fat diet. Finally, GF
recipients were colonized with cecal microbiota from
humanized donors fed either diet, and were kept on the low
fat diet. Mice colonized with the microbiota from HFD-fed
donors gained significantly more adiposity than mice col-
onized with the microbiota from low fat diet-fed donors
[95]. More recently, the same group inoculated the GF
mice with gut microbes from four pairs of female twins,
each in which one person was obese and the other had a
healthy weight. Mice that received the obese humans’
microbes gained more body fat, put on more weight, and
showed increased level of markers of metabolic disorders
[96]. Because mice are coprophagic, cohousing is widely
used to investigate the impact of sharing microbial com-
munities on the host phenotype. Strikingly, cohousing mice
152 P. Ge
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associated with the human obese or lean microbiota pre-
vents increased adiposity, and it was further demonstrated
that bacteria from the lean mice were able to invade the
obese microbiota, the best colonizers among the lean
communities belonging to the Bacteroidetes phylum [96].
Whether these species were responsible for the lean-like
state remains to be proven but it indicates that bacterial
species within the human gut microbiota may have the
capacity to protect from obesity.
Interestingly, these fecal transplant experiments have
also demonstrated that the gut microbiota may play a
causal role in the development of the metabolic disorders
associated with obesity. Toll-like receptor 5 (TLR5) is
predominantly expressed basolaterally by intestinal
epithelial cells and serves to detect motile bacteria that
breach the epithelial monolayer and limit their dissemina-
tion. It was first described that TLR5
-/-
mice present
increased adiposity, elevated serum triglycerides and
cholesterol levels, as well as mild loss of glucose tolerance,
insulin resistance, hyperlipidemia and hypertension.
Remarkably, the transfer of TLR5
-/-
cecal contents into
wild-type GF mice recapitulated most aspects of the
metabolic syndrome phenotype [97]. Similarly, another
study demonstrated that gut microbiota determines devel-
opment of Non-alcoholic fatty liver disease in mice [37].
First, conventional mice were fed an HFD for 16 weeks
and two of them were selected based on their opposite
response to HFD. Although both mice were the same
weight, one displayed low fasting glycemia and weak
steatosis (Non-Responder). The other one displayed insulin
resistance and marked steatosis (Responder). Two groups
of GF mice were transplanted with the gut microbiota of
the two selected mice. After being fed an HFD, only the
mice associated with the Responder microbiota developed
fasting hyper-glycemia and hyper-insulinemia as well as
hepatic macrovesicular steatosis [37]. These experiments
demonstrating a causal role of the gut microbiota in obesity
and associated metabolic disorders raise the question
whether gut microbiota transfer in humans could be a new
way to treat obesity and metabolic syndrome as recently
shown in rats [98]. This question will be developed in the
section dedicated to the ‘Therapeutic potential of the gut
microbiota’’ .
Gut microbiota, intestinal permeability
and inflammation: the LPS hypothesis (and beyond)
Obesity is associated with a low-grade inflammation, which
has been implicated in the development of the metabolic
syndrome and insulin resistance [99]. The origin of this
inflammation is unclear and Cani et al. have proposed that
the lipopolysaccharide (LPS, a membrane component of
Gram-negative bacteria) is the triggering factor of the early
development of inflammation and metabolic diseases [100].
This hypothesis is based on the following points: (1) LPS
triggers the secretion of proinflammatory cytokines when it
binds to the complex of CD14 and TLR4 at the surface of
immune cells [101], (2) LPS is continuously produced
within the gut through lysis of Gram-negative bacteria and is
physiologically carried into intestinal capillaries though a
TLR4-dependent mechanism [102], (3) LPS is transported
from the intestine by a mechanism facilitated by chylomi-
crons freshly synthesized from epithelial intestinal cells in
response to fat feeding [103]. Cani et al. first demonstrated
that mice fed an HFD for 2–4 weeks exhibited a significant
increase in plasma LPS that they named metabolic endo-
toxemia [100]. Interestingly, it has been also reported that
patients with type 2 diabetes and patients with non-alcoholic
fatty liver disease had higher LPS levels than control
humans [104,105]. It should be noted that these levels of
LPS are 10–50 times lower than values seen in septicemia or
other infections. Cani et al. also showed that continuous
subcutaneous low-rate infusion of LPS mimicked the HFD
phenotype including excessive weight gain, hyperglycemia,
steatosis, adipose tissue macrophages infiltration and insulin
resistance in mice. Finally, to demonstrate the causal link
between LPS and the development of metabolic diseases,
they challenged LPS receptor (CD14) knock out mice with
an HFD or LPS infusion [100]. CD-14 deficient mice were
protected from metabolic disease induced by both high-fat
feeding and LPS infusion. These results were corroborated
by studies showing that TLR4-deficient mice are resistant to
the development of DIO [106,107]. They also suggest that
GF mice could be protected from DIO through the lack of
LPS in their gut. To further assess the contribution of the gut
microbiota in the development of these metabolic disorders,
they used intestinal-focused antibiotic treatment in high-fat
fed or genetically obese ob/ob mice. Drastic changes in the
gut microbiota through antibiotic treatment completely
blunted the metabolic endotoxemia, and the related meta-
bolic disorders (e.g., macrophages infiltration, glucose
intolerance and insulin resistance) [63,108]. They also
showed that high-fat feeding increased gut permeability and
changed gut microbiota composition with a reduction of
Bacteroides,Clostridium coccoides group and bifidobacteria
[108]. Interestingly, bifidobacteria have been shown to
reduce intestinal LPS levels and to improve gut barrier
function in mice [109,110]. To determine if the metabolic
disorders observed during high-fat feeding can be attributed
to the decrease of bifidobacteria, they used prebiotic dietary
fibers to specifically increase the gut bifidobacteria in high-
fat fed mice. They confirmed that mice fed an HFD exhibit a
higher endotoxemia, a phenomenon completely abolished
through dietary supplementation with the prebiotic fibers
[111]. Moreover, in prebiotic-treated mice, bifidobacteria
positively correlated with improved glucose tolerance and
Gut microbiota and obesity 153
123
negatively correlated with metabolic endotoxemia and body
weight gain [111]. More recently, they deciphered one of the
mechanisms explaining how these specific changes in the
gut microbiota improved metabolic endotoxemia. They
found that the modulation of gut microbiota controls and
increases endogenous production of the intestinotrophic
peptides GLP-2, and consequently improves tight junction
integrity and gut barrier functions by a GLP-2-dependent
mechanism [112]. They also identified the endocannabinoid
(eCB) system as determinant of gut barrier function. More
specifically, they proposed that the eCB system mediates
communication between adipose tissue and the gut micro-
biota. Accordingly, modulating the gut microbiota of obese
and diabetic mice profoundly affected the tone of the
intestinal and adipose tissue eCB system and improved
adipose tissue metabolism [113,114]. Finally, they further
showed that MyD88 (myeloid differentiation primary
response gene 88), a central adaptor molecule of most of the
TLRs, acts as a sensor involved in the interaction between
nutrients, gut microbes and the host during DIO [115].
Indeed, they first revealed that inducible intestinal epithelial
cell-specific deletion of MyD88 partially protects against
DIO, diabetes and inflammation. Remarkably, the gut
microbiota of these MyD88-deleted mice protected GF
recipients after fecal transplant. Finally, it appears that the
gut barrier function may be important in the crosstalk
between gut bacteria and host metabolism, and lps are
probably only one of the players linking the gut microbiota,
the gut permeability and metabolic disorders. Accordingly, it
was also shown that HFD leads to increased bacterial DNA
in ileal mucosa, blood and mesenteric adipose tissue in mice
[116]. Then, a 9-year longitudinal study revealed that blood
bacterial DNA at baseline was higher among participants
who presented with abdominal adiposity and developed
diabetes during the 9-year period than among those who did
not [117] suggesting that translocation of entire bacteria and
the existence of a tissue microbiota could be another con-
tributor to metabolic syndrome [118].
Influence of the gut microbiota on plasma lipids
Dyslipidemia is commonly associated with obesity and
metabolic syndrome and besides its influence on weight
gain and metabolic disorders, it has been shown for a long
time that the gut microbiota impacts the lipid metabolism
of the host. As an example, pioneer studies by Wostmann
et al. in the 1960s demonstrated that GF animals absorb
dietary cholesterol more efficiently than conventional
controls, but display reduced plasma cholesterol [119,
120]. Nevertheless, this topic was not studied thoroughly
until recently when comparison of GF and conventional
mice fed an HFD showed that GF mice display increased
fecal lipid excretion and reduced plasma free fatty acid and
liver triglyceride levels [42]. Interestingly, this study also
revealed that GF mice have reduced cholesterolemia, an
increase in fecal cholesterol excretion, and a moderate
accretion of hepatic cholesterol confirmed by an up-regu-
lation of cholesterol biosynthesis genes in the liver,
suggesting that the gut microbiota alters cholesterol
metabolism in the host [42]. This influence of the gut
microbiota on cholesterol metabolism was further con-
firmed using MS-based lipidomics of serum, white adipose
tissue, and liver of GF and conventional mice [121]. This
impaired cholesterol metabolism could be related to the
lack of cholesterol conversion by the intestinal bacteria.
Indeed, even if only a few cholesterol-reducing bacteria
have been isolated from human or animal gut [122,123],
the conversion of cholesterol to the saturated product
coprostanol by intestinal microorganisms was established
during the 1930s. Coprostanol is poorly absorbed by the
human intestine and an inverse relationship has been
observed between serum cholesterol levels and the
coprostanol-to-cholesterol ratio in human feces [124].
Hence, conversion of cholesterol to coprostanol by the gut
may lead to decreased cholesterol absorption and then
cholesterolemia [125]. Besides cholesterol, comparison of
GF and conventional mice also showed that the gut
microbiota modified a number of lipid species in the serum,
adipose tissue, and liver, with its greatest effect on
triglyceride and phosphatidylcholine species [121]. The
latter is of importance regarding the role of the gut
microbiota in cardiovascular diseases. Indeed, dietary
choline and phosphatidylcholine are converted to
trimethylamine (TMA) by gut microbes. Then, the absor-
bed TMA is metabolized to trimethylamine-N-oxide, a
proatherosclerotic metabolite, by hepatic flavin monooxy-
genases [126,127]. Gut microbiota could also regulate
serum lipids by taking part in bile acid metabolism. Bile
salts are highly effective detergents that promote solubi-
lization and absorption of dietary lipids throughout the
intestine. The bile acids that escape the enterohepatic cir-
culation undergo bacterial metabolism in the colon leading
to over twenty different secondary bile acids in human
feces [128]. Also, deconjugation of bile acids through the
enzyme bile salt hydrolase (BSH) may alter plasma
cholesterol levels. Briefly, glycine or taurine is liberated
from the steroid moiety of the molecule, resulting in the
formation of free bile acids which are less efficiently
reabsorbed than their conjugated counterparts. Hence,
deconjugated bile acids are more readily excreted within
the feces than conjugated bile acids. Cholesterol, being a
precursor of bile acids, is broken down to replace the
processed bile salts leading to a reduction in serum
cholesterol [129].
154 P. Ge
´rard
123
Therapeutic potential of the gut microbiota
Probiotics and prebiotics
Probiotics are defined by the Food and Agricultural
Organization and the World Health Organization as ‘‘live
microorganisms which when administered in adequate
amounts, confer a beneficial health effect on the host’’.
Whereas probiotics are used for decades in agriculture for
their growth-promoting effects, several studies have
demonstrated that probiotics may ameliorate obesity and
associated metabolic disorders both in animal models and
in humans. In particular, probiotics containing Bifidobac-
terium were shown to exert beneficial effects in HFD fed
mice and rats [81,130135], mainly through increased gut
barrier function, leading to reduced bacterial translocation
and endotoxemia, and improvement of inflammation,
insulin sensitivity, fat accumulation as well as cholesterol
and triglyceride serum levels. Similarly, probiotics con-
taining Lactobacillus strains have been shown to be
effective in reducing body fat mass and improving lipid
profiles and glucose homeostasis in animal models of
obesity [136147]. Proposed mechanisms include conju-
gated linoleic acid production, BSH activity, stimulation of
fatty acids oxidation, or inhibition of lipoprotein lipase
activity. Well-controlled studies in humans are scarce but
recent studies suggested that Lactobacillus gasseri may
decrease body weight and abdominal adiposity and
improve postprandial serum lipid responses in overweight
human subjects [148150]. Finally, a meta-analysis based
on 17 randomized clinical trials in humans, 51 studies on
farm animals and 14 experimental models highlighted the
strain-dependent effect of Lactobacillus containing probi-
otics on weight management. Therefore, Lactobacillus
acidophilus administration resulted in a significant weight
gain in humans and in animals. Lactobacillus fermentum
and Lactobacillus ingluviei were associated with weight
gain in animals. Conversely, Lactobacillus plantarum was
associated with weight loss in animals and Lactobacillus
gasseri was associated with weight loss both in obese
humans and in animals [79]. In conclusion, although
encouraging results emerge from rodents experiments, the
efficacy of probiotics remains highly debatable and their
therapeutic used for obesity management has not yet been
recommended [151].
Prebiotics are defined as non-digestible polysaccharides
that promote ‘‘the selective stimulation of growth and/or
activity(ies) of one or a limited number of microbial gen-
us(era)/species in the gut microbiota that confer(s) health
benefit to the host’’ [152]. The most studied prebiotics are
the inulin and various types of fructo-oligosaccharides and
galactooligosaccharides and numerous studies in animal
models showed that they modify gut microbial composi-
tion, enhancing the growth of beneficial Bifidobacteria and
Lactobacillus [111,153155]. However, more recent
studies revealed that prebiotics affect many more bacterial
taxa than previously thought [156,157]. Interestingly, this
microbiota modulation is commonly associated with a
reduction in body weight, body fat and adipocyte size.
These effects are mediated through decreased food intake
and appetite, as well as reduced fatty acid storage [154,
155,158160]. Furthermore, the improvement of gut bar-
rier integrity [112,154] leads to better glucose tolerance
and insulin sensitivity. In humans, beneficial effects of
prebiotics on glycemia and insulinemia have been largely
confirmed whereas impacts on body weight, fat mass and
satiety have not been consistently observed and are still
matter of debate [161165].
Fecal microbiota transplant
Fecal microbiota transplant (FMT) refers to infusion of a
fecal suspension from a healthy individual into the GI tract
of another person to cure a specific disease. Transplantation
of stool for the treatment of GI disease was first reported in
the fourth century in China by Ge Hong, who described the
use of human fecal suspension by mouth for patients who
had food poisoning or severe diarrhea [166]. Sixteen cen-
turies later, its first clinical use was for the treatment of
pseudomembranous colitis and was reported in 1958 in a
four-patient case series [167]. In the recent years, FMT has
gained an increasing interest as an effective treatment
strategy for severe recurrent Clostridium difficile infection
with global success rate over 80 % [168]. Moreover, early
experience suggests that FMT could be used for other GI
and non-GI diseases associated with microbial dysbiosis
and whose aetiologies are uncertain, including IBD, irri-
table bowel syndrome or metabolic diseases. Indeed, as
metabolic phenotypes can be transmitted to GF mice via
gut microbiota transplant, it can be postulated that FMT
may be effective to improve lipid and glucose homeostasis.
In a first pilot study, intestinal microbiota was transferred
from lean human donors to recipients with metabolic
syndrome via a postpyloric enteral feeding tube. Patients
who received microbiota from lean donors had an increase
in peripheral insulin sensitivity 6 weeks after FMT in
comparison with peripheral insulin sensitivity prior to
FMT, although the body weights and adiposity were not
modified. This was associated with increased gut bacterial
diversity, as well as increase in the amount of the butyrate
producer Eubacterium hallii [169]. Therefore, if the legal
framework and the standardization of the FMT are needed
and if more well-designed randomized controlled trials in
the context of metabolic diseases should be performed, this
Gut microbiota and obesity 155
123
study suggests that FMT might be a new way to improve
obesity and associated metabolic disorders in the future.
Conclusions and future challenges
Gut microbiota is now viewed as a novel factor involved in
body weight management. The gut microbiota may,
therefore, participate to energy metabolism through energy
harvest from the diet, regulation of fat storage, regulation
of lipogenesis, or regulation of fatty acid oxidation. Fur-
ther, differences in the composition of gut microbiota in
obese humans and mice suggest that different microbes or
community may influence body weight differently.
Although the cause–effect relationships of the gut micro-
biota with obesity remain unclear, the rapid developments
in high-throughput techniques may make it possible to
unravel the real impact of the gut microbiota on host’s
metabolism. Multidisciplinary research in this field will be
helpful to provide evidence-based data and to shed light on
the roles of specific sets of microbes. The next step will be
the discovery of pharmacological, dietary or fecal trans-
plant interventions to modify the gut microbiota in such a
way that prevents or treats metabolic disorders and/or
obesity.
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... Numerous studies indicated that dietary nutrient intake, as a key environmental factor impacting gut microbiota composition, can induce "dysbiosis" which is defined as an altered microbial community including richness, diversity and composition. The dysbiosis can accelerate the homeostatic imbalance which contributes to multiple disease states [4][5][6][7][8][9], including obesity, diabetes, liver diseases, cancer, brain disorders, as well as cardiovascular disease (CVD) which remains the leading cause of morbidity and mortality worldwide [10,11]. ...
... X. Zhang and P. Gérard / Computational and Structural Biotechnology Journal xxx (xxxx) [1][2][3][4][5][6][7][8][9][10][11][12] circulating TMAO levels, an increase of macrophage foam cell formation and enhancement of aortic atherosclerotic plaque development (Fig. 1) [33,86]. On the contrary, the capacity to TMAO production, and choline or carnitine diet related atherosclerotic plaque burden were respectively eliminated or suppressed in GF or antibiotic treated ApoE −/− mice (C57BL/6 strain) [33,86]. ...
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Cardiovascular diseases (CVD) are a group of disorders of the heart and blood vessels and remain the leading cause of morbidity and mortality worldwide. Over the past decades, accumulating studies indicated that the gut microbiota, an indispensable “invisible organ”, plays a vital role in human metabolism and disease states including CVD. Among many endogenous and exogenous factors that can impact gut microbial communities, the dietary nutrients emerge as an essential component of host-microbiota relationships that can be involved in CVD susceptibility. In this review, we summarize the major concepts of dietary modulation of the gut microbiota and the chief principles of the involvement of this microbiota in CVD development. We also discuss the mechanisms of diet-microbiota crosstalk that regulate CVD progression, including endotoxemia, inflammation, gut barrier dysfunction and lipid metabolism dysfunction. In addition, we describe how metabolites produced by the microbiota, including trimethylamine-N-oxide (TMAO), secondary bile acids (BAs), short chain fatty acids (SCFAs) as well as aromatic amino acids (AAAs) derived metabolites play a role in CVD pathogenesis. Finally, we present the potential dietary interventions which interacted with gut microbiota as novel preventive and therapeutic strategies for CVD management.
... Although the structure of the microorganism is relatively stable, factors including infection, diet, or genetics can also affect the intestinal flora, resulting in the growth of pathogenic bacteria, the loss of normal commensal bacteria, and the decline in diversity (Levy et al., 2017), which is called dysbiosis, and can further lead to diseases such as obesity (Gérard, 2016), autoimmune disease (Knip and Siljander, 2016), neurological disorders (Tremlett et al., 2017), and inflammatory bowel disease (Wlodarska et al., 2015). A study showed that using mass spectrometry to detect chemicals in the peripheral circulation in germ-free (GF) mice found that the synthesis of most substances depends on the gut microbiome (Wikoff et al., 2009). ...
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Epilepsy is a common chronic brain disease. There are many clinical methods to control epileptic seizures, such as anti-seizure medications (ASMs) or surgical removal of epileptogenic lesions. However, the pathophysiology of epilepsy is still unknown, making it difficult to control or prevent it. The host’s immune system monitors gut microbes, interacts with microbes through pattern recognition receptors such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs) expressed by innate immune cells, and activates immune responses in the body to kill pathogens and balance the relationship between microbes and host. In addition, inflammatory responses induced by the innate immune system are seen in animal models of epilepsy and temporal lobe epilepsy brain tissue to combat pathogens or injuries. This review summarizes the potential relationship between gut microbes, innate immunity, and epilepsy based on recent research to provide more hints for researchers to explore this field further.
... The gastrointestinal tract is colonized by microbial communities called gut microbiota [6], which play a relevant role in regulating the innate and adaptive immune system, gut motility, gut barrier homeostasis, nutrient absorption and fat distribution [7]. Dysbiosis, defined as an imbalance in microbial communities [8], can be induced by multiple factors, such as an unhealthy diet [9] or the use of antibiotics and other drugs [10,11], and is related to obesity and non-communicable chronic diseases [12]. Dysbiosis induces gut barrier dysfunction, which leads to the translocation from the gut into the bloodstream of Gram-negative bacterial components, such as lipopolysaccharide [13]. ...
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... 20 Saturated fatty acids (SFAs) could activate the toll-like receptors (TLRs), especially TLR2 and TLR4, 21 then activate nuclear factor kappa B (NF-κB), resulting in inflammatory responses. 22 By contrast, monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) could reduce the concentration of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and relived inflammatory reaction. 18,23,24 However, the role of n-6 PUFAs played in was still controversies. ...
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... The gut microbiota functions as an organ with many metabolism, immunology, and endocrine-like effects that are crucial for human health. 10,11 The pathogenesis of gut microbiota involved in the lipid accumulation may be through its influence on energy balance, nutrient absorption, inflammatory pathway, and the gut-brain axis. 12 However, the effects of early STA administration and its subsequent withdrawal on gut microbiota and bacterial metabolites are poorly understood. ...
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Chapter
The gut microbiota is the community of microbes (bacteria, viruses, fungi) that live in the gastrointestinal tract and are critical for normal nutrient absorption, digestion, and immune system development. These microbes communicate with the central nervous system (CNS) through interactions with the immune system, production of neuroactive metabolites/neurotransmitters, and activation of the vagus nerve. Spinal cord injury (SCI) disrupts the autonomic nervous system (ANS) and impairs communication with organ systems throughout the body, resulting in dysautonomia. This dysautonomia contributes to the pronounced immunosuppression and gastrointestinal dysfunction seen after SCI. Combined with frequent antibiotic use, physical and psychosocial stress, and altered GI motility, SCI-induced dysautonomia likely also causes an imbalance in the composition of the gut microbiome, i.e., gut dysbiosis. Pre-clincal and clinical studies indicate that SCI-induced gut dysbiosis triggers intestinal inflammation, impairs gut motility, and alters the composition of serum metabolites. SCI not only affects the abundance of various gut microbes but also the functional potential of the gut microbiome. As gut dysbiosis develops and the metabolites produced by gut microbiota change, these changes can influence the progress or severity of various SCI-associated comorbidities including metabolic syndrome, cardiovascular disease, liver dysfunction, and depression/anxiety disorders. Therefore, the development of novel therapeutic targets to prevent and treat these comorbidities requires a better understanding of how SCI affects the emergence or reduction in key gut microbial species.
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Background: Dysbiosis of intestinal microbiota may be linked to pathogenesis of obesity and metabolic disorders. Objective: This study compared the gut microbiome of obese Thai children with that of healthy controls and examined their relationships with host lifestyle, adiposity, and metabolic profiles. Methods: This cross-sectional study enrolled obese children aged 7-15. Body composition was evaluated using bioelectrical impedance analysis. Stool samples were analyzed by 16S rRNA sequencing using the Illumina MiSeq platform. Relative abundance and alpha- and beta-diversity were compared with normal-weight Thai children from a previous publication using Wilcoxon rank-sum test and ANOSIM. Relationships of gut microbiota with lifestyle activity, body composition, and metabolic profiles were assessed by canonical correlation analysis (CCA) and Spearman correlation. Results: The study enrolled 164 obese children with a male percentage of 59%. Mean age was 10.4 ± 2.2 years with a BMI z-score of 3.2 ± 1. The abundance of Bacteroidetes and Actinobacteria were found to be lower in obese children compared to nonobese children. Alpha-diversity indices showed no differences between groups, while beta-diversity revealed significant differences in the family and genus levels. CCA revealed significant correlations of the relative abundance of gut microbial phyla with sedentary lifestyle and certain metabolic markers. Univariate analysis revealed that Actinobacteria and Bifidobacterium were positively correlated with HDL-C and negatively correlated with body weight and screen time. Additionally, Actinobacteria was also negatively associated with fasting insulin and HOMA-IR. Lactobacillus showed positive correlation with acanthosis nigricans and adiposity. Cooccurrence analysis revealed 90 significant bacterial copresence and mutual exclusion interactions among 43 genera in obese children, whereas only 2 significant cooccurrences were found in nonobese children. Conclusions: The composition and diversity of gut microbiota in obese Thai children were different from those of their normal-weight peers. Specific gut microbiota were associated with lifestyle, adiposity, and metabolic features in obese children. An interventional study is needed to support causality between specific gut microbiota and obesity.
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Background Browning of white adipose tissue (WAT) is currently considered a potential therapeutic approach to treat or prevent diet-induced obesity. Synbiotics have protective effects against diet-induced obesity; however, its role in adipose tissue browning has been less investigated. Aim of the work to study the possible effect of synbiotics intake on browning of WAT in obese rats. Material and methods Twenty-four adult male Wistar rats were randomly divided into four groups; normal diet (ND) control group, high fat diet (HFD) group, ND group receiving synbiotics, and HFD group receiving synbiotics. After eight weeks, all rats were sacrificed; and samples (blood, WAT, brown adipose tissue, and liver) were collected. Lipid profile, liver enzymes, fasting glucose, and fasting insulin levels were measured. The expression of browning-related genes: uncoupler protein-1 (UCP-1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), and peroxisome proliferator-activated receptors gamma (PPARγ) were measured by real-time polymerase chain reaction (PCR) in adipose tissues. Fibroblast growth factor 21 (FGF21) protein level was measured in serum, adipose and liver tissues, and FGF21 receptor expression was performed by real-time PCR in adipose tissues. Results synbiotics intake was associated with improvement in lipid profile, liver enzymes, and insulin sensitivity in HFD rats. Moreover, the intake was associated with higher gene expression of brown adipocyte-specific markers. As for the FGF21 and its receptor, intriguing results were obtained that needs further in-depth studies. Conclusion synbiotics might protect against diet-induced obesity through induction of thermogenic genes resulting in brown-like adipocyte phenotype in WAT.
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Gut microbes share a symbiotic relationship with humans and perform several metabolic and physiological functions essential for human survival. It has been established in several scientific studies that obesity and other metabolic complications are always associated with disturbed gut microbiota profile, also called gut dysbiosis. In recent years, bariatric surgery has become a treatment of choice for weight loss, and it forms an important part of obesity management strategies across the globe. Interestingly, bariatric surgery has been shown to alter gut microbiota profile and synthesize short-chain fatty acids by gut microbes. In other words, gut microbes play a crucial role in better clinical outcomes associated with bariatric surgery. In addition, gut microbes are important in reducing weight and lowering the adverse events post-bariatric surgery. Therefore, several prebiotics, probiotics and postbiotics are recommended for patients who underwent bariatric surgery procedures for better clinical outcomes. The present review aims to understand the possible association between gut microbes and bariatric surgery and present scientific evidence showing the beneficial role of gut microbes in improving therapeutic outcomes of bariatric surgery.
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