Concern about health risks associated with rising obesity has become nearly universal,
with the mean body mass index (BMI) and the prevalence of obese and overweight individuals
increasing substantially worldwide during the previous three decades. Unfortunately,
prevention and treatment of obesity and related complications have proven complex,
and successful strategies to tackle this pathology remain limited. Epidemiological
studies have highlighted potential environmental exposures, including diet, energy
expenditure, early life influences, sleep deprivation, endocrine disruptors, chronic
inflammation, and microbiome status, contributing to higher risk of obesity (Franks
and McCarthy, 2016). Among these, the microbiome has received extensive attention
during the previous decade.
Variation in gut microorganisms might play an important role in the pathogenesis of
obesity. Although the composition of intestinal microbiota is highly diverse in healthy
individuals, those exhibiting overall adiposity, insulin resistance and dyslipidemia
are characterized by low bacterial richness (Le Chatelier et al., 2013). Moreover,
composition of gut microbiota in obesity individuals differs from that in lean individuals,
although inconsistent changes have been reported. Bacteroidetes prevalence is lower
in obese people, with this proportion increasing along with weight loss based on a
low-calorie diet (Ley et al., 2006a). Lactobacillus and Clostridium species are associated
with insulin resistance, with Lactobacillus positively correlated with fasting glucose
and HbA1c levels, whereas Clostridium showed a negative correlation with these parameters
(Karlsson et al., 2013). These data suggest that specific bacterial phyla, class,
or species or bacterial metabolic activities could be beneficial or detrimental to
the onset of obesity. Therefore, the gut microbiome has been suggested as a driving
force in the pathogenesis of obesity.
Causal evidence linking intestinal microbiota to obesity mostly originates from animal
studies. Germ free (GF) mice are resistant to high-fat diet (HFD)-induced obesity,
despite a higher food intake. Interestingly, administration of subtherapeutic antibiotic
therapy increased adiposity and metabolism-related hormone levels in young mice, with
these changes altering the copies of key genes involved in the metabolism of carbohydrates
to short-chain fatty acids (SCFAs) and the regulation of hepatic metabolism of lipids
and cholesterol (Cho et al., 2012). Furthermore, colonization of GF mice with “obese
microbiota” resulted in a significantly greater increase in total body fat than colonization
with “lean microbiota” (Turnbaugh et al., 2006). Notably, GF mice that received fecal
microbiota transplantation (FMT) from an obese donor gained more weight as compared
with those receiving it from a lean donor (Ridaura et al., 2013), with this result
further accelerating the establishment of the causal role of gut microbiota in the
development of obesity.
Mechanisms by which gut microbiota promote metabolic disturbances are not well understood.
To date, leading theories about the mechanisms include changes in molecular signaling
chemicals released by bacteria in contact with local tissue or distant organs (Schroeder
and Backhed, 2016; Meijnikman et al., 2017) (Fig. 1).
Figure 1
Impact of gut microbiota on local and distant organs contributes to obesity development
and progression. In local tissues, obesity-associated gut microbiota have an increased
capacity to harvest energy from the diet, stimulate gene reprogramming in the colon,
change polypeptide hormones and other bioactive molecules released by EC cells, decrease
the intestinal barrier, and disturb immune homeostasis. Gut microbiota also communicate
with host adipose tissue and the liver and brain. Microbiota-fat-signaling axis. Gut microbiota
participates in the regulation of adipogenesis through distinct mechanisms. LPS triggers
an immune response along with inflammation and immune-cell infiltration. SCFAs also
participate in insulin-mediated fat accumulation in adipocytes via activation their
receptors GPR43 and GPR41, which inhibits lipolysis and encourages adipocyte differentiation.
Gut-liver axis. The presence of a dysbiotic microbiome causes subsequent increases
in gut permeability to bacteria-derived pathogens, including LPS and ethanol. In the
liver, LPS causes inflammation by stimulating immune cells. Certain metabolites, such
as bile acids, SCFAs, and TMAO, also play a role in NAFLD pathophysiology. Microbiota-brain-gut
axis. Gut afferent neuron and gut hormones are key signaling molecules involved in
gut-brain communication and host metabolism. Bioactive molecules involved in this
process include LPS, gut peptides, SCFAs and lactate
Changes in gut microbiota perturb homeostatic interaction between microbiota and the
intestine and might contribute to metabolic disorders. Local contacts between microbiota
and intestine cells determine which signals are sensed and presented and which reactions
are subsequently initiated. Increased energy harvesting by obesity associated gut
microbiota is another possible explanation for obesity. The obese microbiome is typified
by a reduced presence of taxa belonging to the Bacteroidetes phylum and a proportional
increase in members of the Firmicutes phylum, revealing an association with a higher
presence of enzymes for complex carbohydrate degradation and fermentation (Ley et
al., 2006b), which are related to elevated levels of energy harvesting from the diet
(Jumpertz et al., 2011). Additionally, the gut microbiome can stimulate reprogramming
of gene expression in the colon (Qin et al., 2018). Fasting-induced adiposity factor
(Fiaf; also known as angiopoietin-like protein 4), a circulating lipoprotein lipase
inhibitor whose expression is normally selectively suppressed in the gut epithelium
by microbiota (Backhed et al., 2007), plays a central role in triglyceride metabolism
(Kim et al., 2010) by inhibiting lipoprotein lipase (LPL) production in adipose tissue
and modulating fatty acid oxidation. Some specific components of microbiota might
suppress Fiaf in the intestinal epithelia and potentially stimulate host weight gain
by impairing triglyceride metabolism and promoting fat storage. Polypeptide hormones
and other bioactive molecules released by enterochromaffin (EC) cells in the intestine
are also involved in regulating food intake (Gribble and Reimann, 2016). Various Toll-like
receptors (TLRs) expressed in EC cells recognize different pathogen-associated molecular
patterns and alter the release of polypeptide hormones and other bioactive molecules.
For example, lipopolysaccharide (LPS) molecules from Gram-negative bacteria and recognized
by TLR4 cause secretion of cholecystokinin (CCK) through a mechanism dependent upon
MyD88 and protein kinase C (Bogunovic et al., 2007; Palazzo et al., 2007). The altered
intestinal barrier and subsequent translocation of bacteria or bacterial products
is now regarded as an important mechanism associated with obesity. Exposure of cultured
intestinal epithelial cells to commensal or probiotic microbial species results in
upregulation and increased phosphorylation of key tight-junction proteins (Ewaschuk
et al., 2008; Anderson et al., 2010). Additionally, some bacterial products play an
important role in regulating the intestinal barrier, with associated SCFAs capable
of differentially regulating prostaglandin production in myofibroblasts, thereby stimulating
mucin-2 expression in intestinal epithelial cells (Willemsen et al., 2003). Obesity
is related to the generation of low-grade, chronic inflammation (Lumeng and Saltiel,
2011), and gut-derived antigens are considered potential triggers for this activity.
Furthermore, dysbiosis of microbiota can influence the innate and adaptive immune
systems of the host via microbial cell components and metabolite signals.
Microbiota has effects beyond local tissue, with adipose tissue considered a primary
target. Obesity is characterized as a massive expansion of adipose tissue, and growing
evidence suggests that gut microbiota contribute to metabolic disorders through an
axis of communication with adipose tissue. LPS has been identified as a triggering
factor for insulin resistance in adipose tissue. In the trans-cellular pathway, LPS
is actively transported into the cell in proportion to the fat content of the chime,
followed by transfer to other lipoproteins by translocases. LPS-rich lipoproteins
are absorbed by especially large adipocytes exhibiting high metabolic activity (Hersoug
et al., 2016). Additionally, SCFAs produced by gut microbiota also participate in
insulin-mediated fat accumulation in adipocytes through activation of the SCFA receptors
G-protein coupled receptor (GPR)43 and GPR41 in adipocytes, which subsequently inhibits
lipolysis and encourages adipocyte differentiation (Kimura et al., 2013). Intriguingly,
MicroPET-CT results showed that microbiota depletion leads to increased glucose disposal
primarily in inguinal subcutaneous adipose tissue and perigonadal visceral adipose
tissue (Suarez-Zamorano et al., 2015), thereby stimulating energy expenditure through
thermogenesis. This process was largely dependent upon eosinophils and the type 2
cytokines interleukin (IL)-4, IL-13, and IL-5 through alternative activation of M2
macrophages. Specific metabolic effects of some genes in adipocytes are also largely
dependent upon altered microbiota composition. A recent study demonstrated that specific
deletion of the endocannabinoid system synthesizing enzyme in adipocytes (NAPE-PLD)
induced obesity and altered the browning program, with these changes partly mediated
by a shift in gut-microbiota composition. These findings support those from a previous
study showing that FMT was also capable of partially transferring a phenotype to GF
mice (Geurts et al., 2015).
The liver is continually exposed to gut-derived signals, including those originating
from bacterial components and products, through the receipt of ~70% of the blood supply
from the portal vein, which enables direct venous outflow from the intestines. Alteration
of gut commensal bacteria has consistently been associated with increased risk of
obesity related liver disease [e.g., nonalcoholic fatty liver disease (NAFLD)], with
a dysbiotic microbiome frequently observed among obese individuals with NAFLD (Turnbaugh
et al., 2009). NAFLD severity is associated with gut dysbiosis and a shift in the
metabolic function of gut microbiota, with Bacteroides abundance independently associated
with nonalcoholic steatohepatitis (NASH), and Ruminococcus abundance associated with
significant fibrosis (Boursier et al., 2016). GF mice colonized with intestinal bacteria
from HFD mice develop NAFLD and had display hepatic lipid levels similar to those
of donor mice, thereby implicating the gut microbiome in hepatic lipid accumulation
(Le Roy et al., 2013).
Multiple lines of evidence link dysbiosis to obesity related liver disease. NAFLD
presents with intestinal-bacterial overgrowth and enhanced intestinal permeability.
Following bacterial generation of LPS, NF-κB is stimulated to recruit inflammatory
cells, thereby promoting inflammation and fibrosis in advanced NAFLD (Elsharkawy and
Mann, 2007). LPS also activates the NLRP3 infammasome via TLR4 and TLR9, which play
an important role in fibrosis development in NAFLD (Wree et al., 2014). In addition
to direct interactions associated with gut-derived bacterial signals, certain metabolites
also play a role in NAFLD pathophysiology. Gut microbiota has profound effects on
bile-acid metabolism by promoting deconjugation, dehydrogenation and dehydroxylation
of primary bile acids. Additionally, alteration of the gut microbiome leads to changes
in the bile-acid pool, which affects the farnesoid X receptor (FXR) nuclear antagonist
involved in the regulation of bile acid, as well as lipid and glucose metabolism (Li
et al., 2013), and could cause metabolic dysfunction, including obesity and insulin
resistance. SCFAs lower hepatic fatty acid synthase activity and increase hepatic
lipid oxidation, with this shift associated with increased phosphorylation and activation
of adenosine monophosphate-activated protein kinase (AMPK) and its downstream target
acetyl-CoA carboxylase (den Besten et al., 2015). Fiaf is also involved in the mechanism
linking the microbiome to NAFLD, where dysbiotic microbiota inhibits Fiaf secretion
from intestinal cells and leads to activation of LPL, carbohydrate-responsive element
binding protein, (ChREBP) and sterol regulatory element-binding protein 1(SREBP-1),
and subsequent triglyceride accumulation in the liver (Backhed et al., 2004). Ethanol
is another bacterial product involved in NAFLD progression, with blood ethanol levels
statistically significantly increased in patients with NASH (Zhu et al., 2013) and
possibly related to a higher abundance of alcohol-producing Proteobacteria. Trimethylamine
N-oxide (TMAO) is a small, colorless amine oxide generated from choline by gut-microbial
metabolism, and its accumulation reduces bile-acid-synthetic enzymes (Cyp7a1 and Cyp27a1)
and bile-acid transporters (Oatp1, Oatp4, Mrp2 and Ntcp) in the liver (Koeth et al.,
2013). Additionally, patients with NAFLD have a higher level of Erysipelotrichia,
which are linked to choline metabolism (Spencer et al., 2011). Therefore, dysbiosis
in obesity is likely to impact metabolic homeostasis.
Similarly, the central nervous system receives constant neural and chemical input
from the gut and is responsible for integrating this information and generating appropriate
food-reward signaling to maintain homeostasis (Fetissov, 2017). Bacteria and their
metabolites might target the brain directly via vagal stimulation or indirectly through
immune-neuroendocrine mechanisms (Torres-Fuentes et al., 2017a). The vagal nerve transmits
information from enteral content to the nucleus tractus solitaries, where the information
is then distributed to the hypothalamus, which regulates appetite, food intake and
energy balance. Activation of the vagus nerve is partly dependent upon the secretion
of chemical signals, such as gut peptide YY (PYY), glucagon-like peptide 1 (GLP-1)
and CCK, by enteroendocrine cells. Additionally, several bacterial strains can modify
gut-hormone secretion (Balakumar et al., 2016), which can also be released into circulation
and thereby affect appetite and satiety via hypothalamic neuroendocrine pathways.
This effect is at least partly dependent upon microbiota-derived metabolites. For
example, lactate is the preferred substrate for neurons and contributes to postprandial
satiety. Moreover, lactate is capable of being abundantly produced in the gut by Lactobacilli,
Enterobacteriaceae and Bifidobacteria (Silberbauer et al., 2000). SCFAs not only serve
as an important energy source, but also act as chemical messengers or signaling molecules
through their ability to increase proglucagon and pro-PYY gene expression to increase
plasma GLP-1 and PYY levels and either inhibit ghrelin secretion (Nohr et al., 2013)
or regulate appetite by releasing it into circulation. However, the reported results
specific to this activity are inconsistent. For example, acetate, the main SFCA secreted
by intestinal bacteria, is taken up by the brain and plays a direct role in suppressing
appetite via central hypothalamic mechanisms (Frost et al., 2014). Another study reported
that increased production of acetate by altered gut microbiota leads to activation
of the parasympathetic nervous system accompanied by increased ghrelin secretion,
hyperphagia and obesity (Perry et al., 2016). Furthermore, gut bacteria can also affect
the central control of appetite by producing neuroactive metabolites, including serotonin
and γ-aminobutyric acid, because these neurotransmitters are involved in the normal
regulation of energy balance. Additionally, gut microbiota is associated with inflammation
via LPS, which leads to activation of immune cells (B cells or dendritic cells) and
cytokine production (Torres-Fuentes et al., 2017b).
Overall, two broad, but not mutually exclusive, mechanistic categories exist for the
effects of microbiota on metabolic disorders: 1) direct interaction of gut microbiota
with local tissue and 2) indirect interaction with distant organs through metabolic
signals. It is tempting to speculate that the effects of microbiota on metabolism-related
organs, whether capable of modulating inflammatory responses or regulating active
molecular signals, are fundamental elements in the process of obesity, which would
provide an environment factor as the cause of the complex pathology of obesity. There
is compelling evidence supporting modulation of microbiota to treat obesity and related
disorders.
Dietary intake appears to be a major regulator of the structure and function of gut
microbiota. Results show that carbohydrate restriction and diets rich in fiber and
vegetables are associated with health benefits due in part to microbial changes (Cotillard
et al., 2013; Mardinoglu et al., 2018). Administration of prebiotics, probiotics and
synbiotics have long been proposed as ways of modifying metabolic disorders, which
are largely dependent upon altered microbiota composition. Multi-strain probiotic
supplementation can reduce liver transaminases, tumor necrosis factor-α level and
insulin resistance (Sepideh et al., 2016). Additionally, probiotic Lactobacillus rhamnosus
GG is effective in the prevention of hepatic steatosis and injury partly through modulation
of hepatic AMPK activation (Zhang et al., 2015), and probiotic strain Bifidobacterium
animalis subsp. Lactis 420 supplementation reduces bacterial translocation of Gram-negative
bacteria from the Enterobacteriaceae group to normalize adipose-tissue inflammation
(Amar et al., 2011). Interventions with prebiotics can also modulate gut microbiota
and significantly reduce body weight, percent body fat, and desire for high-calorie
foods, as well as improve insulin sensitivity, low-grade chronic inflammation and
lipid metabolism (Dewulf et al., 2013; Hume et al., 2017; Nicolucci et al., 2017).
In addition to its effect on peripheral organs, prebiotic supplementation also improves
appetite control in children with obesity (Hume et al., 2017).
A rather harsh method of modulating microbial composition is FMT, which can alter
the entire microbial community. FMT is a way to normalize the composition and functionality
of gut microbiota by transferring an infusion of a fecal suspension from a healthy
individual to the gastrointestinal tract of another person. This method has now become
widely accepted as a highly successful rescue treatment for recurrent Clostridium
difficile infection (Drekonja et al., 2015). Related data concerning FMT as a treatment
for obesity and related metabolic disorders in humans are relatively sparse. Transplanting
fecal matter from lean donors into obese or individuals with metabolic syndromes was
recently examined. Although the results indicated no significant decrease in BMI at
6-weeks post-transplantation, there was a significant increase in insulin sensitivity
(Vrieze et al., 2012; Kootte et al., 2017). Additionally, loss of microbial diversity
is common in patients with obesity, and gut-microbial diversity was increased significantly
after FMT from a lean donor. Notably in this case, the number of butyrate-producing
bacteria was increased; however, whether enhanced diversity or changes in specific
bacterial species contribute to the effect of FMT remains unknown.
CONCLUSION
Considering the key role of gut microbiota in host metabolism, mechanistic investigations
of microbiota modulation have demonstrated its restorative potential for both gut-microbiota
composition and functionality. Therefore, such modulation represents a promising strategy
for compositional variations and a potential therapeutic target for the treatment
of obesity and other metabolic diseases. However, there remains considerable controversy
regarding the precise role of gut microbiota in obesity, and more interventional clinical
trials are critical for continued progress.