Protein Cell 2018, 9(5):397–403

https://doi.org/10.1007/s13238-018-0546-3 Protein & Cell

COMMENTARY
Insights into the role of gut microbiota
in obesity: pathogenesis, mechanisms,
and therapeutic perspectives
Lijuan Sun1,2, Lanjing Ma1, Yubo Ma3, Faming Zhang4, Changhai Zhao2, Yongzhan Nie1&
1
State Key Laboratory of Cancer Biology & Institute of Digestive Diseases Xijing Hospital, The Fourth Military Medical
University, Xi’an 710032, China
2
Department of Clinical Nutrition, Xi Jing Hospital, The Fourth Military Medical University, Xi’an 710032, China

Protein & Cell

3
Department of Dermatology and Venereology, Peking University First Hospital, Research Center for Medical Mycology,
Peking University, Beijing 100034, China
4
Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210001, China
& Correspondence: [email protected] (Y. Nie)

Concern about health risks associated with rising obesity detrimental to the onset of obesity. Therefore, the gut
has become nearly universal, with the mean body mass microbiome has been suggested as a driving force in the
index (BMI) and the prevalence of obese and overweight pathogenesis of obesity.
individuals increasing substantially worldwide during the Causal evidence linking intestinal microbiota to obesity
previous three decades. Unfortunately, prevention and mostly originates from animal studies. Germ free (GF) mice
treatment of obesity and related complications have proven are resistant to high-fat diet (HFD)-induced obesity, despite a
complex, and successful strategies to tackle this pathology higher food intake. Interestingly, administration of subthera-
remain limited. Epidemiological studies have highlighted peutic antibiotic therapy increased adiposity and metabo-
potential environmental exposures, including diet, energy lism-related hormone levels in young mice, with these
expenditure, early life influences, sleep deprivation, endo- changes altering the copies of key genes involved in the
crine disruptors, chronic inflammation, and microbiome sta- metabolism of carbohydrates to short-chain fatty acids
tus, contributing to higher risk of obesity (Franks and (SCFAs) and the regulation of hepatic metabolism of lipids
McCarthy, 2016). Among these, the microbiome has and cholesterol (Cho et al., 2012). Furthermore, colonization
received extensive attention during the previous decade. of GF mice with “obese microbiota” resulted in a significantly
Variation in gut microorganisms might play an important greater increase in total body fat than colonization with “lean
role in the pathogenesis of obesity. Although the composition microbiota” (Turnbaugh et al., 2006). Notably, GF mice that
of intestinal microbiota is highly diverse in healthy individu- received fecal microbiota transplantation (FMT) from an
als, those exhibiting overall adiposity, insulin resistance and obese donor gained more weight as compared with those
dyslipidemia are characterized by low bacterial richness (Le receiving it from a lean donor (Ridaura et al., 2013), with this
Chatelier et al., 2013). Moreover, composition of gut micro- result further accelerating the establishment of the causal
biota in obesity individuals differs from that in lean individu- role of gut microbiota in the development of obesity.
als, although inconsistent changes have been reported. Mechanisms by which gut microbiota promote metabolic
Bacteroidetes prevalence is lower in obese people, with this disturbances are not well understood. To date, leading the-
proportion increasing along with weight loss based on a low- ories about the mechanisms include changes in molecular
calorie diet (Ley et al., 2006a). Lactobacillus and Clostridium signaling chemicals released by bacteria in contact with local
species are associated with insulin resistance, with Lacto- tissue or distant organs (Schroeder and Backhed, 2016;
bacillus positively correlated with fasting glucose and HbA1c Meijnikman et al., 2017) (Fig. 1).
levels, whereas Clostridium showed a negative correlation Changes in gut microbiota perturb homeostatic interaction
with these parameters (Karlsson et al., 2013). These data between microbiota and the intestine and might contribute to
suggest that specific bacterial phyla, class, or species or metabolic disorders. Local contacts between microbiota and
bacterial metabolic activities could be beneficial or intestine cells determine which signals are sensed and

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 COMMENTARY Lijuan Sun et al.

Signals from gut microbiota to local tissue

Increased energy Reprogrammed Changed release of Increased intestinal Induced low-grade

harvested from diet gene in colon bioactive molecule permeability inflammation

Enteroendocrine cell

Firmicutes/Bacteroidetes Specific bacteria Bacterial component Dysbiosis

LPS SCFA LPS Bile acids SCFA Ethanol Choline Neuro- Lactate SCFA LPS
actives

Enteroendocrine cell
Fiaf
Protein & Cell

Ś ś Ŝ GLP-1 PYY CCK

Ś ś Ŝ ŝ Ş ş Ś
CD4 Ś
LPS-rich Vagal Ś ś
NKT afferent
lipoprotein
nerve
AMPK
TMAO Ś
CHREBP
GPR43 SREBP-1
Immune
GPR41 cells FXR

Ś Inflammation Ś Inflammation and fibrosis Ś Appetite changes

ś Macrophage recruitment ś Lipid and glucose metabolic disorders ś Nervous system inflammation
Ŝ Fat storage suppression Ŝ AMPK and ACC activation
ŝ CHREBP and SREBP activation
Ş Liver injury
ş Decreased VLDL

Signals from gut microbiota to distant organs

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.

presented and which reactions are subsequently initiated. belonging to the Bacteroidetes phylum and a proportional
Increased energy harvesting by obesity associated gut increase in members of the Firmicutes phylum, revealing an
microbiota is another possible explanation for obesity. The association with a higher presence of enzymes for complex
obese microbiome is typified by a reduced presence of taxa carbohydrate degradation and fermentation (Ley et al.,

398 © The Author(s) 2018

Gut microbiota and obesity COMMENTARY

2006b), which are related to elevated levels of energy har- mediated fat accumulation in adipocytes through activation
vesting from the diet (Jumpertz et al., 2011). Additionally, the of the SCFA receptors G-protein coupled receptor (GPR)43
gut microbiome can stimulate reprogramming of gene and GPR41 in adipocytes, which subsequently inhibits
expression in the colon (Qin et al., 2018). Fasting-induced lipolysis and encourages adipocyte differentiation (Kimura
adiposity factor (Fiaf; also known as angiopoietin-like protein et al., 2013). Intriguingly, MicroPET-CT results showed that
4), a circulating lipoprotein lipase inhibitor whose expression microbiota depletion leads to increased glucose disposal
is normally selectively suppressed in the gut epithelium by primarily in inguinal subcutaneous adipose tissue and
microbiota (Backhed et al., 2007), plays a central role in perigonadal visceral adipose tissue (Suarez-Zamorano
triglyceride metabolism (Kim et al., 2010) by inhibiting et al., 2015), thereby stimulating energy expenditure through
lipoprotein lipase (LPL) production in adipose tissue and thermogenesis. This process was largely dependent upon
modulating fatty acid oxidation. Some specific components eosinophils and the type 2 cytokines interleukin (IL)-4, IL-13,
of microbiota might suppress Fiaf in the intestinal epithelia and IL-5 through alternative activation of M2 macrophages.
and potentially stimulate host weight gain by impairing Specific metabolic effects of some genes in adipocytes are
triglyceride metabolism and promoting fat storage. also largely dependent upon altered microbiota composition.
Polypeptide hormones and other bioactive molecules A recent study demonstrated that specific deletion of the
released by enterochromaffin (EC) cells in the intestine are endocannabinoid system synthesizing enzyme in adipocytes
also involved in regulating food intake (Gribble and Reim- (NAPE-PLD) induced obesity and altered the browning

Protein & Cell

ann, 2016). Various Toll-like receptors (TLRs) expressed in program, with these changes partly mediated by a shift in
EC cells recognize different pathogen-associated molecular gut-microbiota composition. These findings support those
patterns and alter the release of polypeptide hormones and from a previous study showing that FMT was also capable of
other bioactive molecules. For example, lipopolysaccharide partially transferring a phenotype to GF mice (Geurts et al.,
(LPS) molecules from Gram-negative bacteria and recog- 2015).
nized by TLR4 cause secretion of cholecystokinin (CCK) The liver is continually exposed to gut-derived signals,
through a mechanism dependent upon MyD88 and protein including those originating from bacterial components and
kinase C (Bogunovic et al., 2007; Palazzo et al., 2007). The products, through the receipt of ∼70% of the blood supply
altered intestinal barrier and subsequent translocation of from the portal vein, which enables direct venous outflow
bacteria or bacterial products is now regarded as an impor- from the intestines. Alteration of gut commensal bacteria has
tant mechanism associated with obesity. Exposure of cul- consistently been associated with increased risk of obesity
tured intestinal epithelial cells to commensal or probiotic related liver disease [e.g., nonalcoholic fatty liver disease
microbial species results in upregulation and increased (NAFLD)], with a dysbiotic microbiome frequently observed
phosphorylation of key tight-junction proteins (Ewaschuk among obese individuals with NAFLD (Turnbaugh et al.,
et al., 2008; Anderson et al., 2010). Additionally, some 2009). NAFLD severity is associated with gut dysbiosis and
bacterial products play an important role in regulating the a shift in the metabolic function of gut microbiota, with Bac-
intestinal barrier, with associated SCFAs capable of differ- teroides abundance independently associated with nonal-
entially regulating prostaglandin production in myofibrob- coholic steatohepatitis (NASH), and Ruminococcus
lasts, thereby stimulating mucin-2 expression in intestinal abundance associated with significant fibrosis (Boursier
epithelial cells (Willemsen et al., 2003). Obesity is related to et al., 2016). GF mice colonized with intestinal bacteria from
the generation of low-grade, chronic inflammation (Lumeng HFD mice develop NAFLD and had display hepatic lipid
and Saltiel, 2011), and gut-derived antigens are considered levels similar to those of donor mice, thereby implicating the
potential triggers for this activity. Furthermore, dysbiosis of gut microbiome in hepatic lipid accumulation (Le Roy et al.,
microbiota can influence the innate and adaptive immune 2013).
systems of the host via microbial cell components and Multiple lines of evidence link dysbiosis to obesity related
metabolite signals. liver disease. NAFLD presents with intestinal-bacterial
Microbiota has effects beyond local tissue, with adipose overgrowth and enhanced intestinal permeability. Following
tissue considered a primary target. Obesity is characterized bacterial generation of LPS, NF-κB is stimulated to recruit
as a massive expansion of adipose tissue, and growing inflammatory cells, thereby promoting inflammation and
evidence suggests that gut microbiota contribute to meta- fibrosis in advanced NAFLD (Elsharkawy and Mann, 2007).
bolic disorders through an axis of communication with adi- LPS also activates the NLRP3 infammasome via TLR4 and
pose tissue. LPS has been identified as a triggering factor for TLR9, which play an important role in fibrosis development in
insulin resistance in adipose tissue. In the trans-cellular NAFLD (Wree et al., 2014). In addition to direct interactions
pathway, LPS is actively transported into the cell in propor- associated with gut-derived bacterial signals, certain
tion to the fat content of the chime, followed by transfer to metabolites also play a role in NAFLD pathophysiology. Gut
other lipoproteins by translocases. LPS-rich lipoproteins are microbiota has profound effects on bile-acid metabolism by
absorbed by especially large adipocytes exhibiting high promoting deconjugation, dehydrogenation and dehydroxy-
metabolic activity (Hersoug et al., 2016). Additionally, SCFAs lation of primary bile acids. Additionally, alteration of the gut
produced by gut microbiota also participate in insulin- microbiome leads to changes in the bile-acid pool, which

© The Author(s) 2018 399

 COMMENTARY Lijuan Sun et al.

affects the farnesoid X receptor (FXR) nuclear antagonist PYY levels and either inhibit ghrelin secretion (Nohr et al.,
involved in the regulation of bile acid, as well as lipid and 2013) or regulate appetite by releasing it into circulation.
glucose metabolism (Li et al., 2013), and could cause However, the reported results specific to this activity are
metabolic dysfunction, including obesity and insulin resis- inconsistent. For example, acetate, the main SFCA secreted
tance. SCFAs lower hepatic fatty acid synthase activity and by intestinal bacteria, is taken up by the brain and plays a
increase hepatic lipid oxidation, with this shift associated direct role in suppressing appetite via central hypothalamic
with increased phosphorylation and activation of adenosine mechanisms (Frost et al., 2014). Another study reported that
monophosphate-activated protein kinase (AMPK) and its increased production of acetate by altered gut microbiota
downstream target acetyl-CoA carboxylase (den Besten leads to activation of the parasympathetic nervous system
et al., 2015). Fiaf is also involved in the mechanism linking accompanied by increased ghrelin secretion, hyperphagia
the microbiome to NAFLD, where dysbiotic microbiota inhi- and obesity (Perry et al., 2016). Furthermore, gut bacteria
bits Fiaf secretion from intestinal cells and leads to activation can also affect the central control of appetite by producing
of LPL, carbohydrate-responsive element binding protein, neuroactive metabolites, including serotonin and γ-
(ChREBP) and sterol regulatory element-binding protein 1 aminobutyric acid, because these neurotransmitters are
(SREBP-1), and subsequent triglyceride accumulation in the involved in the normal regulation of energy balance. Addi-
liver (Backhed et al., 2004). Ethanol is another bacterial tionally, gut microbiota is associated with inflammation via
product involved in NAFLD progression, with blood ethanol LPS, which leads to activation of immune cells (B cells or
Protein & Cell

levels statistically significantly increased in patients with dendritic cells) and cytokine production (Torres-Fuentes
NASH (Zhu et al., 2013) and possibly related to a higher et al., 2017b).
abundance of alcohol-producing Proteobacteria. Trimethy- Overall, two broad, but not mutually exclusive, mecha-
lamine N-oxide (TMAO) is a small, colorless amine oxide nistic categories exist for the effects of microbiota on
generated from choline by gut-microbial metabolism, and its metabolic disorders: 1) direct interaction of gut microbiota
accumulation reduces bile-acid-synthetic enzymes (Cyp7a1 with local tissue and 2) indirect interaction with distant
and Cyp27a1) and bile-acid transporters (Oatp1, Oatp4, organs through metabolic signals. It is tempting to specu-
Mrp2 and Ntcp) in the liver (Koeth et al., 2013). Additionally, late that the effects of microbiota on metabolism-related
patients with NAFLD have a higher level of Erysipelotrichia, organs, whether capable of modulating inflammatory
which are linked to choline metabolism (Spencer et al., responses or regulating active molecular signals, are fun-
2011). Therefore, dysbiosis in obesity is likely to impact damental elements in the process of obesity, which would
metabolic homeostasis. provide an environment factor as the cause of the complex
Similarly, the central nervous system receives constant pathology of obesity. There is compelling evidence sup-
neural and chemical input from the gut and is responsible for porting modulation of microbiota to treat obesity and related
integrating this information and generating appropriate food- disorders.
reward signaling to maintain homeostasis (Fetissov, 2017). Dietary intake appears to be a major regulator of the
Bacteria and their metabolites might target the brain directly structure and function of gut microbiota. Results show that
via vagal stimulation or indirectly through immune-neuroen- carbohydrate restriction and diets rich in fiber and vegeta-
docrine mechanisms (Torres-Fuentes et al., 2017a). The bles are associated with health benefits due in part to
vagal nerve transmits information from enteral content to the microbial changes (Cotillard et al., 2013; Mardinoglu et al.,
nucleus tractus solitaries, where the information is then 2018). Administration of prebiotics, probiotics and synbiotics
distributed to the hypothalamus, which regulates appetite, have long been proposed as ways of modifying metabolic
food intake and energy balance. Activation of the vagus disorders, which are largely dependent upon altered micro-
nerve is partly dependent upon the secretion of chemical biota composition. Multi-strain probiotic supplementation can
signals, such as gut peptide YY (PYY), glucagon-like peptide reduce liver transaminases, tumor necrosis factor-α level
1 (GLP-1) and CCK, by enteroendocrine cells. Additionally, and insulin resistance (Sepideh et al., 2016). Additionally,
several bacterial strains can modify gut-hormone secretion probiotic Lactobacillus rhamnosus GG is effective in the
(Balakumar et al., 2016), which can also be released into prevention of hepatic steatosis and injury partly through
circulation and thereby affect appetite and satiety via modulation of hepatic AMPK activation (Zhang et al., 2015),
hypothalamic neuroendocrine pathways. This effect is at and probiotic strain Bifidobacterium animalis subsp. Lactis
least partly dependent upon microbiota-derived metabolites. 420 supplementation reduces bacterial translocation of
For example, lactate is the preferred substrate for neurons Gram-negative bacteria from the Enterobacteriaceae group
and contributes to postprandial satiety. Moreover, lactate is to normalize adipose-tissue inflammation (Amar et al., 2011).
capable of being abundantly produced in the gut by Lacto- Interventions with prebiotics can also modulate gut micro-
bacilli, Enterobacteriaceae and Bifidobacteria (Silberbauer biota and significantly reduce body weight, percent body fat,
et al., 2000). SCFAs not only serve as an important energy and desire for high-calorie foods, as well as improve insulin
source, but also act as chemical messengers or signaling sensitivity, low-grade chronic inflammation and lipid meta-
molecules through their ability to increase proglucagon and bolism (Dewulf et al., 2013; Hume et al., 2017; Nicolucci
pro-PYY gene expression to increase plasma GLP-1 and et al., 2017). In addition to its effect on peripheral organs,

400 © The Author(s) 2018

Gut microbiota and obesity COMMENTARY

prebiotic supplementation also improves appetite control in licenses/by/4.0/), which permits unrestricted use, distribution, and
children with obesity (Hume et al., 2017). reproduction in any medium, provided you give appropriate credit to
A rather harsh method of modulating microbial composi- the original author(s) and the source, provide a link to the Creative
tion is FMT, which can alter the entire microbial community. Commons license, and indicate if changes were made.
FMT is a way to normalize the composition and functionality
of gut microbiota by transferring an infusion of a fecal sus-
pension from a healthy individual to the gastrointestinal tract ABBREVIATIONS
of another person. This method has now become widely ACC, acetyl CoA carboxylase; AMPK, adenosine monophosphate
accepted as a highly successful rescue treatment for activated protein kinase; BMI, body mass index; CCK,
recurrent Clostridium difficile infection (Drekonja et al., cholecystokinin; ChREBP, carbohydrate responsive element
2015). Related data concerning FMT as a treatment for binding protein; CNS, central nervous system; EC,
obesity and related metabolic disorders in humans are rel- enterochromaffin; FAS, fatty acid synthase; Fiaf, fasting-induced
atively sparse. Transplanting fecal matter from lean donors adiposity factor; FMT, fecal microbiota transplantation; FXR,
into obese or individuals with metabolic syndromes was farnesoid X receptor; GABA, γ-aminobutyric acid; GF, germ free;
recently examined. Although the results indicated no signif- GI, gastrointestinal; GLP-1, glucagon like peptide 1; GPR, G-protein
icant decrease in BMI at 6-weeks post-transplantation, there coupled receptor; HFD, high-fat diet; LPL, inhibiting lipoprotein
was a significant increase in insulin sensitivity (Vrieze et al., lipase; LPS, lipopolysaccharides; NAFLD, non-alcoholic fatty liver

Protein & Cell

2012; Kootte et al., 2017). Additionally, loss of microbial disease; NASH, nonalcoholic steatohepatitis; NTS, nucleus tractus
diversity is common in patients with obesity, and gut-micro- solitaries; PYY, peptide YY; SCFA, short-chain fatty acids; SREBP-1,
bial diversity was increased significantly after FMT from a sterol regulatory element-binding protein 1; TLRs, Toll-like receptors.
lean donor. Notably in this case, the number of butyrate-
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