World Journal of

WJ G Gastroenterology
Submit a Manuscript: https://www.f6publishing.com World J Gastroenterol 2021 July 7; 27(25): 3837-3850

DOI: 10.3748/wjg.v27.i25.3837 ISSN 1007-9327 (print) ISSN 2219-2840 (online)

MINIREVIEWS

Gut microbiota in obesity

Bing-Nan Liu, Xiao-Tong Liu, Zi-Han Liang, Ji-Hui Wang

ORCID number: Bing-Nan Liu 0000- Bing-Nan Liu, Xiao-Tong Liu, Zi-Han Liang, Ji-Hui Wang, School of Bioengineering, Dalian
0001-6850-8466; Xiao-Tong Liu Polytechnic University, Dalian 116034, Liaoning Province, China
0000-0002-7236-6226; Zi-Han Liang
0000-0001-6902-0358; Ji-Hui Wang Ji-Hui Wang, Engineering Research Center of Health Food Design & Nutrition Regulation,
0000-0002-6363-0769. Dongguan University of Technology, Dongguan 523808, Guangdong Province, China

Author contributions: Liu BN Corresponding author: Ji-Hui Wang, PhD, Professor, School of Bioengineering, Dalian
wrote the paper; Liu XT, Liang ZH, Polytechnic University, No. 1 Qinggongyuan, Dalian 116034, Liaoning Province, China.
and Wang JH collected the data; all [email protected]
authors have read and approved
the final manuscript.
Abstract
Supported by The Dalian Science
Obesity is a major global health problem determined by heredity and environ-
and Technology Bureau, No.
ment, and its incidence is increasing yearly. In recent years, increasing evidence
2019RQ099; and the Department of
linking obesity to the gut microbiota has been reported. Gut microbiota manage-
Education of Liaoning Province,
ment has become a new method of obesity treatment. However, the complex
No. J2020097.
interactions among genetics, environment, the gut microbiota, and obesity remain
Conflict-of-interest statement: The poorly understood. In this review, we summarize the characteristics of the gut
authors declare no conflicts of microbiota in obesity, the mechanism of obesity induced by the gut microbiota,
interest for this article. and the influence of genetic and environmental factors on the gut microbiota and
obesity to provide support for understanding the complex relationship between
Open-Access: This article is an obesity and microbiota. At the same time, the prospect of obesity research related
open-access article that was to the gut microbiota is proposed.
selected by an in-house editor and
fully peer-reviewed by external
Key Words: Gut microbiota; Obesity; Dysbiosis; Genetics; Ecology
reviewers. It is distributed in
accordance with the Creative
©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
Commons Attribution
NonCommercial (CC BY-NC 4.0)
license, which permits others to
Core Tip: Obesity is closely related to the gut microbiota. The study of the gut
distribute, remix, adapt, build
microbiome provides a basis for the reconstruction of the gut microbiota of obese
upon this work non-commercially, patients. Here, we discuss the characteristics of the gut microbiota in obesity, the
and license their derivative works mechanism by which the gut microbiota induces obesity, and the relationships between
on different terms, provided the genetic and environmental factors and the gut microbiota in obesity.
original work is properly cited and
the use is non-commercial. See: htt
p://creativecommons.org/License
Citation: Liu BN, Liu XT, Liang ZH, Wang JH. Gut microbiota in obesity. World J
s/by-nc/4.0/
Gastroenterol 2021; 27(25): 3837-3850
Manuscript source: Invited URL: https://www.wjgnet.com/1007-9327/full/v27/i25/3837.htm
manuscript DOI: https://dx.doi.org/10.3748/wjg.v27.i25.3837

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Liu BN et al. Gut microbiota in obesity

Specialty type: Gastroenterology INTRODUCTION

and hepatology
Obesity is a complex metabolic disorder caused by a variety of genetic and nongenetic
Country/Territory of origin: China factors (such as environmental factors). The World Health Organization defines
obesity as having a body mass index (BMI) greater than 30, but the definition varies
Peer-review report’s scientific from country to country. In China, for example, a BMI of 28 or greater is considered
quality classification obese. A comprehensive analysis shows that approximately one-third of the world’s
Grade A (Excellent): 0 population are overweight, and approximately 10% are obese[1]. It is predicted that by
2030, the number of obese people worldwide will reach 1.12 billion[2]. The health risk
Grade B (Very good): B, B
of obesity has caused widespread concern and has become an important global health
Grade C (Good): C, C
problem. Obesity not only manifests as changes in appearance but is also associated
Grade D (Fair): 0
with lipid and glucose metabolism disorders, chronic inflammation, oxidative stress,
Grade E (Poor): 0
and an increased risk of a variety of diseases, most notably cardiovascular disease,
diabetes, and cancer[3,4]. In recent years, increasing evidence has shown that an
Received: March 11, 2021
imbalance in the gut microbiota may be a factor leading to obesity[5,6].
Peer-review started: March 11, 2021 Up to 100 trillion symbiotic microbes live in the gut, called the gut microbiota,
First decision: April 5, 2021 which comprises 10 times the number of cells in the body itself[7]. The gut microbiota
Revised: April 14, 2021 relies on food residues that the human body does not digest, mucus secreted by the
Accepted: May 21, 2021 gut, and dead cells that are shed as nutrients to maintain its high population levels[8].
Article in press: May 21, 2021 The active gut microbiota will produce a large number of physiologically active
Published online: July 7, 2021 substances, including short-chain fatty acids, vitamins, and health-beneficial products
such as anti-inflammatory, analgesic, and antioxidant products, along with potentially
P-Reviewer: Jin W, Shimizu Y, harmful products such as neurotoxins, carcinogens, and immunotoxins[9,10]. These
Soto-Montenegro M products can enter the blood, directly regulate the expression of genes, and affect
S-Editor: Zhang H human immune and metabolic processes. Therefore, a healthy gut microbiota is
essential for maintaining the body’s metabolism and energy balance. An imbalance in
L-Editor: Wang TQ
the gut microbiota can cause metabolic disorders and increase central appetite, leading
P-Editor: Yuan YY to obesity. This article reviews the research progress of the relationship between the
gut microbiota and obesity.

LITERATURE SEARCH
PubMed (https://pubmed.ncbi.nlm.nih.gov/) was used for search with the following
keywords: Obesity, gut microbiota, dysbiosis, energy absorption, appetite, fat storage,
chronic inflammation, and circadian rhythm. More than 4000 published papers inclu-
ding 178 clinical trial related to gut microbiota in obesity from 2000 through 2021 have
been searched.

RESULTS
After the search, we summarize some characteristics of the gut microbiota of obese
patients. Many results suggest that an increased Firmicutes/Bacteroidetes ratio at the
phylum level is an important feature of the gut microbiota in obesity. The family
Christensenellaceae and the genera Methanobacteriales, Lactobacillus, Bifidobacteria, and
Akkermansia are usually considered as probiotics, and their relative abundance is often
inversely associated with obesity. Gut microbiota regulates obesity by regulating
energy absorption, central appetite, fat storage, chronic inflammation, and circadian
rhythms. Finally, the effects of genetic and environmental factors on gut microbiota in
obesity are discussed.

THE HEALTHY GUT MICROBIOTA

The development of the Human Microbiome Project has promoted the in-depth study
of the gut microbiota[11,12]. With the application of metagenomic and 16S ribosomal
RNA gene sequencing, the diversity of the gut ecosystem has been widely studied,
which enables us to accurately understand the composition and function of the gut
microbiota[13]. So far, the gut microbes of 6457 taxa have been collected in the
gutMEGA database[14]. The normal gut microbiota of the human body is mainly
composed of Firmicutes, Bacteroides, Proteus, Actinomycetes, Fusobacteria, and Verrucomi-
crobia, among which Firmicutes and Bacteroides dominate[15]. The core functions of a
healthy gut microbiota include the biodegradation of polysaccharides, the production

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 Liu BN et al. Gut microbiota in obesity

of short-chain fatty acids, the enrichment of specific lipopolysaccharides, and the

production of vitamins and essential amino acids[16]. A healthy gut microbiota is
generally highly diverse; conversely, the relative lack of diversity in the gut microbiota
leads to diseases such as obesity[17]. Another sign of a healthy gut microbiota is
dynamic equilibrium, which refers to its ability to resist perturbation and return to a
healthy state, such as with antibiotic treatment[18]. Therefore, changes in the structure
and metabolism of the gut microbiota will affect the body’s physiological processes,
such as nutrient absorption and energy metabolism.

ASSOCIATION OF THE GUT MICROBIOTA WITH OBESITY

The hypothesis that the gut microbiota may be a relevant environmental factor in
obesity has led to the study of the gut microbiomes of obese individuals. The first
evidence for a link between the gut microbiota and obesity was from studies of germ-
free mice. Transplanting gut microbes from conventionally raised mice into germ-free
mice increased the transplants’ fat content and insulin resistance levels even with
reduced food intake, which proved that gut microbes can increase the accumulation of
adipose tissue in the host[19]. Furthermore, 16S rRNA gene sequencing showed that
obesity may be associated with two dominant bacterial phyla: Firmicutes and
Bacteroidetes. The gut microbiota of obese mice showed a 50% decrease in the
abundance of Bacteroidetes and a proportional increase in Firmicutes[20]. Turnbaugh
et al[21] further confirmed that the Firmicutes/Bacteroidetes ratio increased signi-
ficantly in obese mice and proved that the capacity of the microbiota in obese mice to
harvest energy from the diet was stronger. Similar phenomena occur in humans; for
example, the proportion of Firmicutes in the gut of obese children was increased, and
the proportion of Bacteroidetes was decreased[22]. A study of the Ukrainian popu-
lation found that the Firmicutes/Bacteroidetes ratio increased with increasing BMI
[23]. However, some other studies have found opposite results. Zhang et al[24] found
that the difference in the abundance of Bacteroidetes was not significant between obese
and normal people. A study comparing the gut microbiota of obese and healthy peo-
ple based on the public database of the intestinal program in the United States analy-
zed the gut microbiota of 1655 healthy and 898 obese adults and found that the ratio of
Firmicutes/Bacteroidetes in obese people was relatively low[25]. Therefore, more
research is needed to explore the relationship between the gut microbiota and obesity.
Other works have associated obesity with specific bacteria, such as the family
Christensenellaceae and the genera Methanobacteriales, Lactobacillus, Bifidobacteria, and
Akkermansia. Recently, the family Christensenellaceae was found to be associated with
weight loss, and its relative abundance was inversely related to host BMI[26].
Akkermansia muciniphila is a key bacterium for weight loss. Supplementation with A.
muciniphila improves metabolic parameters in overweight and obese subjects[27].
Lactobacillus and Bifidobacterium are traditional probiotics that play an important role in
the balance of the human intestinal microecology. Crovesy et al[28] summarized the
effect of Lactobacillus on body weight in overweight subjects and found that the
beneficial effects were species specific. The abundance of Lactobacillus paracasei (L.
paracasei) was negatively correlated with obesity, while the abundances of L. reuteri
and L. gasseri were significantly correlated with obesity. At present, evidence of
Bifidobacterium resistance to obesity has been obtained from animal experiments.
Following administration of Bifidobacterium in animal models of diet-induced obesity,
it also showed a strain-dependent effect on obesity[29]. However, reduced Bifidobac-
terium abundance in the gut is associated with obesity[30]. Million et al[31] found that
M. smithii and B. animalis were associated with normal weight, while L. reuteri was
associated with obesity. These findings suggest that obesity-related microorganisms
are species specific and that bacteria in the same genus may have opposite effects,
which may be related to the complex metabolic mechanism of obesity.
The persons with obesity can be divided into two different types: Subcutaneous
obesity and visceral obesity. As mentioned above, an elevated Firmicutes/Bac-
teroidetes ratio is a biomarker for obesity. However, the relative abundance of
Firmutes in morbid obesity is positively correlated with brown adipocytes markers in
subcutaneous adipose tissue, but not in visceral adipose tissue[32]. The browning of
the white adipose tissue is conducive to maintaining a relatively healthy obesity
phenotype, suggesting that the higher relative abundance of Firmutes may be
beneficial for subcutaneous obesity. In an experiment of rapid weight loss through a
very low calorie diet in obese postmenopausal women, a decrease abundance of
Roseburia and increased Christensenellaceae (unknown genus) were found to be

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Liu BN et al. Gut microbiota in obesity

positively correlated with several gene expression pathways, such as protein-amino

acid N-glycation, in subcutaneous adipose tissue[33]. Probiotics play a positive role in
visceral obesity. Increased Akkermansia population reduced body weight and visceral
obesity in mice fed a high-fat/high-sugar diet[34]. The probiotic mixture including L.
acidophilus, L. rhamnosus, L. paracasei, Pediococcus pentosaceus, B. lactis, and B. breve signi-
ficantly reduced BMI and intrahepatic fat fraction in patients with nonalcoholic fatty
liver disease after 12 wk of administration. Except L. paracasei, the abundance of the
other five probiotics increased in the gut of the probiotic mixture group[35]. Tavella et
al[36] proposed that the relevance of large numbers of Christensenellaceae, Porphyromon-
adaceae and Rikenellaceae in the elderly gut microbiota contributed to the reduction of
visceral adipose tissue. Due to the lack of studies on gut microbiota specifically
targeting subcutaneous obesity and visceral obesity, further studies are needed to
determine whether there are significant differences in gut microbiota characteristics
between patients with subcutaneous obesity and visceral obesity.
From the above analysis, the role of microorganisms in obesity is strain specific, as
there are both beneficial and harmful bacteria within the same taxon. Therefore, it is
difficult to classify obesity-related bacterial communities according to their taxonomic
relationships. Recent studies have introduced the concept of a ‘guild’ into the study of
the gut microbiota, defining a group of microorganisms that utilize similar resources
or perform the same biological function as the same guild to identify potential clusters
associated with specific disease phenotypes and identify candidate gut microbes that
may contribute to human health and disease[37]. Using a clinical study of genetically
obese children, the researchers found that the abundance of one strain of E. coli
increased sharply after 30 d of eating a diet rich in nondigested carbohydrates, while
the abundance levels of the other four strains decreased[37]. Therefore, guilds, as an
important form of intermember organization in ecology, can better reflect the changes
in specific responses of strains.
The diversity of the gut microbiota is another important factor related to obesity.
Most studies have shown that the diversity and richness of the gut microbiome are
reduced in obese subjects[38-40]. Wu et al[25] found that the α-diversity of obese
people was significantly lower than that of healthy people, but there was no significant
difference in the structure of the gut microbiota (β-diversity) between them. However,
some studies believed that there was not necessarily a correlation between the
diversity of the gut microbiota and diseases[41]. Strict statistical analysis showed that
only in approximately 1/3 of the cases was there a significant relationship between
bacterial diversity and “microbiota-related diseases”. Since bacterial ecosystems may
possess a considerable degree of stability (including resistance to disease), the
impression seems to be that bacterial diversity is closely related to disease occurrence
and progression[41]. Obesity, as a flora-related disease without specific pathogens,
may be directly related to the dysbiosis of the bacterial ecosystem. Therefore, in the
face of the dilemma of diversity research, ecological theory is needed for guidance. The
association between gut microbiomes and obesity has been summarized in Table 1.

OBESITY MECHANISMS INDUCED BY THE GUT MICROBIOTA

Energy absorption
Studies have found that genetically obese mice consume more carbohydrates and
protein through the gut microbiota to provide energy for the host[42,43]. In animal
experiments, it was found that in the case of no differences in diet or weight of the
mice, the total body fat of the germ-free mice colonized by the ‘obese microbiota’
increased significantly compared with those colonized by the ‘lean microbiota’[21].
This finding indicates that the obese-type gut microbiota has an increased ability to
absorb energy from the diet. Multiomics analysis showed increased lipid absorption in
obese hosts. Colonization of Clostridia in germ-free mice downregulated the genes that
control lipid absorption[44]. Therefore, the gut microbiota of obese patients can
promote the absorption of energy, resulting in excessive accumulation of energy and
increased weight gain.
The gut microbiota ferments hard-to-digest carbohydrates into short-chain fatty
acids (SCFAs), which are either absorbed by the gut or excreted in feces. SCFAs are
crucial for energy homeostasis regulation[45]. SCFAs are composed mainly of acetate,
propionate, and butyrate. Acetate can produce beneficial effects on the energy
metabolism of the host by secreting glucagon-like peptide-1, peptide YY, and other
intestinal hormones, reduce systemic lipolysis and proinflammatory cytokine levels,
and increase energy consumption and lipid oxidation[46]. Propionate promotes

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Table 1 Association between gut microbiomes and obesity

Preclinical or
Microbiota characteristics in obesity Study subjects Ref.
clinical
Firmicutes/Bacteroidetes ratio increased Preclinical Mice Ley et al[20], Turnbaugh et
al[21]

Clinical Childhood Indiani et al[22]

Clinical Adult ukrainian Koliada et al[23]

population

The relative abundance of Christensenellaceae was inversely related to Clinical Human Waters et al[26]
host BMI
Clinical Postmenopausal women Alemán et al[33]

Clinical Italian elderly Tavella et al[36]

Increased Akkermansia population reduced body weight Clinical Human Depommier et al[27]

Preclinical Mice Anhêet al[34]

Lactobacillus paracasei decreased, while Lactobacillus reuteri and Lactobacillus Clinical Human Crovesy et al[28], Million et
gasseri increased al[31]

Bifidobacteria reduced Preclinical Rats Waldram et al[30]

Methanobacteriales smithii and Bifidobacterium were associated with normal Clinical Human Million et al[31]
weight

BMI: Body mass index.

intestinal lipolysis and energy homeostasis in mice through the AMPK/LSD1 pathway
[47]. Butyrate is the colon’s main energy source, and intestinal epithelial cells derive
most of their energy from the oxidation of butyrate. The increase in butyrate-
producing bacteria in the gut microbiota increases the production of butyrate, thereby
improving lipid metabolism through the butyrate-SESN2/CRTC2 pathway[48].
However, excessive butyrate may reduce the proportion of probiotics and reverse the
metabolic effects[48]. In recent years, SCFAs have attracted special attention due to
their beneficial effects on intestinal homeostasis and energy metabolism, but their role
in obesity remains controversial. Higher concentrations of fecal SCFAs are associated
with gut permeability, metabolic disorder markers, obesity, and hypertension[49].
Teixeira et al[50] found that fecal SCFAs in women were positively correlated with
obesity, waist circumference, and other indicators of metabolic syndrome. Overall,
SCFAs seem to be a double-edged sword. Although they can protect the host from
diet-induced obesity, excessive SCFAs provide extra energy for the host, thus promo-
ting obesity.

Central appetite
In recent years, the microbiota has emerged as one of the key regulators of gut-brain
function. This gut-brain axis has received increasing attention in the study of the
biological and physiological bases of obesity and its related diseases. The microbiota
and the brain communicate with each other through a variety of pathways, including
endocrine, immune, and neural pathways[51]. The gut microbiota affects the host’s
central nervous system through the gut-brain axis. The central nervous system can also
affect the composition and structure of the gut microbiota. The gut microbiota
influences food intake by regulating brain function in a number of ways, such as by
contributing to the production of neuromodulators, such as serotonin, which plays an
important role in regulating gastrointestinal function[52]. Lactate produced by Lactoba-
cillus and Bifidobacterium, which acts as a substrate for neuron cells, can prolong satiety
after a meal[53]. The gut microbiota also participates in the gut-brain axis by regula-
ting gut hormones secreted by enteroendocrine cells. Peptide YY, pancreatic poly-
peptide, and glucagon-like peptide-1 (GLP-1) are gut-brain peptides that play impor-
tant roles in information communication of the gut-brain axis. Peptide YY and pancre-
atic polypeptide are anorexia hormones secreted by the gut. GLP-1 lowers glucagon
levels, slows gastric emptying, stimulates insulin synthesis, and reduces food intake
[54,55]. Studies have found that the levels of peptide YY and GLP-1 in obese patients
are significantly decreased. However, after fat reduction surgery, the levels of peptide
YY and GLP-1 gradually increase[56]. Schéle et al[57] compared the gene expression

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Liu BN et al. Gut microbiota in obesity

levels of food intake-regulating neuropeptides in germ-free and conventionally raised

mice and found that the gut microbiota decreased the expression of two genes enco-
ding the body fat-inhibiting neuropeptides Gcg and Bdnf, which may contribute to the
induction of fat mass by the gut microbiota. The gut microbiota and its metabolites
have been shown to stimulate gut satiety. This short-term regulation of gut satiety,
which is associated with bacterial growth, can be combined with long-term appetite
regulation controlled by neuropeptide energy circuits in the hypothalamus[58].

Fat storage
In 2004, researchers reported the ability of the gut microbiota to regulate fat storage
[19]. The gut microbiota increases the absorption of glucose in the host’s intestine and
the content of glucose in the serum, thereby increasing the expression levels of two
basic transcription factors, ChREBP (carbohydrate response element binding protein)
and SREBP-1 (sterol regulatory element binding protein), which induce fat synthesis in
the liver. Lipoprotein lipase (LPL) helps triglycerides enter the circulatory system from
the liver, where they are absorbed by fat cells. Intestinal epithelial cells can produce
Fiaf, an inhibitor of LPL. Fiaf is selectively inhibited in normal mouse intestinal
epithelial cells, thereby increasing the host’s energy storage. Aronsson et al[59] found
that L. paracasei regulated ANGPTL4, a central player in fat storage regulation, using a
mouse model with high-fat diet-induced obesity. L. paracasei could induce the
expression of ANGPTL4, partly through the peroxisomal proliferator-activated
receptors α and γ. ANGPTL4 inhibited LPL, leading to decreased fat storage. L.
paracasei-colonized mice resisted high-fat diet-induced obesity[60]. In vitro, L. paracasei
inhibits the Akt/mTOR pathway, indicating that several regulatory pathways are
involved in different intracellular lipid accumulations mediated by L. paracasei.

Chronic inflammation
Chronic inflammation is one of the characteristics of metabolic disorders such as
obesity[61]. Evidence shows that these disorders are characterized by the gut micro-
biota and its metabolites crossing the intestinal barrier, affecting various metabolic
organs, such as the liver and adipose tissue, leading to chronic inflammation[62].
Through fecal microbiota transplantation, the microbiota of normal mice was trans-
planted to chronic colitis mice. Fecal microbiota transplantation could reduce colitis in
mice with chronic intestinal inflammation by regulating the expression of proinflam-
matory genes, antimicrobial peptides and mucin[63]. Lipopolysaccharide (LPS), an
endotoxin, has been shown to be expressed at elevated levels in obesity and adipose
tissue inflammation[64]. LPS binds to Toll-like receptor 4 on immune cells, thereby
activating a proinflammatory cascade in the gut[65]. Studies have shown that in-
creased levels of butyrate-producing Ruminococcaceae and Lachnospiraceae lead to
reduced levels of members of the LPS family S247, thereby reducing chronic low-grade
inflammation[66]. The gut microbiota can also help prevent high-fat diet-induced
intestinal barrier dysfunction by inhibiting cannabinoid receptor type 1[66]. The
endocannabinoid system is a major regulator of fat synthesis in the gut and fat cells,
and its activation can increase appetite and food intake. In addition, the effects of the
consumption of antibiotics on the microbiota are sufficient to block the obesity
protection phenotype, further indicating the roles of the microbiota in chronic inflam-
mation and obesity.
SCFAs play a key role in the interaction between the gut microbiota and the
activation or inhibition of the inflammatory cascade. Butyrate is an anti-inflammatory
metabolite known to inhibit pathways leading to the production of pro-inflammatory
cytokines[67]. Through epigenetic interactions, butyrate stimulates adipoliolysis and
mitochondrial oxidative phosphorylation, thereby achieving greater energy consump-
tion and preventing obesity[68]. As stated above, butyrate has also been shown to
reduce LPS in the gut, thereby reducing LPS-related effects. Another SCFA, acetate,
has a more controversial role in chronic inflammation and obesity. On the one hand,
acetate can be used as a substrate for cholesterol synthesis, thus helping to raise serum
cholesterol levels, which can increase the risk of obesity[69]. On the other hand, acetate
has been reported to suppress appetite and reduce the risk of obesity[70]. Acetate is an
important metabolite, and its role in the regulation of the gut microbiota and obesity is
quite complicated. Therefore, further research is needed to clarify the exact mecha-
nisms of the interactions between SCFAs and chronic inflammation, microbiota
composition, and obesity.

Circadian rhythm
The gut microbiota has been shown to influence host circadian rhythms in a diet-

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 Liu BN et al. Gut microbiota in obesity

dependent manner[71]. The interruption of the circadian rhythm may lead to an

increase in the incidence of obesity[72]. Microorganisms regulate lipid uptake and
storage by regulating the circadian transcription factor NFIL3. The study also found
that the ILC3-STAT3 signaling pathway is a key molecular pathway for the interaction
between the microbiota and the circadian clock. A recent study has shown that the gut
microbiota programs rhythmic histone acetylation through HDAC3 (histone deacety-
lase 3) expression in intestinal epithelial cells so that Cd36 (lipid transporter gene)
transcription becomes rhythmic, which promotes lipid absorption and obesity[73]. The
recruitment of histone modifiers to chromatin is a key mechanism for generating
rhythm. Therefore, the gut microbiota regulates the circadian rhythm through
HDCA3. Feeding rhythms are considered to be a potential regulator of circadian
rhythms and the gut microbiota. Studies have shown that time-restricted feeding
reduces the harmful effects of a high-fat diet by regulating the circadian rhythm of the
gut microbiota[74,75]. The feces of individuals experiencing jet lag and individuals
with regular schedules were transplanted into germ-free mice. As a result, the
transplanted mice that experienced jet lag developed obesity and insulin resistance.
Due to impaired feeding rhythms, jet lag induces microbiota dysbiosis, promoting
glucose intolerance and obesity[76].
Metabolites of the gut microbiota can also affect the host rhythm system. Bile
metabolism is an example of the rhythmic interaction between host and gut microbes.
Microbial bile salt hydrolases are related to the regulation of the circadian clock and
lipid metabolism-related genes[77]. Gut bacteria such as Lachnospiraceae, Clostri-
diaceae, Ruminococcaceae, Lactobacillus, Bacteroides, and Bifidobacterium play a role in
the biotransformation of bile salts[78]. SCFAs directly regulate the expression of clock
genes in liver cells. Treatment with acetate or butyrate regulated the expression of the
clock genes Per2 and Bmal1 in hepatic cells synchronized with serum shock[71].
Another study suggested that SCFAs induce indirect regulation of the internal
circadian clock because no phase change in the peripheral circadian clock was detected
in cultured fibroblasts or cultured liver slices[79].
The mechanism of obesity induced by the gut microbiota is summarized in Table 2.
Dysbiosis of the microbiota causes metabolic disorders and promotes the occurrence
and development of obesity through the direct interaction between the microbiota and
local tissues or the indirect interaction between metabolites and remote organs
(Figure 1). Although we can often detect specific different microorganisms between
obese and normal individuals and verify the role of the bacteria in obesity through
germ-free mouse experiments, more attention should be paid to ecological theory
applications in relation to the gut microbiota as a group. The gut microbiota affects
appetite, energy absorption, fat storage, circadian rhythm, and chronic inflammation,
leading to obesity. Therefore, targeted reconstruction of the gut microbiota structure,
such as through fecal bacterial transplantation, is one of the means of treating obesity.

MICROBIOTA IN OBESITY: LINKS WITH GENETICS AND TRANSMISSION

Obesity is the result of interactions between genetic and environmental factors. It is
not surprising that host genetics shapes the gut microbiota. In fact, several genetic
variations explain differences in the composition and diversity of the gut microbiota in
obese people. Whole-genome association was used to determine the relationship
between the genetic variation of twins and different species of bacteria. More than 12
health-related gut microorganisms were identified[80]. These microorganisms are
environment-acquired, but genes also have a certain impact on them, such as the
associations between Bifidobacterium and the lactase gene locus[80] and AMY1-CN (CN
variation of the AMY1 Locus, which encodes salivary amylase) as a genetic factor
related to the composition and function of the microbiome[81]. The abundance of
resistant starch-degrading microbes in the gut microbiota of high-AMY1-CN subjects
increased, which resulted in a higher incidence of obesity after the microbes were
transferred to germ-free mice[81]. In another study, host kinship indicated the
structural similarity of the gut microbiota in wild house mice. The exon sequencing
results of host genes were compared with the microbiota structure, and 20 host genes
were found to be related to the diversity or abundance of the gut microbiota, including
a cytokine IL12A gene with three nonconsensus mutations. Among the 20 related
genes, there are a large number of homologous genes of human-microbiota interac-
tions, including genes related to immune regulation and obesity[82]. Furthermore, a
human genome-wide association analysis revealed that there was an association
between an obesity-related genus (Akkermansia) and a variant near the phospholipase

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Liu BN et al. Gut microbiota in obesity

Table 2 Mechanism of obesity induced by gut microbiota

Effect Microbiota characteristics Mechanism Ref.

Increased Expansion of Desulfovibrio and loss of Clostridia Elevated the expression of genes that control lipid Petersen et al
energy absorption such as CD36 [44]
absorption

Extra energy for The inverse association between fecal SCFAs and gut Excessive SCFAs de la Cuesta-
the host microbiota diversity; Faecalibacterium prausnitzii, Roseburia Zuluaga et al
faecis, and other Clostridiales increased; Akkermansia [49]
muciniphila, Alistipes finegoldii, Bacteroides,
Christensenellaceae, Methanobrevibacter, and Oscillospira
decreased

Increased A community dominated by members of the Clostridial The levels of peptide YY and GLP-1 in obese patients Wu et al[54],
appetite clusters XIVa and IV decrease significantly Salehi et al
[55], Federico
et al[56]

Decreased Fat Germ free mice colonized with Lactobacillus paracasei Increase the expression of ANGPTL4, and inhibit LPL, Aronsson et al
storage leading to decreased fat storage [59], Tazi et al
[60]

Increased fat Transplanting gut microbes from conventionally raised mice Increasing the expression of ChREBP and SREBP-1, Bäckhed et al
storage into germ-free mice Fiaf is inhibited, activate LPL, help triglycerides enter [19]
the circulatory system from the liver

Decreased Increase levels in the butyrate-producing bacteria such as Inhibit pathways leading to the production of pro- Kang et al[66],
chronic Ruminococcaceae and Lachnospiraceae inflammatory cytokines; Stimulate adipoliolysis and Lührs et al[67],
inflammation mitochondrial oxidative phosphorylation, thereby Jia et al[68]
achieving greater energy consumption; Reduce LPS,
thereby reducing chronic low-grade inflammation

Interruption of Bile salts biotransformation bacteria such as Lachnospiraceae, Regulate transcription of key genes involved in Joyce et al[77],
circadian Clostridiaceae, Ruminococcaceae, Lactobacillus, Bacteroides, circadian rhythm (Dbp, Per1/2) and lipid metabolism Parkar et al[78]
rhythm and Bifidobacterium (Pparγ, Angptl4)

SCFAs: Short-chain fatty acids; LPL: Lipoprotein lipase; LPS: Lipopolysaccharide.

D1 gene, which is related to BMI[83].

In addition, the gut microbiota can be transmitted from mother to child. In a
passage experiment with germ-free mice, it was found that the gut microbiota of these
mice was very stable. These microbiota types accounted for the majority of the gut
microbiota of the mice in the normal environment, which proved that most of the gut
microbiota of mice came from vertical transmission from the mother[84]. Studies have
shown that the microbiota exists in the placenta, amniotic fluid, umbilical cord blood,
and meconium, and maternal microorganisms may play an important role in the
establishment of the child’s microbiota[85]. Therefore, maternal obesity during
pregnancy is accompanied by dysbiosis of the gut microbiota and metabolic disorders,
and the maternal microbiota is passed on to the child, which can lead to metabolic
disorders in the child. Obesity-related bacteria are present in the placenta and amniotic
fluid in obese mothers. The fetus swallows these bacteria, resulting in gut microbiota
colonization in the uterus. Studies have confirmed that maternal obesity is related to
dysbiosis of the gut microbiota in offspring[86]. Therefore, the increased risk of obesity
in children with obese mothers can be partly explained by the spread of gut microbes
from obese mothers to their offspring.

MICROBIOTA IN OBESITY: LINKS WITH ENVIRONMENTAL FACTORS

Although genes play important roles in the gut microbiota, environmental factors have
a more significant impact. A study of 1000 Israelis from all over the world who have
very similar eating habits and lifestyles found that their ancestry was not related to the
microbiome. The overall heritability of the microbiome may be less than 2%, and more
than 20% of the variation in the microbiome is related to diet, drugs, and anthropo-
metric measurements[87].
Diet is one of the most important factors inducing obesity. The eating habits of
developed countries and regions have gradually become characterized by high fat and
high sugar consumption, which has contributed to the gradual increase in obesity. Gut
microbes depend on the host diet to survive and harvest energy, and dietary changes

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 Liu BN et al. Gut microbiota in obesity

Figure 1 Gut microbiota and obesity. Both genetic and environmental factors can cause dysbiosis of the gut microbiota. Dysbiosis can increase energy
absorption through changes in gene expression and excessive accumulation of short-chain fatty acids (SCFAs); improve central appetite through gut-brain axis, gut
hormones, and neuromodulators; regulate fat storage through transcription factors and lipoprotein lipase; cause chronic inflammation through regulation of
inflammatory gene expression and lipopolysaccharide; and disrupt the circadian rhythum by affecting the circadian transcription factors, epigenetic modifications, and
the synthesis of bile and SCFAs. These factors appear to increase susceptibility to obesity. The figure was created with BioRender.com. SCFA: Short-chain fatty
acids; LPL: Lipoprotein lipase; LPS: Lipopolysaccharide.

have a great impact on the gut microbiota. For example, the abundance of Bacteroidetes
decreased while that of Firmicutes and Proteobacteria increased in mice fed a high-fat
diet. These changes were observed in mice resistant to weight gain, suggesting that
dietary fat has a direct effect on the microbiome[88,89]. Sleep disturbance is another
cause of obesity. Lack of sleep leads to disrupted circadian rhythms, which can affect
the gut microbiome and contribute to obesity. Chronic sleep fragmentation resulted in
increased food intake and reversible changes in the gut microbiota, with increases in
the abundance levels of Lactobacillaceae and Ruminococcus and a decrease in the
abundance of Lactobacillaceae. These factors lead to systemic and visceral white
adipose tissue inflammation and changes in insulin sensitivity[90]. Stress activates
genes that affect metabolism and promotes the consumption of sweet and fatty foods,
thus increasing appetite and contributing to obesity[91]. Stress significantly affects the
microbiota-gut-brain axis at all stages of life[51]. During stress, independent of diet,
the α-diversity of the gut microbiota increased, 50% of identified genera changed, and
the abundance of Bacteroides decreased, while the abundance levels of less dominant
taxa increased[92]. In addition, unhealthy lifestyle choices (sedentary, lack of exercise),
emotional disorders, and drugs can also contribute to obesity. In short, as a “migrant”,
the gut microbiota itself is obtained from the environment; thus, environmental factors
have a greater impact on it and can affect the occurrence and development of obesity.

STUDY LIMITATIONS
Although there are many factors contributing to obesity, the link between gut
microbiota and obesity is widely accepted. In this review, the relationship between gut
microbiota and obesity and the mechanism of gut microbiota inducing obesity are
provided. However, the researches on gut microbiota in obesity are limited by the
underrepresentation of individuals. This drawback limits the generality of these
findings. Because of the specificity of the strains, microbes from the same genus may
have opposite effects on obesity, which partly explains some of the contradictory
results. In addition, this review only discusses the occurrence and development of
obesity from the perspective of gut microbiota, and does not make further analysis of
the relevant treatment plan.

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Liu BN et al. Gut microbiota in obesity

CONCLUSION
Dysbiosis of the gut microbiota has been shown to be closely linked to obesity. Many
gut microorganisms have been identified to be related to obesity. They induce the
occurrence and development of obesity by increasing host energy absorption,
increasing central appetite, enhancing fat storage, contributing to chronic inflam-
mation, and regulating circadian rhythms. Due to the complexity and diversity of the
gut microbiota, the mechanism by which the gut microbiota induces obesity still needs
to be further studied. Obesity is the result of a combination of genetic and environ-
mental factors. Data analysis based on larger samples to clarify the mechanism of the
association between the gut microbiota and obesity, functional group studies of
ecological significance to identify potential pathogenic members of the gut microbiota
associated with obesity, and specific microbiota management for obese individuals
will be the focus of future research.

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