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Diets, Gut Microbiota and Metabolites

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DOI: 10.1007/s43657-023-00095-0

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Phenomics
https://doi.org/10.1007/s43657-023-00095-0

REVIEW

Diets, Gut Microbiota and Metabolites

Yilian Liu1   · Wanglei Zhong1   · Xiao Li1   · Feng Shen2   · Xiaonan Ma1   · Qi Yang1   · Shangyu Hong1   ·
Yan Sun3 

Received: 26 July 2021 / Revised: 10 January 2023 / Accepted: 12 January 2023

© International Human Phenome Institutes (Shanghai) 2023

Abstract
The gut microbiota refers to the gross collection of microorganisms, estimated trillions of them, which reside within the gut
and play crucial roles in the absorption and digestion of dietary nutrients. In the past decades, the new generation ‘omics’
(metagenomics, transcriptomics, proteomics, and metabolomics) technologies made it possible to precisely identify micro-
biota and metabolites and describe their variability between individuals, populations and even different time points within
the same subjects. With massive efforts made, it is now generally accepted that the gut microbiota is a dynamically changing
population, whose composition is influenced by the hosts’ health conditions and lifestyles. Diet is one of the major contribu-
tors to shaping the gut microbiota. The components in the diets vary in different countries, religions, and populations. Some
special diets have been adopted by people for hundreds of years aiming for better health, while the underlying mechanisms
remain largely unknown. Recent studies based on volunteers or diet-treated animals demonstrated that diets can greatly and
rapidly change the gut microbiota. The unique pattern of the nutrients from the diets and their metabolites produced by the
gut microbiota has been linked with the occurrence of diseases, including obesity, diabetes, nonalcoholic fatty liver disease,
cardiovascular disease, neural diseases, and more. This review will summarize the recent progress and current understand-
ing of the effects of different dietary patterns on the composition of gut microbiota, bacterial metabolites, and their effects
on the host's metabolism.

Keywords  Gut microbiota · Metabolites · Diets · Nutrients · Metabolic diseases

Abbreviations TMA Trimethylamine

NAFLD Nonalcoholic fatty liver disease sBA Secondary bile acid
CVD Cardiovascular disease KD Ketogenic diet
LPS Lipopolysaccharide HFD High-fat diet
BCAA​ Branched-chain amino acid WD Western diet
SCFA Short-chain fatty acid HGD High-glucose diet
HFrD High-fructose diet
VD Vegan diet
Yilian Liu, Wanglei Zhong, Xiao Li, and Feng Shen have VeD Vegetarian diet
contributed equally to this paper.
MD Mediterranean diet
* Shangyu Hong GFD Gluten-free diet
shangyu_hong@fudan.edu.cn CD Chow diet
* Yan Sun RELMβ Resistin-like molecule β
ysun@mmri.edu NF-κB Nuclear factor-κB
1
MyD88 Myeloid differentiation factor 88
State Key Laboratory of Genetic Engineering and School
of Life Sciences, Human Phenome Institute, Fudan
IRAK Interleukin 1 receptor associated kinase
University, 2005 Songhu Road, Yangpu District, TRAF6 Tumor necrosis factor receptor associated factor
Shanghai 200433, China 6
2
Department of Hepatobiliary Surgery, Dongfeng Hospital, TAK1 Transforming growth factor β activated kinase 1
Hubei University of Medicine, Shiyan 442001, Hubei, China IRS1/2 Insulin receptor substrate 1/2
3
Masonic Medical Research Institute, 2150 Bleecker St, Utica, mTOR Mammalian target of rapamycin
NY 13501, USA

13
Vol.:(0123456789)

GABA Gamma-aminobutyric acid
OTUs Operational taxonomic units
GLP-1 Glucagon-like peptide-1
Introduction
There are more than 160 species of microorganisms in the
human gastrointestinal tract (Laterza et al. 2016). Piles of
evidence had demonstrated that the disorder of gut micro-
biota might result in diseases, such as obesity (Ley et al.
2005), type 2 diabetes mellitus (T2DM) (Pascale et  al.
2019), nonalcoholic fatty liver disease (NAFLD) (Ma et al.
2017), cardiovascular disease (CVD) (Tang et al. 2019), neu-
ral diseases (Olson et al. 2018), polycystic ovary syndrome
(Qi et al. 2019), and cancer (Raza et al. 2019). Accumulat-
ing evidence, which was well reviewed by Wu et al. (2021),
suggests that the metabolites produced by the gut microbiota
may be one of the major contributors. These metabolites,
including lipopolysaccharide (LPS), branched-chain amino
acid (BCAA), short-chain fatty acid (SCFA), trimethylamine
(TMA), secondary bile acid (sBA), and so on, are often asso-
ciated with the metabolic states, activation of inflammation,
and regulation of the hosts’ genes involved in energy stor-
age and consumption (Blaut 2015; Gentile and Weir 2018;
Manco et al. 2010; Neis et al. 2015; Tsukumo et al. 2009;
Zhu et al. 2016).
Diets have a great influence on the gut microbiota (Bibbo
et al. 2016; Requena et al. 2018). Due to the availability,
tradition, religion, and special purposes related to diseases
or lifestyles, the nutrients in the diets vary in different coun-
tries and populations. Among the popular diets studied, the
different proportion of nutrients features these diets and was
believed to contribute to physiological consequence in the
consumers of these diets, mainly the ketogenic diet (KD),
the high-fat diet (HFD), the western diet (WD), the high-glu-
cose diet (HGD), the high-fructose diet (HFrD), the vegan
diet (VD), the vegetarian diet (VeD), the Mediterranean
diet (MD), and the gluten-free diet (GFD) (Rinninella et al.
2019). KD contains the highest proportion of fat (generally
over 70%) and the lowest proportion of carbohydrates (less
than 10%) among the aforementioned diets (Veech 2004).
Both HFD and WD have higher levels of fat than other diets
except KD (Bortolin et al. 2018; Woodie and Blythe 2018),
while HGD and HFrD contain high levels of carbohydrates
(Johnston et al. 2013). VD, VeD and MD are featured with
a high level of dietary fiber but low in animal-derived fat
and protein (Haddad et al. 1999; Kastorini et al. 2011).
GFD is a diet lacking a specific class of proteins and gluten
(Biesiekierski 2017). The dietary fats, carbohydrates, pro-
teins and dietary fibers were believed to impact gut microbi-
ota (Candido et al. 2018; Deng et al. 2022; Kim et al. 2016).
In general, the composition of the gut microbiota changes
13
Y. Liu et al.
rapidly and frequently and shifts over one to two days when
the hosts switch their diets (David et al. 2014; Walker et al.
2011; Wu et al. 2011). Long-term consumption of these
diets plays a dominant role in shaping the hosts' gut micro-
biota and forming a stable and distinguished enterotype (Wu
et al. 2011). For example, HFD increases the abundance
of Firmicutes but decreases the abundance of Verrucomi-
crobia (Bisanz et al. 2019). On the contrary, KD decreases
the abundance of Firmicutes but increases the abundance
of Verrucomicrobia (Xie et al. 2017; Zhang et al. 2018b). In
the last decade, tremendous efforts have been made to extend
our knowledge of how these diets impact the gut microbiota
and the host's metabolism. In this review, we will summa-
rize the large body of data on how these diets affect gut
microbiota and metabolites. We will also discuss how the
metabolic status of the hosts will be impacted by these diets
and the underlying mechanisms.
High‑Fat Diet
HFD refers to the dietary pattern with the fat content gener-
ally being 40–60%. Consumption of HFD profiles a pattern
on gut microbiota and results in a different collection of
bacterial metabolites, which has been proven to contribute
to the prevalence of overweight, and lead to obesity, T2DM,
and CVD (Stocks et al. 2013; Wan et al. 2019; Woodie and
Blythe 2018).
Extensive evidence has demonstrated the influence of
HFD consumption on the composition of gut microbiota.
At the phylum level, HFD consumption decreases the
abundance of Verrucomicrobia (Everard et al. 2014), but
increases the abundance of Proteobacteria (Hildebrandt
et al. 2009). At the genus level, the abundance of Biloph-
ila, Butyrivibrio, Parabacteroides, and Roseburia  were
increased, but the abundance of Allobaculum, Coprococcus,
Eubacterium, Lactobacillus, and Prevotella were decreased
by HFD consumption (Everard et al. 2014). At the species
level, HFD consumption increases the abundance of Biloph-
ila wadsworthia  (Devkota et  al. 2012),  and decreases
the abundance of  Bacteroides fragilis (Sun et  al. 2018)
and Akkermansia muciniphila (Schneeberger et al. 2015).
However, the reported effects of HFD on microbiota vary
across studies. The reason might be the different sources of
major nutrients in the HFD, different times on HFD, differ-
ent animal handling policies, etc. To find out the robust and
reproducible changes in microbial composition induced by
HFD feeding, Bisanz et al. performed a meta-analysis based
on 27 studies involving 1, 101 samples (including mouse and
human samples) (Bisanz et al. 2019). Their analysis demon-
strated that HFD consumption induces reproducible shifts in
the gut microbiota and revealed an increased ratio of Firmi-
cutes: Bacteroidetes in all of those analyzed datasets from
Diets, Gut Microbiota and Metabolites
mice. This increased ratio of Firmicutes: Bacteroidetes was
later reaffirmed by Munch et al. when they analyzed 16s
ribosomal RNA of the fecal samples from mice fed with a
chow diet (CD) or HFD for 30 weeks (Munch et al. 2019).
The impact of HFD on human gut microbiota is more com-
plicated and addresses more debates without a consensus
(Magne et al. 2020). Another concern about HFD-induced
changes in microbiota is whether the changes in the micro-
bial composition are directly caused by HFD consumption
or the obese state of the hosts resulting from HFD consump-
tion. Hildebrandt et al. distinguished these two scenarios
by using resistin-like molecule β (RELMβ) knockout mice,
which are resistant to diet-induced obesity, and they con-
cluded that the high-fat diet itself, and not the obese state,
was responsible for the altered microbiota (Hildebrandt et al.
2009).
Gut microbiota can impact the host through the metabo-
lites they produced, including LPS, BCAAs, SCFAs, TMA,
sBA, and so on (Gentile and Weir 2018; Manco et al. 2010;
Neis et al. 2015; Zhu et al. 2016).
HFD consumption increases the circulating level of
LPS and BCAAs by enhancing intestinal permeability and
decreases SCFA by suppressing the abundance of SCFA-
producing bacteria such as Akkermansia muciniphila (Alza-
ben et al. 2015; Cani et al. 2008). LPS is mainly produced by
Gram-negative bacteria (Kirkland and Ziegler 1984). Previ-
ous studies have shown that high LPS levels would cause
subclinical inflammation, insulin resistance, and an increase
in fat mass (Horton et al. 2014; Pedersen et al. 2016). In the
liver, LPS activates nuclear factor-κB (NF-κB) and myeloid
differentiation factor 88 (MyD88), and leads to NAFLD (Ma
et al. 2017). In adipocytes, LPS will cause insulin resistance
by activating the MyD88- interleukin 1 receptor associated
kinase (IRAK)-tumor necrosis factor receptor associated fac-
tor 6 (TRAF6)-transforming growth factor β activated kinase
1 (TAK1)-insulin receptor substrate 1/2 (IRS1/2) signaling
axis (Saad et al. 2016). BCAAs, including valine, leucine,
Table 1  The impacts of HFD on gut microbiota, secondary metabolites and metabolic status
Microbiota
Phylum Genus Species
HFD Firmicutes↑ Bilophila↑ B. wadsworthia↑
Proteobacteria↑ Butyrivibrio↑ B. fragilis↓
Bacteroidetes↓ Parabacteroides↑ A. Muciniphila↓
Verrucomicrobia↓ Roseburia↑
Allobaculum↓
Coprococcus↓
Eubacterium↓
Lactobacillus↓
Prevotella↓
HFD high fat diet, LPS lipopolysaccharide, BCAA​ branched chain amino acid, SCFA short chain fatty acid, T2DM type 2 diabetes mellitus,
NAFLD Nonalcoholic fatty liver disease
and isoleucine, mainly come from food and intestinal flora.
BCAAs contribute to the development of obesity-associated
insulin resistance in humans and rodents (Goffredo et al.
2017; Newgard et al. 2009), which are associated with the
progression of obesity-related metabolic disorders, including
T2DM (Asghari et al. 2018) and NAFLD (Li et al. 2013).
There are two proposed mechanisms by which BCAAs may
impair insulin sensitivity (Newgard et al. 2009). One is that
BCAAs activate mammalian target of rapamycin (mTOR)
signaling, and they lead to insulin resistance. Another pro-
posed mechanism is that the increased BCAAs turnover
drives the production of toxic mitochondrial BCAAs cat-
abolites (e.g., propionyl CoA, succinyl CoA, branched-chain
keto acids), which are in turn proposed to impair mitochon-
drial oxidative metabolism and thereby induce mitochondrial
stress and lead to insulin resistance (Asghari et al. 2018).
HFD consumption decreases the circulating level of
SCFAs by suppressing the abundance of SCFAs-producing
bacteria, Akkermansia Muciniphila (Alzaben et al. 2015;
Cani et al. 2008; Derrien et al. 2004). The bacteria ferment
and degrade indigestible carbohydrates to produce SCFAs,
including acetate, propionate, and butyrate (Macfarlane and
Macfarlane 2011). It has been demonstrated that propion-
ate and butyrate concentrations correlate inversely with the
risk of obesity, insulin resistance, and NAFLD (Ampong
et al. 2020). Mechanistically, the SCFAs bind to their recep-
tors and increase the production of glucagon-like peptide-
1(GLP-1) and peptide tyrosine tyrosine, which affect host's
energy balance and lipid metabolism (Hernandez et al. 2019;
Koh et al. 2016; Liu et al. 2020; Sircana et al. 2018).
With the extensive research on gut microbiota in the con-
text of HFD consumption, it seems safe to say that HFD
consumption can rapidly and reproducibly alter the mouse's
gut microbiota and metabolites, which have a major impact
on both immunological and metabolic status of the hosts
(Table 1).
Secondary metabolites Metabolic status
LPS↑ Subclinical inflammation↑
BCAA↑ Insulin resistance↑
SCFA↓ Adipose mass↑
Metabolic disorders↑
T2DM↑
NAFLD↑
13

Western Diet
WD is a typical diet pattern in western countries. It is
high in both saturated fats (> 40%) and refined carbohy-
drates (> 40%) and has higher efficiency to induce obesity,
increase visceral adipose tissue, hepatic steatosis, inflam-
mation, fasting hyperglycemia, and dyslipidemia in rats
compared to HFD mentioned above (Bortolin et al. 2018;
Tiniakos et al. 2010).
WD consumption has adverse effects on gut micro-
biota, which include disorder of intestinal flora, damage
of intestinal mucosal, increased intestinal permeability,
and consequent inflammation (Chassaing et  al. 2015;
Schroeder et  al. 2018; Zinocker and Lindseth 2018).
In 2021, Low et al. comprehensively compared the gut
microbiota between the mice fed with WD and normal
diets and found that these changes are largely reversible
and repeatable (Low et al. 2021). At the phylum level,
Firmicutes and Verrucomicrobiota showed significantly
higher abundances, while Bacteroidota and Cyanobac-
teria have lower abundances in WD-fed mice than in
control mice (Low et al. 2021). At the family level, eight
families have significantly higher abundances while 16
families were significantly less abundant in WD-fed
mice than in normal diets-fed mice (Low et al. 2021).
Nine families were similarly abundant among the groups
(Low et al. 2021). In 2022, Romualdo et al. analyzed the
impacts of WD on mouse's gut microbiota and linked
the changes in gut bacteria with liver steatosis. Their
data confirmed the WD-induced alteration in mouse's
gut microbiota with differences in phyla and families
(Romualdo et al. 2022). The combined information from
the abovementioned studies were listed in Table 2.
Similar to HFD, WD increases the plasma level of
LPS and decreases the level of SCFAs (Kaye et al. 2020;
Simkin 2019), which contribute to the increased insulin
resistance, body weight, plasma and liver triglycerides,
cholesterol, and risk of CVD (Baena et al. 2017). The
direct comparison of the gut microbiota between WD-
and HFD-fed rats showed minor differences between the
two groups (Bortolin et al. 2018). Overall, WD induced
similar alterations in gut microbiota and metabolites
when compared with HFD (Table  2). Nevertheless, a
closer look at the features of gut microbiota and metabo-
lites in WD-fed mammals will be helpful for us to under-
stand the mechanisms of this popular obesogenic diet.
13
Y. Liu et al.
Ketogenic Diet
KD is a normal caloric diet that is high in fat (over 70% in
most cases), low in carbohydrates, and moderate in pro-
tein. KD consumption results in a very low carbohydrate
uptake (less than 10% of total caloric intake), and forces
ketone production (Veech 2004). KD is initially introduced
as an effective treatment for drug-resistant epilepsy (Hohn
et al. 2019). Later, KD is also applied as a treatment for
other neuronal diseases (Rusek et al. 2019). But nowadays,
KD is prevalently used by people aiming to lose weight,
and the mechanism is under investigation (Badman et al.
2009; Garbow et al. 2011; Kosinski and Jornayvaz 2017).
Meanwhile, some studies raised the concern that the con-
sumption of KD might cause some adverse effects such as
NAFLD and insulin resistance (Dashti et al. 2003; Ellen-
broek et al. 2014; Jornayvaz et al. 2010).
KD dramatically influences the composition of gut
microbiota (Table 3). At the phylum level, KD decreases
the abundance of Firmicutes but increases the abundance
of  Bacteroidetes  and  Proteobacteria (Xie et  al. 2017;
Zhang et al. 2018b). At the family level, KD decreases the
abundance of  Enterobacteriaceae,  Sinobacteraceae,
and Comamonadaceae, but increases the abundance of
Ruminococcaceae and Mogibacteriaceae (Gutierrez-Rep-
iso et al. 2019). At the genus level, KD decreases the abun-
dance of Serratia, Erwinia, and Citrobacter, and increases
the abundance of Oscillospira and Butyricimonas (Gutier-
rez-Repiso et al. 2019). KD was also reported to decrease
the abundance of Dialister and Cronobacter and increases
the abundance of Desulfovibrio, Prevotella, Lactobacil-
lus, and Parabacteroides (Lindefeldt et al. 2019; Ma et al.
2018; Olson et al. 2018; Tagliabue et al. 2017; Xie et al.
2017). At the species level, KD decreases the abundance
of Bifidobacteria, but increases the abundance of Akker-
mansia muciniphila (Ma et al. 2018; Olson et al. 2018),
which has been reported to be associated with weight
loss, improved insulin sensitivity, alleviated insulinemia,
decreased plasma total cholesterol, and the development
of T2DM and hypertension (Brahe et al. 2015; Dao et al.
2016; Depommier et al. 2019; Kong et al. 2021; Li et al.
2017; Liu et al. 2017; Yassour et al. 2016; Zhang et al.
2013). However, to what extent the regulated abundance
of Akkermansia muciniphila contributes to the physiologi-
cal impact of KD remains unclear.
The consumption of KD leads to the change of metab-
olites of gut microbiota. Akkermansia muciniphila  is
regarded as a key propionate-producing bacterium and
butyrate production is dominated by  Ruminococcus
Diets, Gut Microbiota and Metabolites

Table 2  The impacts of WD on gut microbiota, secondary metabolites and metabolic status

Microbiota Secondary Metabolic status
metabolites
Phylum Class Order Family Genus

WD Firmicutes↑ Clostridia↑ Clostridiales↑ Erysipel- Coprococcus↑ LPS↑ vWAT↑

Proteobacteria↑ Deltaproteobac- Desulfovibrion- otrichaceae↑ Ruminococcus↑ SCFA↓ Body weight↑
Verrucomicro- teria↑ ales↑ Streptococ- Desulfovibrio↑ Plasma triglycer-
bia↑ Bacili↑ Lactobacillales↑ caceae↑ Faecalibacte- ides↑
Actinobacteria↓ Bacterioidia↓ Bacterioidales↓ Clostridiaceae↑ rium↓ Liver triglycer-
Bacteroidetes↓ Fusobacteria↓ Fusobacteriales↓ Eubacterium Fusobacterium↓ ides↑
Cyanobacteria↓ coprostanoli- Bacteroides↓ Plasma choles-
Fusobacteria↓ genes group↑ Prevotella↓ terol↑
Enterococcaceae↑ Alloprevotella↓ Liver cholesterol↑
Christensenel- Alistipes↓ Insulin resistance↑
laceae↑ RC9 gut group↓ Adipose mass↑
Staphylococ- Parabacteroides↓
caceae↑ Odoribacter↓
Akkermansi-
aceae↑
Ruminococ-
caceae↑
Desulfovibrion-
aceae↑
Lachnospiraceae↓
Lactobacil-
laceae↓
Clostridia UCG-
014↓
Butyricicoc-
caceae↓
Clostridia
vadinBB60
group↓
Acholeplasmata-
ceae↓
Monoglobaceae↓
RF39↓
Peptococcaceae↓
Bacteroidaceae↓
Rikenellaceae↓
Muribaculaceae↓
Bifidobacte-
riaceae↓
Coriobacteriales
Incertae Sedis↓
Eggerthellaceae↓
Gastranaer-
ophilales↓
Prevotellaceae↓
Porphyromona-
daceae↓
Fusobacte-
riaceae↓

WD western diet, LPS lipopolysaccharide, SCFA short chain fatty acid, vWAT​visceral adipose tissue

bromii (Morrison and Preston 2016). However, a recent
study reported a reduction of SCFAs in KD-fed mice when
compared to normal chow diet-fed mice (Li et al. 2021).
In their report, Li et al. also revealed that KD feeding
decreased four main tryptophan metabolites and changed
the levels of 10 sBAs, among the 40 sBAs monitored (Li
et al. 2021). Further studies will be needed to clarify the
impacts of KD on the metabolism of SCFAs, sBAs and
tryptophan, and the consequences on the hosts' metabolic
status. In 2018, Olson et al. reported that the consump-
tion of KD decreased systemic gamma-Aminobutyric
acid (GABA) and elevated hippocampal GABA/glutamate

13

Table 3  The impacts of KD on gut microbiota, secondary metabolites and metabolic status
Microbiota
Phylum Family Genus
KD Bacteroidetes↑ Ruminococcaceae↑ Oscillospira↑
Proteobacteria↑ Mogibacteriaceae ↑ Butyricimonas↑
Firmicutes↓ Enterobacteriaceae↓ Desulfovibrio↑
Sinobacteraceae↓ Prevotella↑
Comamonadaceae↓ Lactobacillus↑
Parabacteroides↑
Bifidobacteria↓
Serratia↓
Erwinia↓
Citrobacter↓
Dialister↓
Cronobacter↓
KD ketogenic diet, SCFA short chain fatty acid, sBA secondary Bile Acids
levels, which play critical roles in the anti-seizure effect
induced by KD (Olson et al. 2018).
Although more and more attention was put on the impact
of KD on the gut microbiota and their metabolites, there
are still several critical questions and concerns remained
unanswered. First, as partially addressed by Li et al. in their
report, both the sources and proportions of fat in the KD are
critical for the KD-induced alteration in gut microbiota and
their metabolites (Li et al. 2021). The differential alteration
that would impact the hosts differently will be an intriguing
topic for future investigation. Second, it has been shown that
there is a biphasic effect of KD in microbiota: a quick but
dramatic decrease in the richness and diversity of the bacte-
ria, followed by a slow recovery of bacterial concentration
(Swidsinski et al. 2017). Thus, the microbiota analyzed at
different time points may show different results. Third, the
proportion of fat, carbohydrates, and proteins varies a lot in
different versions of KDs. The KDs used in animal studies
are generally more extreme than the KD used in patients, and
the KDs used by patients with epilepsy are generally more
extreme than the KDs used by weight losers, which may
cause inconsistency in the conclusion from animal studies
and clinical trials (Li et al. 2021; Zhu et al. 2022).
High‑Glucose or Fructose Diet
Excessive sugar intake contributes to the development of
NAFLD, CVD, and T2DM in both direct and indirect man-
ners (Stanhope 2016). Consumption of two commonly used
high-sugar diets: HGD or HFrD results in similar fatty liver
parameters, including elevated levels of hepatic triacylglyc-
erol and insulin resistance (Johnston et al. 2013). Data from
multiple groups suggested that fructose consumption is spe-
cifically linked to gut microbial dysbiosis, which mediated
the hosts' metabolic changes (Di Luccia et al. 2015; Do et al.
13
Y. Liu et al.
Secondary metabolites Metabolic status
Species
A. muciniphila↑ SCFA↑ Insulin resistance↓
sBA↓
2018; Mastrocola et al. 2018; Vasques-Monteiro et al. 2021).
However, this idea was challenged by Bier et al. (2020).
They claimed that antibiotic treatment significantly reduced
microbial diversity and altered the microbial composition,
but had minimal or no effect on the metabolic phenotypes of
the HFrD-treated rats (Bier et al. 2020). Further investiga-
tion will be needed to find out the cause of this inconsist-
ency. Nevertheless, there's no doubt that HFD or HFrD has a
great impact on gut microbiota. At the phylum level, HGD-
or HFrD-fed mice had a significantly lower abundance
of Bacteroidetes and a higher abundance of Proteobacte-
ria compared to normal diet-fed mice after 12 weeks of feed-
ing (Do et al. 2018). At the family levels, the levels of nine
different families were significantly changed in the feces of
C57BL/6J mice fed with HFrD for 12 weeks (Table 4) (Ahn
et al. 2020). While at the genus level, they found HFrD feed-
ing increased the abundance of Akkemansia but decreased
the abundance of Dehalobacterium and an unknown genus
in Mogibacteriaeae (Ahn et al. 2020). At the species level,
HFrD-fed mice had higher levels of Akkermansia muciniph-
ila, Clostridium sp, Lachnoclostridium clostridium alden-
ense, Roseburia sp, Lachnoclostridium clostridium scindens,
and lower levels of Clostridium disporicum, Lactobacillus
johnsonii, Bacteroides acidifaciens, Allobaculum sp in their
feces after one-week feeding. Different mice strains may also
respond differently to fructose (Montrose et al. 2021).
The intestinal permeability of HGD or HFrD group mice
was enhanced due to the lower expression of tight junction
proteins, such as zonula occludens-1 and occluding, which
can increase the intestinal permeability and contribute to
the translocation of LPS (Cani et al. 2008; Do et al. 2018).
Given the increased abundance of Proteobacteria (Do et al.
2018), one of the major producers of LPS (Rizzatti et al.
2017), it is not a surprise that HFrD increases plasma LPS
(Rivero-Gutierrez et al. 2017), and the increased plasma
levels of LPS leads to insulin resistance in murine fed with
Diets, Gut Microbiota and Metabolites
Table 4  The impacts of HGD or HFrD on gut microbiota, secondary metabolites and metabolic status
Microbiota
Phylum Family Genus
HGD or HFrD Proteobacteria↑ S24-7↑ Akkermansia↑
Bacteroidetes↓ Pseudomona- Dehalobacterium↓
daceae↑ Unknown genus
Verrucomicrobi- (Mogibacte-
aceae↑ riaceae)↓
Rikenellaceae↓
Dehalobacte-
riaceae↓
Lachnospiraceae↓
Mogibacteriaceae↓
Ruminococcaceae↓
Turicibacteraceae↓
HGD or HFrD high glucose diet or high fructose diet, LPS lipopolysaccharide
HGD or HFrD (Pedersen et al. 2016; Rivero-Gutierrez et al.
2017). Silva et al. also compared the fecal metabolites from
mice fed with ND, HGD or HFrD, and found that high glu-
cose or fructose feeding caused different alterations in fecal
SCFAs (Silva et al. 2018). Their results indicated that both
high glucose- and high fructose-feeding caused higher levels
of fecal acetate. But only high fructose-, not high glucose-
fed mice had lower levels of fecal butyrate. On the other
side, high glucose- but not high fructose-fed mice had signif-
icantly higher levels of fecal propionate compared to normal
chow diet-fed mice (Silva et al. 2018). Ahn et al. also raised
the concern of substantial variability in both fecal metabo-
lites and microbial profiles between animals within the same
feeding group, as well as at different time points for one
animal across the feeding interval (Ahn et al. 2020). Thus,
it is recommended to have multiple feces sampling collected
during a feeding trial to obtain representative levels of fecal
metabolites and microbial populations.
In recent decades, the introduction of high-fructose corn
syrup in the food industry dramatically increased the con-
sumption of fructose. How the HFrD would change our lives
and the safe limit of daily fructose consumption remains
largely unknown. Further investigation on fructose-induced
alteration of microbiota and their metabolites is needed for a
better understanding of the impact of fructose consumption.
Vegan or Vegetarian Diet
There are two kinds of vegetarianism: one is vegetarian,
and the population are on the traditional vegetarian diet;
the other one is vegan, also named a strict vegetarian, and
a vegan avoids all animal and animal-derived products.
Accordingly, these two plant foods-based diets are featured
a high level of fiber and carbohydrates but low in fat and
protein (Haddad et al. 1999). Both vegan diet and vegetarian
Secondary Metabolic status
metabolites
Species
A. muciniphila↑ LPS↑ Insulin resistance↑
C. sp↑ Hepatic inflamma-
L. clostridium tion↑
aldenense↑ Hepatic lipid accu-
R. sp↑ mulation↑
L. clostridium Enlargement of
scindens↑ adipocytes↑
C. disporicum↓
L. johnsonii↓
B. acidifaciens↓
A. sp↓
diet are advocated as a dietary strategy for maintaining good
health and treating metabolic disorders, including obesity,
diabetes, and CVD (Craig 2009; Jenkins et al. 2014; Le and
Sabate 2014; Tonstad et al. 2013).
The influence of vegan and vegetarian diets on gut micro-
biota has been studied in many laboratories, and the results
are somewhat contradictory. The overall differential micro-
biota composition in vegans or vegetarians, when compared
to omnivores, and inconsistency were well summarized in
a systematic review (Trefflich et al. 2020). The reasons for
the inconsistency could be the different ways the vegan or
vegetarian were defined, the different regions the subjects
were recruited, the time the subjects stayed on the diets, and
how the samples were collected and analyzed. One single
study with the biggest number of differences in microbiota
composition is from Zhang et al. (2018a). They recruited
29 healthy volunteers and divided them into three groups (a
study group with 15 members normally consume an omnivo-
rous but were put on a three-months lacto-ovo-vegetarian
diet, an omnivorous group with seven members stayed on an
omnivorous diet and a vegetarian group with seven members
stayed on a vegetarian diet). They collected samples on day
0 and day 91 from each group and surveyed the effect on
the diversity of gut microbiota by metagenomic sequencing
(Zhang et al. 2018a). A combined short-term effect (Day
91 vs Day 0 in the study group) and long-term effects (the
omnivorous group vs the vegetarian group at Day 91 and
Day 0) on gut microbiota were listed in Table 5.
Bacterial metabolites were more abundant while lipid and
amino acid metabolites were less abundant in the plasma
metabolome of vegans when compared to omnivores (Wu
et  al. 2016). A vegetarian diet increases the abundance
of Prevotella, which produces SCFAs (de Moraes et al.
2017; Rios-Covian et al. 2016). The elevation of SCFAs may
contribute to diet-induced weight loss and increased insu-
lin sensitivity in vegans (De Filippo et al. 2010; Pilis et al.
13
 Y. Liu et al.

Table 5  The impacts of VD or VeD on gut microbiota, secondary metabolites and metabolic status
Microbiota Secondary metabolites Metabolic status
Phylum Genus Species

VD or VeD Firmicutes↑ Prevotella↑ P. copri↑ SCFA↑ Insulin sensitivity↑

Proteobacteria↑ Capnocytophaga↑ B. Hydrogenotrophica↑ TMA↓
Bacteroidetes↓ Porphyromonas↑ C. Ramosum↑ sBA↓
Verrucomicrobia↓ Roseburia↑ C. Symbiosum↑
Faecalibacterium↑ P. duerdenii↑
Lachnospira↑ S. peroris↑
Veillonella↑ V. dispar↑
Actinobacillus↑ V. parvula↑
Atopobium↑ V. atypica↑
Actinoplanes↑ M. luteus↑
Cryptobacterium↑ A. Segnis↑
Micrococcus↑ A. actinomycetemcomitans↑
Aggregatibacter↑ C. concisus↑
Aeromonas/Pseudomona↑ H. haemolyticus↑
Campylobacter↑ H. influenzae↑
Haemophilus↑ H. parainfluenzae↑
Klebsiella↑ K. pneumonia↑
Neisseria↑ N. mucosa↑
Alistipes↓ B. Vulgatus↓
Parabacteroides↓ B. fragilis↓
Peptostreptococcus↓ B. Dorei↓
Desulfitobacterium↓ B. Thetaiotaomicron ↓
Ruminococcus↓ B. Uniformis↓
Dialister↓ B. Finegoldii↓
Phascolarctobacterium↓ B. Stercoris↓
Acetobacterium↓ P. gingivalis↓
Bulleidia↓ P. Distasonis↓
Holdemania↓ P. buccalis↓
Dorea↓ P. oris↓
Caldanaerobacter↓ P. tannerae↓
Lachnoclostridium↓ L. amylovorus↓
Lactobacillus↓ C. Clostridioforme↓
Lactococcus↓ C. Kluyveri↓
Oscillospira↓ C. coccoides-E. rectale↓
Bifidobacterium↓ C. Innocuum↓
Eggerthella↓ C. Paraputrificum↓
Corynebacterium↓ R. torques↓
Oxalobacter↓ D. invisus↓
Ruegeria↓ P. Succinatutens↓
Taylorella↓ E. Coli↓
Syntrophobacter↓ E. faecium↓
Ralstonia↓ R. Eubacterium rectale↓
Campylobacter↓ D. longicatena↓
Desulfovibrio↓ B. hansenii↓
Bilophila↓ A. caccae↓
Succinivibrio↓ F. magna↓
Halomas↓ T. pseudo ethanolicus↓
Methanosphaera↓ P. denticolens↓
Dehalogenimona↓ M. curtisii↓
Streptobacillus ↓ E. hermannii↓
Akkermansia ↓ S. fumaroxidans↓
A. baumannii↓
D. piger↓
D. alaskensis↓
D. aespoeensis↓
B. wadsworthia↓
E. ictaluri/ tarda↓
M. stadtmanae↓
D. lykanthroporepellens↓
F. ulcerans↓

VD or VeD vegan diet or vegetarian diet, SCFA short chain fatty acid, sBA secondary Bile Acids, TMA trimethylamine

13
Diets, Gut Microbiota and Metabolites
2014; Tindall et al. 2018; Xie et al. 2017). The vegetarian
or vegan diets are low in choline, phosphatidylcholine, and
L-carnitine, which cause the reduction of TMA in the hosts.
TMA can be further oxidized to trimethylamine N-oxide,
which could trigger insulin resistance and increase the risk
of T2DM and NAFLD in humans and rodents (Barrea et al.
2018; Fu et al. 2020; Heianza et al. 2019; Schugar et al.
2017; Shan et al. 2017). Primary bile acids are produced by
the liver and secreted into the intestine, and then converted
to sBAs by gut microbiota. The increased level of sBAs has
been reported to positively correlate with the risk of insulin
resistance and T2DM (Sircana et al. 2018). sBAs activate
farnesoid X receptor (FXR) and G protein-coupled bile acid
receptor-1 (also named TGR5), which are both expressed in
endocrine L cells. The activation of FXR and TGR5 stimu-
lates the secretion of GLP-1, which improves insulin sensi-
tivity (Pathak et al. 2018). Vegans had lower levels of total
BA and sBA in their feces than omnivores (Trefflich et al.
2019), which might be because of the high intake of fibers
and low intake of fat (O'Keefe et al. 2015). Whether a plant-
derived diet improves insulin sensitivity by impacting the
levels of sBA remains unknown.
Mediterranean Diet
MD is a diet with a high level of vegetables, fruits, fish,
whole grains, beans, wine and olive oil, popular in south-
ern European countries around the olive-tree-bearing
regions of the Mediterranean basin. It has been reported
that higher adherence to the MD is associated with a lower
risk of CVD and metabolic syndrome (Kastorini et al.
Table 6  The impacts of MD on gut microbiota, secondary metabolites and metabolic status
Microbiota
Phylum Family Genus
MD Bacteroidetes↑ Lachnospiraceae↑ Lactobacillus ↑
Bifidobacteria↑
Clostridium ↓
MD Mediterranean diet, SCFA short chain fatty acid, sBA secondary Bile Acids, TMA trimethylamine, T2DM type 2 diabetes mellitus
2011; Ryan et al. 2013; Salas-Salvado et al. 2014; Wang
et al. 2021).
The high level of dietary fibers and low content of
red meat in an MD orchestrate a special pattern of gut
microbiota (Table 6), which is believed to mediate, at least
partially, the beneficial effects of MD (De Filippis et al.
2016; Garcia-Mantrana et al. 2018; Ghosh et al. 2020;
Mitsou et al. 2017; Rinninella et al. 2019; Tindall et al.
2018; Wang et al. 2021). De Filippis et al. first convinc-
ingly demonstrated the connection between MD and gut
microbiota (De Filippis et al. 2016). In 2020, based on
16S rRNA sequencing data, Ghosh et al. reported that, at
the species level, a 12-month MD intervention increased
the abundance of  Faecalibacterium prausnitzii, Rose-
buria hominis, Eubacterium rectale, Eubacterium eligens,
Eubacterium xylanophilum, Bacteroides thetaiotaomicron,
Prevotella copri, and Anaerostipes hadrus in 612 subjects
across five European countries (Ghosh et al. 2020). These
species positively associate with the production of SCFAs
and negatively associate with the development of T2DM
(Machiels et  al. 2014; Qin et  al. 2012). Consistently,
better adherence to the MD was associated with signifi-
cantly higher levels of total SCFA (Garcia-Mantrana et al.
2018). On the other side, MD decreased the abundance
of Ruminococcus torques, Collinsella aerofaciens, Copro-
coccus comes, Dorea formicigenerans, Clostridium ram-
osum, Veillonella dispar, Flavonifractor plautii, and Actin-
omyces lingnae (Ghosh et al. 2020). In 2021, Wang et al.
based on metagenomics sequencing analysis, confirmed
the impacts of MD on these species, which were featured
as fiber metabolizers and SCFA producers (Wang et al.
2021). Based on their analysis, the abundances of whole
grams, vegetables, fruits and reduced red meat in MD were
Secondary metabolites Metabolic status
Species
C. albicans↑ SCFA↑ T2DM↓
F. prausnitzii↑ TMA↓ Obesity↓
R. hominis↑ sBA↓ Insulin sensitivity↑
E. rectale↑
E. eligens↑
E. xylanophilum↑
B. thetaiotaomicron↑
P. copri↑
A. hadrus↑
R. torques↓
C. aerofaciens↓
C. comes↓
D. formicigenerans↓
C. ramosum↓
V. dispar↓
F. plautii↓
A. lingnae↓
13

the determining components shaping the specific pattern
of gut microbiota in MD-consuming individuals (Wang
et al. 2021).
In addition to the aforementioned SCFAs, the other
metabolites were also found to be affected by MD and play
roles in hosts' pathophysiological conditions. Tindall et al.
demonstrated that MD can reduce the plasma level of TMA,
leading to a lower risk of insulin resistance (Tindall et al.
2018). Ghosh et al. demonstrated that MD can decrease the
level of sBA (Ghosh et al. 2020), which is positively associ-
ated with insulin resistance (Sircana et al. 2018).
Gluten‑Free Diet
Gluten is a mixture of hundreds of distinct proteins but is
primarily made up of two different classes of proteins: glia-
din and glutenin (Biesiekierski 2017). GFD is a diet that
excludes all gluten-containing foods, such as pasta, pizza,
beer, oatmeal, toast, sandwiches, cakes, bread, cookies, etc.
GFD is the only efficient treatment available for Celiac dis-
ease, a chronic inflammatory pathology of the small intestine
triggered by dietary gluten (Newnham 2017), which affects
about 1% of the general population worldwide (Catassi et al.
2015; Lionetti et al. 2015). GFD is also taken by healthy
people aiming for better health, but the potential usage of
GFD in preventing obesity and diabetes is controversial
(Haupt-Jorgensen et al. 2018).
Zafeiropoulou et al. (2020) compared the gut micro-
biota of celiac disease children on GFD (45 patients) and
gluten-containing diets (20 patients). And then, among
these 20 children on gluten-containing diets, 13 patients
participated in a 12 months prospective study and started
to consume GFD (Zafeiropoulou et al. 2020). Their fecal
samples were collected at six months and 12 months on
GFD and analyzed by 16s ribosomal RNA sequencing. In
their cross-sectional study, Zafeiropoulou et al. identified
51 Operational taxonomic units (OTUs) with significantly
higher abundance, and three OTUs with significantly
lower abundance in GFD diet children (Zafeiropoulou
et al. 2020). In the prospective study, they found seven
significantly decreased and three increased OTUs in the
Table 7  The impacts of GFD on gut microbiota, secondary metabolites and metabolic status
Microbiota
Family Genus
GFD Enterobacteriaceae↑ Roseburia↓
Bacteroidaceae↑ Bifidobacterium↓
Clostridiaceae↑ Lactobacillus↓
Victivallaceae↑
Lachnospiraceas↓
Veillonellaceae↓
GFD gluten-free diet, SCFA short chain fatty acid, NAFLD nonalcoholic fatty liver disease
13
Y. Liu et al.
samples at both six and 12 months on GFD compared to
baseline samples.
The effects of GFD on healthy people were
also investigated. The abundance of  Bifidobacte-
rium,  Clostridium lituseburense, and  Faecalibacte-
rium prausnitzii was decreased but the abundance of Enter-
obacteriaceae  and  Escherichia coli  was increased in
healthy people after one month of GFD consumption (De
Palma et al. 2009). The results from a similar clinical trial
on healthy adults on GFD for one month demonstrated that
GFD can decrease the abundance of some beneficial bacte-
ria, such as Bifidobacterium longum and Lactobacillus, but
also increase the abundance of Enterobacteriaceae, which
is regarded as harmful bacteria (Sanz 2010). Bonder et al.
(2016) investigated the change in intestinal microbiota of
21 healthy participants who were kept on GFD for four
weeks, and their results showed that the abundance of Veil-
lonellaceae changed most obviously in GFD and its abun-
dance was markedly decreased. Besides, the abundance
of Ruminicoccus bromii and Roseburia was also decreased
by GFD (Bonder et al. 2016). On the contrary, the abun-
dance of Victivallaceae, Clostridiaceae, and Coriobacte-
riaceae was increased (Bonder et al. 2016).
GFD will lead to the change of metabolites of intestinal
microbiota (Table 7). As mentioned above, GFD decreases
the abundance of Bifidobacterium and Lactobacillus, both
were the source of SCFAs. Therefore, it is not a surprise to
see that GFD consumers have a lower circulating level of
SCFAs (Di Cagno et al. 2011; Garcia-Mazcorro et al. 2018).
Given the strong impacts of SCFAs on insulin sensitivity
(Hernandez et al. 2019), logically, the decreased circulat-
ing level of SCFAs by GFD will increase the risk of meta-
bolic diseases. Indeed, GFD consumption increased the risk
of NAFLD in Celiac disease patients (Tovoli et al. 2018;
Imperatore et al. 2018). Although some studies suggest that
GFD consumption reduced the risk of obesity and diabetes
(Haupt-Jorgensen et al. 2018), others argued that GFD might
aggravate obesity, serum lipid levels, insulin resistance, and
atherosclerosis (Alzaben et al. 2015; Anania et al. 2017;
Kemppainen et al. 1995; Mariani et al. 1998). More studies
are needed to increase our understanding of how a GFD is
Secondary metabolites Metabolic status
Species
R. bromii↓ SCFA↓ NAFLD↑
C. lituseburen↓ Hepatic steatosis↑
F. prausnitzii↓ Serum Lipid levels↑
E. coli↑ Insulin resistance↑
B. longum↓ Atherosclerosis↑
Diets, Gut Microbiota and Metabolites
associated with metabolic disease and to apply GFD effec-
tively and safely.
Conclusion
Leveraging advanced technology, researchers have made
huge progress in the identification and systematization
of microbiota in the past decades. However, researchers
realized a big obstacle when generalizing results from
the previous literature: the inconsistency among differ-
ent  laboratories (Bier et  al. 2020; Bisanz et  al. 2019;
Trefflich et al. 2020), or even within the same laboratory
(Ahn et al. 2014). Many factors contribute to these incon-
sistencies. First, the techniques used for identifying the
microbes are different, from real-time PCR, 16s ribosomal
RNA sequencing to metagenomic sequencing. Second, the
diets provided for the patients are different. For instance,
the fat content and ratio in HFD vary from study to study,
although they are all called HFD. Third, even though the
diets fed to animals are better controlled, the diet storage
condition also makes difference (Yi et al. 2022). Fourth,
the environment in different animal facilities affects the
microbiota in the animals. Fifth, the genetic background
of the research objects also affects the microbiota (Ahn
et al. 2014). A better description of the detailed materials
and methods will be very helpful and necessary in future
microbiota-related publications.
The differences in major components in the diets not
only discriminate them from others but also shape specific
patterns of gut microbiota in the hosts. The proportion of
macronutrients, namely fats, carbohydrates and proteins
in the diets varies in KD, HFD, WD, HGD/HFrD, and
so does the gut microbiota. However, the composition of
the microbiota does not necessarily match the contents of
the macronutrients. For example, fat-rich HFD and WD
both cause a significant increase in the abundance of Fir-
micutes in the hosts' gut (Bisanz et al. 2019; Low et al.
2021), but KD, with an even higher level of fat, induces a
dramatic reduction of Firmicutes (Xie et al. 2017; Zhang
et al. 2018b), and V/VeD, with an extremely low level of
fat, surprisingly increased the abundance of Firmicutes
in the gut (Zhang et al. 2018a). The precise connection
between the components in the diets and the gut micro-
biota still needs a lot of work, with the consideration of
the complicated ecological system in the gut.
Here, we review the large body of data that is struc-
turing our understanding of how the diets alter the gut
microbiota, bacterial metabolites, and the hosts' metabolic
status. Given the large population and fast dynamic of the
gut microbiota, what we have known about gut microbiota
is just the tip of the iceberg. Many questions remain unan-
swered: How do these altered microbes crosstalk with each
other and influence the hosts' pathophysiology? What are
the key sensors or message receivers in the hosts that help
the hosts quickly and harmoniously adapt to the dietary
changes? Nowadays, more and more people acknowledge
the featured diets as medical treatments or nutritional strat-
egies aiming for better health. But, the potential adverse
effects of some diets are underestimated. How the gut
microbiota gets involved in these beneficial and/or harm-
ful effects is largely unknown. Without any doubt, further
research is warranted and will keep extending our knowl-
edge of the gut microbiota.
Acknowledgements  This work was supported by grants from the
National Key R&D Program of China (2019YFA0802300 to S. H.),
Training Program of the Major Research Plan of the National Natu-
ral Science Foundation of China (91957117), National Natural Sci-
ence Foundation of China (31971082), Shanghai Pujiang Program
(18PJ1400500), and Open Research Fund of the National Key Labo-
ratory of Genetic Engineering (SKLGE1805) to S. H., Y.S. was sup-
ported by the Halfond-Weil Postdoctoral Fellowship.
Authors' Contributions  SH concepted  the idea for the article, all
authors contributed to the literature search and data analysis, and YL,
WZ, XL, FS, SH, YS drafted and/or critically revised the work. All
authors read and approved the final manuscript.
Data availability  All data generated or analyzed during this study are
included in this published article (and its supplementary information
files).
Declarations 
Conflict of interest  On behalf of all authors, the corresponding author
states that there is no conflict of interest.
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