ORIGINAL RESEARCH

published: 25 February 2022

doi: 10.3389/fmicb.2022.778512

The Impact of Instant Coffee and

Decaffeinated Coffee on the Gut
Microbiota and Depression-Like
Behaviors of Sleep-Deprived Rats
Xinyi Gu 1,2† , Shuyi Zhang 1,2,3† , Weini Ma 1,2 , Qixue Wang 1,2 , Ying Li 1,2 , Chenyi Xia 4 ,
Ying Xu 4 , Ting Zhang 1,2 , Li Yang 1,2 and Mingmei Zhou 1,2*
1
Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China,
2
Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research,
Shanghai University of Traditional Chinese Medicine, Shanghai, China, 3 School of Rehabilitation Science, Shanghai
University of Traditional Chinese Medicine, Shanghai, China, 4 Department of Physiology, School of Basic Medical Sciences,
Shanghai University of Traditional Chinese Medicine, Shanghai, China

Objective: Based on our previous research, chronic paradoxical sleep deprivation (PSD)
Edited by: can cause depression-like behaviors and microbial changes in gut microbiota. Coffee, as
Ekaterina Avershina, the world’s most popular drink for the lack of sleep, is beneficial to health and attention
Inland Norway University of Applied
Sciences, Norway
and can eliminate the cognitive sequelae caused by poor sleep. The purpose of this
Reviewed by:
study is to investigate the effects of coffee and decaffeinated coffee on PSD rats.
Silvia Arboleya,
Research Design and Methods: A total of 32 rats were divided into four groups:
Institute of Dairy Products of Asturias,
Spanish National Research Council control group, PSD model group, conventional coffee group, and decaffeinated
(CSIC), Spain coffee group. Behavioral tests, including sucrose preference test, open field test,
Zabdiel Alvarado-Martínez,
University of Maryland, College Park, forced swimming test, and tail suspension test, as well as biochemical detection
United States for inflammatory and antioxidant indexes were performed. The effects of coffee and
*Correspondence: decaffeinated coffee on the gut microbiota of PSD rats were investigated by 16S rRNA
Mingmei Zhou
gene sequencing.
[email protected]
† These authors have contributed Results: Coffee and decaffeinated coffee significantly improved the depression-like
equally to this work
behaviors. Moreover, the serum levels of interleukin-6 and tumor necrosis factor alpha
Specialty section: were decreased in both coffee and decaffeinated coffee groups, as well as the levels
This article was submitted to of superoxide dismutase and GSH-Px were increased. Gut microbiota analysis revealed
Microorganisms in Vertebrate
that the abundance of S24-7, Lachnospiraceae, Oscillospira, and Parabacteroides were
Digestive Systems,
a section of the journal significantly increased in PSD rats, while the abundance of Akkermansia and Klebsiella
Frontiers in Microbiology were significantly decreased. After the treatment of coffee and decaffeinated coffee, the
Received: 21 September 2021 abundance of the above gut microbiota was all restored in different degrees. Coffee had
Accepted: 04 January 2022
Published: 25 February 2022 relatively more significant effects on PSD-induced depressive-like behaviors, while the
Citation: difference between coffee and decaffeinated coffee was not obvious in correcting the
Gu X, Zhang S, Ma W, Wang Q, disorder of gut microbiota.
Li Y, Xia C, Xu Y, Zhang T, Yang L and
Zhou M (2022) The Impact of Instant Conclusions: These findings have shown that both coffee and decaffeinated coffee are
Coffee and Decaffeinated Coffee on
effective for sleep deprivation-induced depression-like behaviors and the dysbiosis of
the Gut Microbiota
and Depression-Like Behaviors gut microbiota and indicated that caffeine may be not the only key substance of coffee
of Sleep-Deprived Rats. for regulating gut microbiota.
Front. Microbiol. 13:778512.
doi: 10.3389/fmicb.2022.778512 Keywords: coffee, decaffeinated coffee, sleep deprivation, depression, gut microbiota

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Gu et al. Coffee, Decaffeinated Coffee Regulate Microbiota

INTRODUCTION these effects of using chlorogenic acid alone are not obvious,
considering that it may be the synergistic effect of non-caffeine
As the most consumed drink in the world, coffee is second compounds in coffee (Camfield et al., 2013). To study the
only to water (Butt and Sultan, 2011). In European countries, effects of coffee on humans, Bunker and McWilliams proposed
most adults drink coffee every day (Lopez Garcia et al., 2014). a criteria in 1979 to define decaffeinated coffee and coffee, using
Evidence has been found in recent years that coffee has benefit commercial-branded coffee and espresso (caffeine-containing
to the health. People who drink three or four cups of coffee coffee and caffeine-containing coffee 5 mg per cup) (Adan
a day have a lower risk of developing type 2 diabetes, which et al., 2008). Studying the impact of coffee or decaffeinated
may be due to the presence of green folic acid and caffeine in coffee on cognition can better understand daily habits in life
coffee (George et al., 2008). Moreover, a large amount research and further clarify the benefits of coffee or decaffeinated coffee
reveals that caffeine in the coffee with moderate consumption (Ho and Chung, 2013).
(three-to-five cups, volume not identified) has the effect of Sleep deprivation has become a health problem in the
anti-Alzheimer’s disease (Mahshad and Mazen, 2017). Caffeine modern society (Malinalli et al., 2018). Sleep deprivation
and coffee with a dose of 600 ml/day are helpful to reduce can be acute or chronic (Jamie et al., 2019). By definition,
the risk of depression (Grosso et al., 2016). It is said that 24 h without sleep is acute sleep loss, and less than 6 h
caffeine and modafinil could improve neuroinflammation and of sleep per night for 6 nights or more in a row is
anxiety during sleep deprivation in rats by inhibiting microglial considered chronic sleep deprivation (Krishnan et al., 2016).
activation (Meetu et al., 2018), while an excessive dose of caffeine The consequences of sleep deprivation are enormous, especially
(70 mg/kg) showed anxiogenic effect (Kayir and Uzbay, 2006). in mental illness (World Health Organization, 2017). Evidence
Drinking coffee also can enhance cognitive function, in which suggests that rapid eye movement sleep changes occur in
it is believed that coffee has the benefit for attention and can most patients with mental illness, such as depression (Benca
eliminate cognitive sequelae caused by poor sleep (Franke et al., et al., 1992). Furthermore, sleep deprivation may also occur
2014). However, excessive intake of coffee or caffeine can lead to in the same symptoms (Dieter et al., 2019). A study found
the development of physiological tolerance, and when a habitual that the cytokine secretion induced by low-level exposure of
caffeine consumer suddenly reduces or ceases taking caffeine, he immune cells to bacterial cell wall components contributes
or she may experience withdrawal symptoms (Hughes et al., 1998; to normal sleep patterns, while excessive cytokine levels are
Stachyshyn et al., 2021). associated with disrupted sleep (Galland, 2014). At the same
Coffee contains more than 1,000 different compounds time, recent investigations indicated that the alteration of gut
including phenolics, diterpenes, and melanoidins (Renouf et al., microbiome patterns was evident in people with depression
2014), of which about 1% is caffeine (Hoelzl et al., 2010; Kim (Barandouzi et al., 2020).
et al., 2017). Studies have proven that caffeine can improve Our previous study found that chronic paradoxical sleep
attention measurement and alertness (Haskell et al., 2005; deprivation (PSD) could lead to depression-like behaviors, as
Childs and Wit, 2006). However, excessive caffeine intake can well as dysbiosis in the host’s gut microbiota (Ma et al.,
lead to negative health consequences, such as psychomotor 2019). PSD could alter monoamine neurotransmitters such
agitation, insomnia, headaches, and gastrointestinal discomfort as norepinephrine and serotonin, as well as increase neuro-
(Wierzejska, 2012). Caffeine and its metabolites pass freely inflammatory cytokines including IL-1β and TNF-α, microglial
across the placenta into a fetus. Studies have shown that it activation, and neuronal apoptosis in the brain (Daniele et al.,
may bring damage to the fetus by affecting the expression of 2017; Mengmei et al., 2017). Sleep deprivation also leads to an
genes related to cell damage (Abdelkader et al., 2013). Some accumulation of reactive oxygen species and oxidative stress,
recent systematic reviews have shown that moderate intake specifically in the gut (Alexandra et al., 2020). In addition,
(three cups a day) of various types of coffee can reduce all- some preclinical studies have shown that gut microbiota can
cause mortality in healthy people. These benefits may be due to affect behaviors and brain conditions through neuroimmunity,
some biologically active compounds instead of caffeine, mainly neuroendocrine, neural, and humoral pathways (Dinan and
phenolic acids and diterpenoids, like cafestol and kahweol (Ding Cryan, 2013; Kelly et al., 2016). Coffee has been proven to regulate
et al., 2015; Tsujimoto et al., 2017; Li et al., 2019). Thus, the gut microbiota (González et al., 2020), which depends more
decaffeinated coffee appeared on the market. Decaffeinated on polyphenols and other non-digestible constituents of coffee
coffee contains only a small amount of caffeine, and the like polysaccharides and melanoidins (Kolb et al., 2020). Coffee
International Coffee Organization defines that the content of is the most common beverage used to combat fatigue and
caffeine is less than 0.3% in decaffeinated coffee. Chlorogenic fatigue caused by sleep deprivation, while decaffeinated coffee is
acid, a kind of phenolic phytochemicals, can represent the considered as a healthier alternative to traditional coffee. For the
principal non-caffeine components in coffee. Decaffeinated coffee purpose of better understanding the effects of these two beverages
with high chlorogenic acid content improves alertness and on sleep deprivation, we first observed the intervention effect of
reduces negative emotions (Camfield et al., 2013). However, coffee and decaffeinated coffee on the PSD rat model induced by
multi-platform technology, mainly related to depression-related
Abbreviations: FST, forced swimming test; GSH-Px, glutathione peroxidase; IL-
behavioral changes and serum inflammation and oxidative
6, interleukin-6; OFT, open field test; PSD, paradoxical sleep deprivation; SOD,
superoxide dismutase; SPT, sucrose preference test; TNF-α, tumor necrosis factor stress indicators. Then, we investigated their impacts on the
alfa; TST, tail suspension test. corresponding alterations in the gut microbiota.

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Gu et al. Coffee, Decaffeinated Coffee Regulate Microbiota

MATERIALS AND METHODS standing upright with hind legs). Every grooming or rearing was
counted as one point alone, every grid crossed was counted as one
Materials point, and the behavioral score was the total number of points.
Commercial instant coffee powder (200 mg/kg; Nestlé, La The open-field arena was thoroughly cleaned with 70% ethanol
Tour-de-Peilz, Switzerland) and decaffeinated coffee powder at the interval of each test.
(200 mg/kg; Nestlé, La Tour-de-Peilz, Switzerland) were
Sucrose Preference Test
dissolved in pure water as previously described (Shin et al., 2010;
Turner et al., 2012). Each group was administered by gavage in The sucrose preference test (SPT) was performed as previously
the same volume (0.5 ml/100 g) once a day. Rats in the control described (Zhai et al., 2015). All rats were reared in a single
and the model group were given saline. cage during the experiment. The rats were trained to adapt by
exposing them to two bottles (one containing 1% sucrose solution
Animals and the other containing tap water) for 24 h. Then, the test
A total of 32 inbred-strain male Wistar rats [240 ± 10g, license: was performed after 4 h of water deprivation. Two bottles (one
SCXK (Hu) 2008-0016] were purchased from Shanghai Sippr-BK with 1% sucrose solution and the other with tap water) were
Laboratory Animal Co., Ltd. The rats of the same group were weighed and presented to each rat for 1 h. The position of the two
housed in animal cages at a density of 4 per cage under standard bottles was randomly determined. Sucrose solution and tap water
experimental conditions (room temperature for 24 ± 1◦ C, consumption (g) were measured, and the sucrose preference
relative humidity for 55 ± 15% and 12 h dark/light cycle [07:00– was calculated using the equation: sucrose solution (g)/[sucrose
19:00 at 40 w light condition)]. The rats had free access to food solution (g) + water (g)] × 100%.
and water. Animal welfare and experimental protocols strictly Forced Swimming Test
referred to the guide of the care and use of laboratory animals and
After administration, each rat was placed in a transparent
the ethics and regulations of Shanghai University of Traditional
container (50 cm in height, 18 cm in diameter) with water in
Chinese Medicine. After the rats have been adaptively fed for
30 cm depth (25 ± 1◦ C). The test lasted 6 min, and the immobility
1 week, they were randomly divided into four groups as follows:
time during the final 4 min was recorded by the person blinded to
control group (CON), PSD model group (SD), conventional
the purpose of the experiment. The immobility state was defined
coffee group (CC), and decaffeinated coffee group (DC). Coffee
as the state of rats floating in the water and only keeping the
and pure water were administrated on 9:30 a.m. of each day
head above the water without struggling or any motions. The
of PSD processing.
test time was from 14:00 to 18:00, and the water was changed
Paradoxical Sleep Deprivation Procedure after each test.
The modified multi-platform method was used for PSD Tail Suspension Test
processing as described (Cheng et al., 2016). The method was
Each rat was individually suspended 50 cm above the floor by the
based on the loss of muscle tone that characterizes the rapid
tail, using a tape. The test lasted 6 min, and the immobility time
eye movement sleep condition or paradoxical sleep. Animals
during the final 4 min was recorded by the person blinded to the
would experience a sudden loss of the sleep cycle when falling
purpose of the experiment. The immobility state was defined as
into the water, and the method is proved to be feasible in the
the state only when rats remain completely motionless. The test
previous study (Machado et al., 2004). The rats were given free
time was from 14:00 to 18:00.
access to water and food in a climate-controlled room (24 ± 1◦ C,
55 ± 15%) on a 12 h light/dark schedule (light on at 07:00–19:00). Sample Collection
The box for PSD was sterilized with 75% alcohol every day. The
After the last sleep deprivation and administration were
PSD procedure lasted for 7 days.
performed, the rats were individually housed in a metabolic
cage, which could separate and collect urine and feces. Fresh
Behavioral Testing
When the PSD was finished on the morning of the eighth day, feces were collected continuously with sterile operation (Eriksson
the behavioral tests of each group were performed under the et al., 2004; Ward and Hubscher, 2012), and stored at −80◦ C
conditions of dim light and low noise in the following order. Each for subsequent analysis. Then rats were sacrificed, and blood was
test started 30 min after the daily administration of coffee. collected from the abdominal aorta. Blood was centrifuged at 4◦ C
at 3,000 r/min for 15 min (Centrifuge 5702R, Eppendorf), and the
Open Field Test supernatants were stored at −80◦ C prior to use.
The open field test (OFT) was performed as previously
described (Zhai et al., 2015). The test was performed in a Biochemical Parameters in Serum
quiet room. The apparatus is a self-made rectangular arena Serum samples were thawed on ice. The levels of interleukin-
(80 cm × 80 cm × 40 cm), with the floor being divided into 25 6 (IL-6), tumor necrosis factor alpha (TNF-α), superoxide
equal-size squares, and the side walls were black. After the PSD dismutase (SOD), and glutathione peroxidase (GSH-Px)
procedure, the rats were set in the center of the arena one by in serum samples were detected by commercial enzyme
one to explore for 5 min. The following behaviors were recorded: linked immunosorbent assay (ELISA) kits, referring to the
the number of crossing (grid lines crossed with at least three instructions provided by the manufacturer (Nanjing Jiancheng
paws) and the total number of grooming and rearing (defined as Bioengineering Institute, Nanjing, China).

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Gu et al. Coffee, Decaffeinated Coffee Regulate Microbiota

Microbial Community Profiling Conventional coffee significantly increased the total behavioral
The E.Z.N.A. soil DNA Kit (Omega Bio-Tek, Norcross, GA,
R score (P < 0.05), while decaffeinated coffee also increased the
United States) was used to extract the microbial community score (P > 0.05).
genomic DNA from fecal samples. The microbial DNA regions The results of SPT showed the effects of coffee and
V3–V4 of the bacterial 16S rRNA gene were amplified with decaffeinated coffee on the changes of sucrose consumption
primer pairs 338F (50 -ACTCCTACGGGAGGCAGCAG-30 ) and (Figure 1B). Compared to the control group, sucrose
806R (50 -TACHVGGGTWTCTAAT-30 ) (Sinha et al., 2017). consumption was significantly reduced in the PSD model
The PCR product was extracted from 2% agarose gel and group (P < 0.05). However, the sucrose consumption was
purified using the AxyPrep DNA Gel Extraction Kit (Axygen significantly higher after the treatment of conventional coffee
Biosciences, Union City, CA, United States). Purified amplicons and decaffeinated coffee than in the model group (P < 0.01,
were pooled in equimolar and paired-end sequences on P < 0.05).
an Illumina MiSeq PE300 platform/NovaSeq PE250 platform Chronic PSD remarkably increased immobility time in
(Illumina, San Diego, CA, United States) according to the forced swimming test (FST) and tail suspension test (TST)
standard protocols by Majorbio Bio-Pharm Technology Co., (Figures 1C,D) (P < 0.05). The immobility time in the
Ltd. (Shanghai, China). The raw reads were deposited into the conventional coffee and decaffeinated coffee group was
NCBI Sequence Read Archive database (Accession Number: significantly lower than the PSD model group (P < 0.01,
SRP337042; PRJNA762663). P < 0.05).
Fastp software (1 version 0.20.0) and FLASH software
2
( version 1.2.7) were used for the quality control of the original Coffee and Decaffeinated Coffee
sequencing sequence and splicing (Magoč and Salzberg, 2011; Ameliorate the Level of Inflammatory
Shifu et al., 2018). UPARSE software (3 version 7.1) was used and Antioxidant Factors in PSD Rats
to perform an operational taxonomic unit (OTU) clustering The effects of conventional coffee and decaffeinated coffee on
of sequences based on 97% similarity, as well as to eliminate inflammatory factors and antioxidant factors in the serum of
chimeras (Stackebrandt and Goebel, 1994; Edgar, 2013). The PSD rats were investigated (Table 1). Compared with the control
Venny 2.14 was employed to map the Venn diagram of OTUs group, the levels of IL-6 and TNF-α in PSD rats were significantly
among four groups. Alpha diversity index (Chao1 index, Ace increased (P < 0.001, P < 0.01). IL-6 and TNF-α levels were
index, Simpson index, and Shannon index) was based on Mothur remarkably decreased after the treatment of conventional coffee
9 (version 1.30.25 ), and beta diversity was performed based on (P < 0.01, P < 0.05), and the level of TNF-α was significantly
partial least squares discriminant analysis (PLS-DA) for assessing decreased with the treatment of decaffeinated coffee (P < 0.05).
the clustering patterns on the weighted UniFrac matrices and the Furthermore, the levels of SOD and GSH-Px in the model group
ANOSIM function of QIIME 11 (version 1.9.16 ). were much lower than in the control group (P < 0.01, P < 0.001).
The levels of SOD and GSH-Px were significantly increased with
Data Statistical Analysis the treatment of conventional coffee (P < 0.05, P < 0.01), and the
All the data were presented as mean ± standard deviation. The level of GSH-Px was significantly increased after the treatment of
statistical analyses were carried out using IBM statistical product decaffeinated coffee (P < 0.05).
and service solutions (SPSS) Statistic Version 21.0 (SPSS; IBM,
Armonk, NY, United States). One-way ANOVA test and two Effects of Coffee and Decaffeinated
tailed Student’s t-test were used to analyze significant differences
between the two groups. A p-value of less than 0.05 or 0.01 was
Coffee on the Gut Microbiota
considered statistical significance. Composition
OTU Classification Statistics
The number of OTUs of each sample, as well as common and
RESULTS unique OTUs, was shown by the Venn diagram (Supplementary
Figure 1), which could describe sample similarity and overlap
Coffee and Decaffeinated Coffee intuitively (Cheng et al., 2016). The OTUs alone in each group
Improved the Depressive-Like Behaviors were as follows: CON group 479; SD group 663; CC group 494;
and DC group 465. The total number of OTU in each group was
in PSD Rats
3,359 (CON), 3.814 (SD), 3,458 (CC), and 3,430 (DC). Therefore,
After 7 days of sleep deprivation procedure, as showed in
the ratio of the OTU alone in each group to the total OTU was
Figure 1A, the total behavioral score in the PSD model group
3.41, 4.72, 3.51, and 3.31%, respectively. A total of 1,343 OTUs
was significantly lower than the control group (P < 0.001).
were shared among the four groups. The results showed that the
1
https://github.com/OpenGene/fastp out number of the PSD model group increased, while both coffee
2
http://www.cbcb.umd.edu/software/flash and decaffeinated coffee treatments could reduce it.
3
http://drive5.com/uparse/
4
http://bioinfogp.cnb.csic.es/tools/venny/index.html The Diversity of the Gut Microbiota
5
https://www.mothur.org/wiki/Download_mothur The Chao1 index, Ace index, Simpson index, and Shannon index
6
http://qiime.org/install/index.html were selected to analyze the alpha diversity (Figure 2). The

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Gu et al. Coffee, Decaffeinated Coffee Regulate Microbiota

FIGURE 1 | Effects of coffee and decaffeinated coffee on different behaviors in the PSD model. Total behavior score (A), sucrose consumption (B), immobility time of
FST (C), immobility time of TST (D). Values were expressed as means ± SEM (n = 8). *P < 0.05, ***P < 0.001 significant differences compared to the control group;
# P < 0.05, ## P < 0.01 significant differences compared to the SD group. CON, control group; SD, PSD model group; CC, conventional coffee group; DC,

decaffeinated coffee group.

TABLE 1 | Inflammatory and antioxidant factors in the serum.

Parameter n CON SD CC DC

IL-6 (pg/ml) 8 4.19 ± 1.04 17.58 ± 3.71*** 10.25 ± 3.01## 14.03 ± 2.42
TNF-α (pg/ml) 8 5.07 ± 0.79 12.57 ± 2.67** 8.34 ± 3.16# 9.22 ± 2.66#
SOD (U/ml) 8 156.32 ± 11.61 104.57 ± 13.45** 140.35 ± 15.26# 137.88 ± 16.39
GSH-Px (U/ml) 8 319.23 ± 22.70 167.53 ± 17.13*** 217.53 ± 27.35## 193.50 ± 23.62#

Values were expressed as means ± SEM.

**P < 0.01, ***P < 0.001 significant differences compared to the control group; # P < 0.05, ## P < 0.01 significant differences compared to the SD group.
CON, control group; SD, PSD model group; CC, conventional coffee group; DC, decaffeinated coffee group.

value of Simpson was significantly decreased, and the value of group. These results indicated that PSD caused disturbances in
Shannon was significantly increased in the PSD model group the gut microbiota. The treatment of conventional coffee and
compared with the control group (P < 0.01, P < 0.01). After decaffeinated coffee could improve the PSD-induced changes in
the administration of conventional coffee, the value of Simpson the gut microbiota, and both had similar therapeutic effects.
was significantly increased and the value of Shannon was
significantly lower than that in the PSD model group (P < 0.05, Analysis of the Gut Microbiota Composition
P < 0.05), while those values had no significantly changes with At the phylum level, gut microbiota was mainly composed of
the administration of decaffeinated coffee. Firmicutes, Verrucomicrobia, Proteobacteria, and Bacteroidetes
PLS-DA analysis was performed to analyze the beta diversity (Figure 4A). Compared with the control group, the abundance
among the four groups. As shown in Figure 3, the composition of Firmicutes and Bacteroidetes was remarkably elevated in
of the gut microbiota of the control group and the PSD model the model group (P < 0.05, P < 0.001). After the treatment
group was significantly separated and changed. In addition, of conventional coffee, the abundance of Firmicutes and
the composition of the gut microbiota of the conventional Bacteroidetes was significantly reduced (P < 0.05, P < 0.001),
coffee group and the decaffeinated coffee group was similar, and and after the treatment of decaffeinated coffee, only the
both tended to be closer to the control group than the model abundance of Bacteroidetes had a significant decrease (P < 0.001).

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Gu et al. Coffee, Decaffeinated Coffee Regulate Microbiota

FIGURE 2 | Alpha diversity in each group. Chao1 diversity (A); Ace diversity (B); Simpson diversity (C); Shannon diversity (D). Values were expressed as
means ± SEM (n = 6 or 7). **P < 0.01 significant differences between the SD group and the control group; # P < 0.05 significant differences of the CC group or DC
group as compared to the SD group. CON, control group; SD, PSD model group; CC, conventional coffee group; DC, decaffeinated coffee group.

Moreover, compared with the control group, the abundance (P < 0.01), Parabacteroides (P < 0.05), and Klebsiella (P < 0.05)
of Verrucomicrobia was remarkably decreased in the model were the differential microbiota of the top six highest contents,
group (P < 0.001). With the treatment of conventional coffee between the PSD and normal group (Figures 6A,B). After
and decaffeinated coffee, the abundance of Verrucomicrobia was the treatment of conventional coffee, the abundance of
significantly reversed (P < 0.001, P < 0.01). After decaffeinated Akkermansia (P < 0.001), S24-7_norank (P < 0.001),
coffee treatment, the abundance was still much lower than the Lachnospiraceae_unclassified (P < 0.01), Oscillospira (P < 0.05),
control group (P < 0.05). For the abundance of Proteobacteria, and Klebsiella (P < 0.01) significantly reversed, while the
there was no significant difference between the model group and abundance of Akkermansia (P < 0.01), S24-7_norank (P < 0.01),
the control group, and after the administration of conventional Lachnospiraceae_unclassified (P < 0.001), Parabacteroides
coffee and decaffeinated coffee, the abundance was much higher (P < 0.05), and Klebsiella (P < 0.01) significantly reversed after
than the model group (P < 0.05, P < 0.05) and the control group the treatment of decaffeinated coffee (Figure 6B).
(P < 0.05, no statistical significance) (Figure 4B).
At the family level, the abundance of Verrucomicrobiaceae
(P < 0.001), S24-7 (P < 0.001), Ruminococcaceaea (P < 0.01), DISCUSSION
Enterobacteriaceae (P < 0.001), Porphyromonadaceae (P < 0.05),
and Lachnospiraceae (P < 0.01) showed a significant difference Chronic sleep deprivation is a stressor that impairs the brain
between the PSD and normal group (Figures 5A,B). Compared function and causes cognitive impairment, as well as increases
with the PSD model group, those relatively abundance except oxidative stress and the risk for Alzheimer’s disease or depression
Porphyromonadaceae were significantly reversed after the (McEwen, 2006; Ma et al., 2019). The results of the behavior
treatment of conventional coffee, and those relatively abundance tests in our study showed the similar depression-like behaviors
except Ruminococcaceae were significantly reversed after the after PSD induced, and the symptom could be improved in
treatment of decaffeinated coffee (Figure 5B). a different extent with the treatment of conventional coffee
At the genus level, Akkermansia (P < 0.001), S24-7_norank and decaffeinated coffee (Figure 1). It has been reported that
(P < 0.001), Lachnospiraceae_unclassified (P < 0.01), Oscillospira caffeinated coffee and caffeine were beneficial to depression-like

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Gu et al. Coffee, Decaffeinated Coffee Regulate Microbiota

and soluble fiber on oxidative stress is increasing these years

(Martini et al., 2016). It has been reported that chronic coffee
and caffeine ingestion would increase the activity of SOD, as
well as protect the antioxidant system in the brain (Abreu
et al., 2011). Light-dark roasted coffee (rich in chlorogenic
acid) showed a more significant effect in increasing the level
of SOD (Kotyczka et al., 2011). Evidence showed that some
diterpenoids (kafestol and kahweol) in coffee could increase
the concentration of GSH (Scharf et al., 2001). Furthermore,
caffeine also has the exact effect of antioxidant and anti-
inflammatory (Daniela et al., 2017; Soohan et al., 2017;
Haroon et al., 2019).
Coffee has been confirmed to confer various health benefits,
and drinking coffee can alter a host’s gut microbiota (Chong
et al., 2020). Coffee may partly depend on the modulation of
gut microbiota to influence health (González et al., 2020). It
has been proven that polyphenols in coffee can change the
environment, or they can be catabolized by gut microbiota
(Aura, 2008; Couteau et al., 2010). In the microbial community
profiling, both caffeinated coffee and decaffeinated coffee could
reduce the number of OTUs that increased after PSD induction.
FIGURE 3 | PLS-DA score plots for beta diversity of the microbial community Only the Simpson index and Shannon index in alpha diversity
among each group (n = 6 or 7). CON, control group; SD, PSD model group;
CC, conventional coffee group; DC, decaffeinated coffee group.
index were restored significantly after coffee treatment. In
the beta diversity analysis, there was a significant separation
between the control group and the model group. With the
treatment of coffee and decaffeinated coffee, the composition
behaviors, while the effect of decaffeinated coffee was not obvious of the gut microbiota tended to approach the control group,
(Paz-Graniel et al., 2020; Xue et al., 2020). which indicated that both coffee and decaffeinated coffee restored
Elevated levels of IL-6 and TNF-α, as well as a negative the composition of the gut microbiota of PSD rats. In our
feedback of SOD and GSH-Px levels in the PSD group (Table 1) results, the levels of Akkermansia (Phylum Verrucomicrobia) and
confirmed that sleep deprivation induced inflammation and Klebsiella (Phylum Proteobacteria) were significantly decreased
oxidative stress. Both IL-6 and TNF-α are the multifunctional in the rats with sleep deprivation (Figure 6B). As a Gram-
cytokines involved in the regulation of the immune response negative pathogen, Klebsiella could cause a variety of infectious
and inflammation, and the production of these pro-inflammatory diseases (Guoying et al., 2020) and has the effect of inducing
cytokines could be increased by different stimuli (Akira the inflammatory response (Atarashi et al., 2017; Marjolaine
et al., 1990; Schindler et al., 1990). As one of the stimuli, et al., 2019). It has been reported that when the Proteobacteria
sleep disturbance was associated with disorders related to increases, intestinal mucus would decrease, resulting in damage
inflammation, such as cardiovascular disease, arthritis, diabetes to the intestinal barrier and low-grade inflammation (Shin et al.,
mellitus, and certain cancers (Michael et al., 2015). In addition, 2015). In our results, sleep deprivation caused an increase in
evidence suggested that sleep deprivation would promote the expression of inflammatory factors, while a decrease in the
oxidative stress (Villafuerte et al., 2016). In our study, the levels pro-inflammatory bacteria Proteobacteria. This indicated that the
of IL-6, TNF-α, SOD, and GSH-Px were all reversed after the inflammation caused by sleep deprivation might be not through
treatment of conventional coffee and decaffeinated coffee, while the gut microbiota pathway. The decrease of Akkermansia
the effect of coffee was relatively more significant than that of is commonly observed in the symptom of sleep deprivation
decaffeinated coffee (Table 1). The anti-inflammatory effect of (Heintz-Buschart et al., 2018; Ting et al., 2019). Akkermansia
coffee has been widely reported (Yamashita et al., 2012; Erikka is known as a beneficial microbe that is inversely associated
et al., 2015). In our study, both in the caffeinated coffee group with obesity, diabetes, cardiometabolic diseases, and low-grade
and the decaffeinated coffee group, a decrease in the levels inflammation (Plovier et al., 2016; Patrice and Willem, 2017).
of pro-inflammatory factors was observed, and the therapeutic With treatment of conventional coffee and decaffeinated coffee,
effect of caffeinated coffee was more obvious, which indicated both levels of Akkermansia were increased significantly, and the
that not only caffeine but also the other ingredients in coffee effect of coffee was more obvious (Figure 6B). A study has
played a role in promoting anti-inflammatory effect, such as found that coffee has antibacterial effects and prebiotic function
chlorogenic acid (Dong et al., 2019). Chlorogenic acid can (Nakayama and Oishi, 2013). Compared to caffeine, which is
inhibit protein tyrosine phosphatase 1B to reduce the expression rapidly absorbed and degraded in the upper digestive tract,
of pro-inflammatory cytokine genes (Giuseppe et al., 2017). polyphenols are difficult to be absorbed in the gastrointestinal
Research on the effect of coffee and its biologically active tract. This caused most of the polyphenols to enter the intestine
substances such as caffeine, phenolic compounds, diterpenoids. and affect the gut microbiota and mucosal cells and increase of

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Gu et al. Coffee, Decaffeinated Coffee Regulate Microbiota

FIGURE 4 | Relative abundances profiling at the phylum level of gut microbiota. (A) Pie chart of the relative abundances of gut microbiota in each group; (B) the
relative abundances of Firmicutes, Verrucomicrobia, Proteobacteria, and Bacteroidetes. Values were expressed as means ± SEM (n = 8). ∗ P < 0.05, ∗∗∗ P < 0.001
significant differences compared to the control group; # P < 0.05, ## P < 0.01, ### P < 0.001 significant differences compared to the SD group. CON, control group;
SD, PSD model group; CC, conventional coffee group; DC, decaffeinated coffee group.

FIGURE 5 | Bacterial taxonomic profiling at the family level of gut microbiota. (A) The relative abundance of Verrucomicrobiaceae, S24-7, Ruminococcaceaea,
Enterobacteriaceae, Porphyromonadaceae, and Lachnospiraceae; (B) values were expressed as means ± SEM (n = 8). *P < 0.05, **P < 0.01, ***P < 0.001
significant differences compared to the control group; # P < 0.05, ## P < 0.01, ### P < 0.001 significant differences compared to the SD group. CON: control group;
SD: PSD model group; CC: conventional coffee group; DC: decaffeinated coffee group.

the abundance of Akkermansia in the intestine (Yuji et al., 2018). reactions in the host (Kaisa et al., 2020). Akkermansia and
A study has shown that tea is rich in polyphenols and caffeine Klebsiella, also Gram-negative bacteria, had lower levels in the
plays a key role in remodeling the disturbed gut microbiota PSD group, compared to the normal control, and high levels of
(including Akkermansia), which may be a synergistic effect inflammatory factors were detected after PSD intervention. These
(Xiaoyu et al., 2018). indicated that the inflammatory response might not necessarily
Our results illustrated that the abundance of Parabacteroides be caused by Parabacteroides, Akkermansia, and Klebsiella, but
(Phylum Bacteroidetes) in the PSD group was significantly higher rather be caused by the release of lipopolysaccharide from other
than the normal control. As a kind of Gram-negative bacteria, types of Gram-negative bacteria or other stress response in
Parabacteroides contains lipopolysaccharide, which is a typical the host. In addition, a high level of Parabacteroides can be
potent endotoxin that can induce strong pro-inflammatory found in patients with depression (Barandouzi et al., 2020),

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Gu et al. Coffee, Decaffeinated Coffee Regulate Microbiota

FIGURE 6 | Bacterial taxonomic profiling at the genus level of gut microbiota. (A) The relative abundance of Akkermansia, S24-7_norank,
Lachnospiraceae_unclassified, Oscillospira, Parabacteroides, and Klebsiella; (B) values were expressed as means ± SEM. (n = 8). *P < 0.05, **P < 0.01,
***P < 0.001 significant differences compared to the control group; # P < 0.05, ## P < 0.01, ### P < 0.001 significant differences compared to the SD group. CON,
control group; SD, PSD model group; CC, conventional coffee group; DC, decaffeinated coffee group.

and our results also showed depression-like behaviors after role in host defense and immunity, including anti-inflammation
PSD induced. With the treatment of decaffeinated coffee, the and anti-oxidant activities. The increase of these gut microbiota
decrease of the level of Parabacteroides was relatively more related to fatty acid metabolism indicated that sleep deprivation
significant than the conventional coffee group. Polyphenols would lead to metabolism disorders, inflammation, and oxidative
in the decaffeinated green tea and black tea could regulate stress. After the administration of conventional coffee and
the abundance of Parabacteroides and induced weight loss decaffeinated coffee, the relative abundance of these gut bacteria
(Rothenberg et al., 2018). For example, chlorogenic acid decreased in different degrees, and coffee had a relatively more
can protect intestinal integrity and reduce inflammation by significant effect. Caffeine consumption could attenuate the
inhibiting the growth of Bacteroides and the accumulation increase in Firmicutes-to-Bacteroidetes ratio in high-fat-fed rats
of Bacteroides-derived lipopolysaccharide (Yan et al., 2020). (Cowan et al., 2014). Interestingly, some recent studies have
In addition, evidence has indicated that both caffeinated and now shown that the increase in this ratio has no relation with
decaffeinated coffee have a similar anti-inflammatory effect the presence of high- fat diet but only related to the content of
(Dong et al., 2019), and not only caffeine, but also some dietary fiber (Dalby et al., 2017; Singh et al., 2020). Moreover,
phenols including pyrocatechol, chlorogenic acid, and so on, due to lifestyle-associated factors such as diet, physical activity,
can prevent the inflammatory responses (Hwang et al., 2016; food additives, and contaminants, the relative abundance of the
Stefanello et al., 2018; Megumi et al., 2020). Therefore, Firmicutes and Bacteroidetes varies greatly among individuals
caffeine and phenols exert anti-inflammatory effects by affecting (Magne et al., 2020). Caffeine intake is linked to weight loss
different gut microbiota. and the regulation of lipid metabolism, partly through its
In our study, the relative abundance of Lachnospiraceae inhibition of adipogenesis-related factors (Su et al., 2013).
(Phylum Firmicutes), S24-7 (Phylum Bacteroidetes), and It has been reported that some phenols and caffeine were
Oscillospira (Phylum Firmicutes) were significantly increased in directly associated with Bacteroides group levels (González
the SD group (Figure 6B). Lachnospiraceae and S24-7 impact et al., 2020). A study has found that caffeine and chlorogenic
their hosts by producing short-chain fatty acids (SCFAs) (Jennifer acid in coffee have a partially positive effect to the SCFAs in
et al., 2017; Matthew et al., 2020). In patients with ulcerative plasma (Kazuchika et al., 2018). The reaction of polyphenols
coliti, an increase in the level of Lachnospiraceae could be in tea with residual carbohydrates and gut microbiota within
observed (Schirmer et al., 2019), which could be explained by the colon produce SCFAs, which enhance lipid metabolism
the fact that stress increases the abundance of Lachnospiraceae (Rothenberg et al., 2018).
(Li et al., 2017). As shown in our study, after the stress of sleep As shown in the previous studies, the differential gut
deprivation, the level of Lachnospiraceae increased significantly. microbiota in our study is commonly seen in patients with
However, as a butyric acid-producing bacteria, increasing the depression (Zheng et al., 2016; Cheung et al., 2019). Gut
content of Lachnospiraceae also has a beneficial effect to the microbiota influences the emotional behavior by affecting
body (Huws et al., 2011; Dong et al., 2020). Oscillospira can be the interactions of the gut–brain axis (Emeran et al., 2015),
seen in the obese animals, which ferments polysaccharide into and sleep deprivation would increase the risk of depression
SCFAs (Na et al., 2018). In addition, Oscillospira is correlated (Robert and Hao, 2014). Chronic PSD could bring about
with inflammatory disease (Uri et al., 2017). SCFAs are involved depression-like performance, which is proven by our study and
in the regulation of the gut immune system, and the production previous researches (Ma et al., 2019; Rahmani et al., 2020).
of the SCFAs is one of the crucial ways that gut microbiota affect In the behavior tests of our study, the effect of coffee to
the hosts (Jost et al., 2020). Besides, SCFAs play an important improve depression is more significant than the decaffeinated

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Gu et al. Coffee, Decaffeinated Coffee Regulate Microbiota

coffee. The main difference between the two drinks is the The effect of conventional coffee was relatively obvious than that
caffeine content. Caffeine is an alkaloid and modulates the of decaffeinated coffee. In microbiome analysis, PSD disturbed
dopaminergic activity through nonspecific antagonism against the composition of gut microbiota, including Akkermansia, S24-
A1/A2 adenosine receptors (Navarro et al., 2018). A moderate 7, Lachnospiraceae, Oscillospira, Parabacteroides, and Klebsiella.
intake of caffeine has a stimulating effect on the central Both the treatment of conventional coffee and decaffeinated
nervous system and can improve psychomotor activities (Adan coffee could restore the abundance levels of these gut microbiota.
et al., 2008). Furthermore, coffee contains many functional In a word, both coffee and decaffeinated coffee are effective
components other than caffeine, such as chlorogenic acid, ferulic for sleep deprivation-induced depression-like behaviors and the
acid, nicotinic acid, trigonelline, quinolinic acid, tannic acid, dysbiosis of gut microbiota. It implies that caffeine is not the
and pyrogallic acid. These compounds have anti-inflammatory only key substance of coffee in the regulation of PSD induced gut
or antioxidative effects. Chlorogenic acid and trigonelline, microbiota disorder.
which are present in high amounts in coffee, have an anti-
inflammatory effect (Godos et al., 2014), and it has been
found that low-grade inflammation seems to be related to DATA AVAILABILITY STATEMENT
the pathogenesis of depression (Sanchez Villegas and Martínez
The datasets presented in this study can be found in online
González, 2013). From our results of the treatment with
repositories. The names of the repository/repositories and
decaffeinated coffee, we know that polyphenols in coffee also
accession number(s) can be found below: https://www.ncbi.nlm.
can improve depression-like behaviors by affecting the gut
nih.gov/, PRJNA762663.
microbiota associated with inflammation such as Akkermansia,
Klebsiella, and Parabacteroides. On the other hand, it has been
suggested that patients with depression have increased oxidative ETHICS STATEMENT
stress and decreased antioxidant defense (Black et al., 2015)
and antioxidant is an important aspect of treating depression The animal study was reviewed and approved by Animal
(Vaváková et al., 2015). Coffee is rich in polyphenols, which not Experiment Center, Shanghai University of Traditional
only has an anti-inflammatory effect but also has antioxidant Chinese Medicine.
activity (Godos et al., 2014; Martini et al., 2016). In our
study, the abundance of the gut microbiota related to oxidative
stress such as S24-7, Lachnospiraceae, and Oscillospira, could AUTHOR CONTRIBUTIONS
be revised by both coffee and decaffeinated coffee. Thus, it
YX, TZ, MZ, CX, and LY accomplished the conception and
is demonstrated that the anti-inflammatory and antioxidant
design of the research. XG, SZ, WM, QW, and YL performed the
effects of polyphenols may be through regulating the gut
experiments. XG and SZ prepared the figures. XG, WM, and SZ
microbiota, further playing a role in the treatment of depression
analyzed and interpreted the data. XG, WM, and YL drafted the
induced by chronic PSD.
manuscript. MZ edited and revised the manuscript. MZ and LY
Some limitations must be considered when interpreting our
approved final version of the manuscript. All authors read and
results. The manufacturing procedure of the instant coffee
approved the final manuscript.
powder we used in the experiment involves the aqueous
extraction of soluble coffee components followed by drying
to form a soluble powder. Although there are no other FUNDING
food additives, the loss of volatile aroma compounds during
concentration through evaporation will lower product quality This work was supported by Natural Science Foundation of
(Beverly et al., 2020), and at the same time, the results of the Shanghai, no. 21ZR1460900, and also sponsored by Innovation
study could not fully represent the activity of coffee. In addition, Project for Undergraduates of Shanghai University of Traditional
the study lacks the analysis of the components of the samples, Chinese Medicine (202110268240).
although there are other relevant literatures for reference, as well
as the analysis of the metabolites of gut microbiota (such as
SCFAs), these need to be strengthened in future research to better ACKNOWLEDGMENTS
judge the role of gut microbiota in coffee on sleep deprivation.
We would like to thank Jing Song for her efforts in animal
experiments and sample analyzation. We would also like
to acknowledge the support from the Majorbio Company
CONCLUSION (Shanghai, China).
In this study, 16S rRNA gene sequencing was applied to assess
the effects of conventional coffee and decaffeinated coffee on the SUPPLEMENTARY MATERIAL
gut microbial community profiling. Our results revealed that the
administration of conventional coffee and decaffeinated coffee The Supplementary Material for this article can be found online
ameliorated depression-like behaviors in rats of PSD induced, as at: https://www.frontiersin.org/articles/10.3389/fmicb.2022.
well as the changed levels of IL-6, TNF-α, SOD, and GSH-Px. 778512/full#supplementary-material

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Gu et al. Coffee, Decaffeinated Coffee Regulate Microbiota

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