Abstract
Introduction: Recent studies indicate that the gut microbiota controls the host’s immune system. Probiotics use different signaling pathways to regulate intestinal permeability, barrier integrity, and energy balance. Methods: This research examined how Akkermansia muciniphila and its extracellular vesicles (EVs) impact inflammation and genes related to the endocannabinoid system in the STC-1 cell line through RT-PCR and ELISA assays. Results: The study’s results indicated that EVs had a significant impact on GLP-1 expression compared to the multiplicity of infections (MOI) ratio. Notably, there was a substantial increase in the expression of PYY and GLP-1 genes across all treatments (p < 0.05). Conversely, the expression of CB-1, CB-2, and FAAH genes notably decreased in the STC-1 cell line when treated with MOI 50 of A. muciniphila and an EV concentration of 100 μg/mL (p < 0.05). Both MOI 50 of A. muciniphila and an EV concentration of 100 μg/mL significantly enhanced the expression of the TLR-2 gene. In contrast, EVs at a concentration of 100 μg/mL substantially reduced TLR-4 gene expression. A. muciniphila-derived EVs notably decreased the levels of inflammatory cytokines (TNF-α and IL-6), while increasing IL-10 expression at MOI 100 and an EV concentration of 100 μg/mL. These findings suggest that A. muciniphila and its EVs could regulate the expression of specific genes, serving as targets for maintaining host energy balance. Conclusions: In summary, this study illustrates that A. muciniphila-derived EVs exhibit anti-inflammatory properties and have the potential to modulate gene expression in cases of obesity and gastrointestinal tract inflammation.
Journal Section:
Research Article
References
1.
Aoun
A
, Darwish
F
, Hamod
N
. The influence of the gut microbiome on obesity in adults and the role of probiotics, prebiotics, and synbiotics for weight loss
. Prev Nutr Food Sci
. 2020
;25
(2
):113
–23
. 2.
Aron-Wisnewsky
J
, Warmbrunn
MV
, Nieuwdorp
M
, Clément
K
. Metabolism and metabolic disorders and the microbiome: the intestinal microbiota associated with obesity, lipid metabolism, and metabolic health—pathophysiology and therapeutic strategies
. Gastroenterology
. 2021
;160
(2
):573
–99
. 3.
Gholizadeh
P
, Mahallei
M
, Pormohammad
A
, Varshochi
M
, Ganbarov
K
, Zeinalzadeh
E
, et al. Microbial balance in the intestinal microbiota and its association with diabetes, obesity and allergic disease
. Microb Pathog
. 2019
;127
:48
–55
. 4.
Nicholson
JK
, Holmes
E
, Kinross
J
, Burcelin
R
, Gibson
G
, Jia
W
, et al. Host-gut microbiota metabolic interactions
. Science
. 2012
;336
(6086
):1262
–7
. 5.
Wang
P
, Gao
X
, Li
Y
, Wang
S
, Yu
J
, Wei
Y
. Bacillus natto regulates gut microbiota and adipose tissue accumulation in a high-fat diet mouse model of obesity
. J Funct Foods
. 2020
;68
:103923
. 6.
Munukka
E
, Rintala
A
, Toivonen
R
, Nylund
M
, Yang
B
, Takanen
A
, et al. Faecalibacterium prausnitzii treatment improves hepatic health and reduces adipose tissue inflammation in high-fat fed mice
. ISME J
. 2017
;11
(7
):1667
–79
. 7.
Díez-Sainz
E
, Milagro
FI
, Riezu-Boj
JI
, Lorente-Cebrián
S
. Effects of gut microbiota–derived extracellular vesicles on obesity and diabetes and their potential modulation through diet
. J Physiol Biochem
. 2022
;78
(2
):485
–99
. 8.
Ashrafian
F
, Shahriary
A
, Behrouzi
A
, Moradi
HR
, Keshavarz Azizi Raftar
S
, Lari
A
, et al. Akkermansia muciniphila-derived extracellular vesicles as a mucosal delivery vector for amelioration of obesity in mice
. Front Microbiol
. 2019
;10
:2155
. 9.
Zhou
Q
, Zhang
Y
, Wang
X
, Yang
R
, Zhu
X
, Zhang
Y
, et al. Gut bacteria Akkermansia is associated with reduced risk of obesity: evidence from the American Gut Project
. Nutr Metab
. 2020
;17
:90
–9
. 10.
Murphy
DE
, de Jong
OG
, Brouwer
M
, Wood
MJ
, Lavieu
G
, Schiffelers
RM
, et al. Extracellular vesicle-based therapeutics: natural versus engineered targeting and trafficking
. Exp Mol Med
. 2019
;51
(3
):1
–12
. 11.
Qin
H-Y
, Xavier Wong
HL
, Zang
KH
, Li
X
, Bian
ZX
. Enterochromaffin cell hyperplasia in the gut: factors, mechanism and therapeutic clues
. Life Sci
. 2019
;239
:116886
. 12.
Lund
ML
, Egerod
KL
, Engelstoft
MS
, Dmytriyeva
O
, Theodorsson
E
, Patel
BA
, et al. Enterochromaffin 5-HT cells–A major target for GLP-1 and gut microbial metabolites
. Mol Metab
. 2018
;11
:70
–83
. 13.
Arora
T
, Akrami
R
, Pais
R
, Bergqvist
L
, Johansson
BR
, Schwartz
TW
, et al. Microbial regulation of the L cell transcriptome
. Sci Rep
. 2018
;8
(1
):1207
. 14.
Agito
MD
, Atreja
A
, Rizk
MK
. Fecal microbiota transplantation for recurrent C difficile infection: ready for prime time
. Cleve Clin J Med
. 2013
;80
(2
):101
–8
. 15.
Nicolucci
AC
, Hume
MP
, Martínez
I
, Mayengbam
S
, Walter
J
, Reimer
RA
. Prebiotics reduce body fat and alter intestinal microbiota in children who are overweight or with obesity
. Gastroenterology
. 2017
;153
(3
):711
–22
. 16.
Cani
PD
, Possemiers
S
, Van de Wiele
T
, Guiot
Y
, Everard
A
, Rottier
O
, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability
. Gut
. 2009
;58
(8
):1091
–103
. 17.
Everard
A
, Belzer
C
, Geurts
L
, Ouwerkerk
JP
, Druart
C
, Bindels
LB
, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity
. Proc Natl Acad Sci U S A
. 2013
;110
(22
):9066
–71
. 18.
Manca
C
, Boubertakh
B
, Leblanc
N
, Deschênes
T
, Lacroix
S
, Martin
C
, et al. Germ-free mice exhibit profound gut microbiota-dependent alterations of intestinal endocannabinoidome signaling
. J Lipid Res
. 2020
;61
(1
):70
–85
. 19.
Silvestri
C
, Di Marzo
V
. The gut microbiome–endocannabinoidome axis: a new way of controlling metabolism, inflammation, and behavior
. Oxford University Press
; 2023
; p. zqad003
.20.
Federici
M
. Our second genome and the impact on metabolic disorders: why gut microbiome is an important player in diabetes and associated abnormalities
. Springer
; 2019
; p. 491
–2
.21.
Badi
SA
, Moshiri
A
, Ettehad Marvasti
F
, Mojtahedzadeh
M
, Kazemi
V
, Siadat
SD
. Extraction and evaluation of outer membrane vesicles from two important gut microbiota members, Bacteroides fragilis and Bacteroides thetaiotaomicron
. Cell J
. 2019
;22
(3
):344
. 22.
Ahmad
R
, Al-Mass
A
, Atizado
V
, Al-Hubail
A
, Al-Ghimlas
F
, Al-Arouj
M
, et al. Elevated expression of the toll like receptors 2 and 4 in obese individuals: its significance for obesity-induced inflammation
. J Inflamm
. 2012
;9
(1
):48
–11
. 23.
Plovier
H
, Everard
A
, Druart
C
, Depommier
C
, Van Hul
M
, Geurts
L
, et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice
. Nat Med
. 2017
;23
(1
):107
–13
. 24.
Chelakkot
C
, Choi
Y
, Kim
DK
, Park
HT
, Ghim
J
, Kwon
Y
, et al. Akkermansia muciniphila-derived extracellular vesicles influence gut permeability through the regulation of tight junctions
. Exp Mol Med
. 2018
;50
(2
):e450
. 25.
Ghaderi
F
, Sotoodehnejadnematalahi
F
, Hajebrahimi
Z
, Fateh
A
, Siadat
SD
. Author Correction: effects of active, inactive, and derivatives of Akkermansia muciniphila on the expression of the endocannabinoid system and PPARs genes
. Sci Rep
. 2022
;12
(1
):12301
. 26.
Théry
C
, Witwer
KW
, Aikawa
E
, Alcaraz
MJ
, Anderson
JD
, Andriantsitohaina
R
, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines
. J Extracell Vesicles
. 2018
;7
(1
):1535750
. 27.
Jo
HY
, Kim
Y
, Park
HW
, Moon
HE
, Bae
S
, Kim
J
, et al. The unreliability of MTT assay in the cytotoxic test of primary cultured glioblastoma cells
. Exp Neurobiol
. 2015
;24
(3
):235
–45
. 28.
Bose
S
, Aggarwal
S
, Singh
DV
, Acharya
N
. Extracellular vesicles: an emerging platform in gram-positive bacteria
. Microb Cell
. 2020
;7
(12
):312
–22
. 29.
Liu
Y
, Defourny
KAY
, Smid
EJ
, Abee
T
. Gram-positive bacterial extracellular vesicles and their impact on health and disease
. Front Microbiol
. 2018
;9
:1502
. 30.
Cani
PD
, de Vos
WM
. Next-generation beneficial microbes: the case of Akkermansia muciniphila
. Front Microbiol
. 2017
;8
:1765
. 31.
Ghaffari
S
, Abbasi
A
, Somi
MH
, Moaddab
SY
, Nikniaz
L
, Kafil
HS
, et al. Akkermansia muciniphila: from its critical role in human health to strategies for promoting its abundance in human gut microbiome
. Crit Rev Food Sci Nutr
. 2023
;63
(25
):7357
–77
. 32.
Yang
M
, Bose
S
, Lim
S
, Seo
J
, Shin
J
, Lee
D
, et al. Beneficial effects of newly isolated Akkermansia muciniphila strains from the human gut on obesity and metabolic dysregulation
. Microorganisms
. 2020
;8
(9
):1413
. 33.
Abuqwider
JN
, Mauriello
G
, Altamimi
M
. Akkermansia muciniphila, a new generation of beneficial microbiota in modulating obesity: a systematic review
. Microorganisms
. 2021
;9
(5
):1098
. 34.
Bian
X
, Wu
W
, Yang
L
, Lv
L
, Wang
Q
, Li
Y
, et al. Administration of Akkermansia muciniphila ameliorates dextran sulfate sodium-induced ulcerative colitis in mice
. Front Microbiol
. 2019
;10
:2259
. 35.
Cani
PD
, Geurts
L
, Matamoros
S
, Plovier
H
, Duparc
T
. Glucose metabolism: focus on gut microbiota, the endocannabinoid system and beyond
. Diabetes Metab
. 2014
;40
(4
):246
–57
. 36.
Yan
Y
, Sha
Y
, Yao
G
, Wang
S
, Kong
F
, Liu
H
, et al. Roux-en-Y gastric bypass versus medical treatment for type 2 diabetes mellitus in obese patients: a systematic review and meta-analysis of randomized controlled trials
. Medicine
. 2016
;95
(17
):e3462
. 37.
D’argenio
G
, Valenti
M
, Scaglione
G
, Cosenza
V
, Sorrentini
I
, Di Marzo
V
. Up-regulation of anandamide levels as an endogenous mechanism and a pharmacological strategy to limit colon inflammation
. FASEB J
. 2006
;20
(3
):568
–70
. 38.
Ottman
N
, Reunanen
J
, Meijerink
M
, Pietilä
TE
, Kainulainen
V
, Klievink
J
, et al. Pili-like proteins of Akkermansia muciniphila modulate host immune responses and gut barrier function
. PLoS One
. 2017
;12
(3
):e0173004
. 39.
Di Marzo
V
, Izzo
AA
. Endocannabinoid overactivity and intestinal inflammation
. Gut
. 2006
;55
(10
):1373
–6
. 40.
Keshavarz Azizi Raftar
S
, Ashrafian
F
, Yadegar
A
, Lari
A
, Moradi
HR
, Shahriary
A
, et al. The protective effects of live and pasteurized Akkermansia muciniphila and its extracellular vesicles against HFD/CCl4-induced liver injury
. Microbiol Spectr
. 2021
;9
(2
):e0048421
–21
. 41.
Ashrafian
F
, Keshavarz Azizi Raftar
S
, Lari
A
, Shahryari
A
, Abdollahiyan
S
, Moradi
HR
, et al. Extracellular vesicles and pasteurized cells derived from Akkermansia muciniphila protect against high-fat induced obesity in mice
. Microb Cell Fact
. 2021
;20
:219
–7
. 42.
Oraby
T
, Tyshenko
MG
, Maldonado
JC
, Vatcheva
K
, Elsaadany
S
, Alali
WQ
, et al. Modeling the effect of lockdown timing as a COVID-19 control measure in countries with differing social contacts
. Sci Rep
. 2021
;11
(1
):3354
. 43.
Seregin
SS
, Golovchenko
N
, Schaf
B
, Chen
J
, Pudlo
NA
, Mitchell
J
, et al. NLRP6 protects Il10−/− mice from colitis by limiting colonization of Akkermansia muciniphila
. Cell Rep
. 2017
;19
(10
):2174
–745
. 44.
Yaghoubfar
R
, Behrouzi
A
, Ashrafian
F
, Shahryari
A
, Moradi
HR
, Choopani
S
, et al. Modulation of serotonin signaling/metabolism by Akkermansia muciniphila and its extracellular vesicles through the gut-brain axis in mice
. Sci Rep
. 2020
;10
(1
):22119
. 45.
Yáñez-Mó
M
, Siljander
PRM
, Andreu
Z
, Zavec
AB
, Borràs
FE
, Buzas
EI
, et al. Biological properties of extracellular vesicles and their physiological functions
. J Extracell Vesicles
. 2015
;4
(1
):27066
. 46.
Deatherage
BL
, Cookson
BT
. Membrane vesicle release in bacteria, eukaryotes, and archaea: a conserved yet underappreciated aspect of microbial life
. Infect Immun
. 2012
;80
(6
):1948
–57
. 47.
Xu
Z
, Hao
X
, Li
M
, Luo
H
. Rhodococcus equi-derived extracellular vesicles promoting inflammatory response in macrophage through TLR2-NF-κB/MAPK pathways
. Int J Mol Sci
. 2022
;23
(17
):9742
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