Abstract
Background: The gut-brain axis is a bidirectional communication pathway connecting the gastrointestinal tract and the brain. Disorders of gut-brain interaction (DGBI) manifest as highly prevalent gastrointestinal disorders such as irritable bowel syndrome (IBS) or functional dyspepsia (FD). Summary: The initial focus of DGBI research was on the effects of psychological stress on digestive functions like gastrointestinal motility, or secretion of gastric acid and pancreatic enzymes. Concepts related to DGBI have expanded in recent decades. Activation of mucosal or systemic immune functions has been observed in DGBI, and it is established that the gastrointestinal microbiome can alter mucosal integrity and permeability, leading to pro-inflammatory cytokine release that affects brain function. Pharmacologic treatments (e.g., tricyclic antidepressants) and non-pharmacologic interventions (e.g., cognitive behavioral therapy) are now standard for DGBI patients. Advances in culture-independent methods to study gastrointestinal microbes reveal new insights into DGBI and gut microbiota appear to play a crucial role in modulating the gut-brain axis and regulating various bodily functions. Key Messages: DGBI are highly prevalent. Research in this field has evolved from studying the effects of psychological stress to recognizing the significant role of the gut microbiome and its metabolites in mucosal integrity and immune responses.
References
1.
Beaumont
W
. Experiments and observations on the gastric juice, and the physiology of digestion
. Boston: Lilly
: Wait and Company
; 1834
.2.
Wittkower
E
. Zur affektiven Beeinflussung der Magensekretion
. Klinische Wochenschrift
. 1931
;10
:3
.3.
Wolff
HG
. Emotions and gastric function
. Science
. 1943
;98
(2553
):481
–4
. 4.
Mendeloff
AI
, Monk
M
, Siegel
CI
, Lilienfeld
A
. Illness experience and life stresses in patients with irritable colon and with ulcerative colitis. An epidemiologic study of ulcerative colitis and regional enteritis in Baltimore, 1960-1964
. N Engl J Med
. 1970
;282
(1
):14
–7
. 5.
Holtmann
G
, Enck
P
. Stress and gastrointestinal motility in humans: a review of the literature
. Neurogastroenterology Motil
. 1991
;3
(4
):245
–54
. 6.
Broad
J
, Hughes
F
, Chin-Aleong
J
, Sifrim
D
, Sanger
GJ
. Regionally dependent neuromuscular functions of motilin and 5-HT4 receptors in human isolated esophageal body and gastric fundus
. Neurogastroenterol Motil
. 2014
;26
(9
):1311
–22
. 7.
Bonaz
B
, Bazin
T
, Pellissier
S
. The vagus nerve at the interface of the microbiota-gut-brain axis
. Front Neurosci
. 2018
;12
:49
. 8.
Leigh
SJ
, Uhlig
F
, Wilmes
L
, Sanchez-Diaz
P
, Gheorghe
CE
, Goodson
MS
, et al. The impact of acute and chronic stress on gastrointestinal physiology and function: a microbiota-gut-brain axis perspective
. J Physiol
. 2023
;601
(20
):4491
–538
. 9.
De la Roca-Chiapas
JM
, Solís-Ortiz
S
, Fajardo-Araujo
M
, Sosa
M
, Córdova-Fraga
T
, Rosa-Zarate
A
. Stress profile, coping style, anxiety, depression, and gastric emptying as predictors of functional dyspepsia: a case-control study
. J Psychosom Res
. 2010
;68
(1
):73
–81
. 10.
Bowers
H
, Gillanders
D
, Ferreira
N
. Moderating effect of IBS acceptance on psychosocial mediators of Irritable Bowel Syndrome
. J Context Behav Sci
. 2020
;16
:30
–6
. 11.
Furman
BL
. Corticotropin-releasing factor receptor agents
. In: Enna
SJ
, Bylund
DB
, editors. xPharm: the comprehensive pharmacology reference
. New York
: Elsevier
; 2007
. p. 1
–2
.12.
Hubbard
CS
, Labus
JS
, Bueller
J
, Stains
J
, Suyenobu
B
, Dukes
GE
, et al. Corticotropin-releasing factor receptor 1 antagonist alters regional activation and effective connectivity in an emotional-arousal circuit during expectation of abdominal pain
. J Neurosci
. 2011
;31
(35
):12491
–500
. 13.
Sweetser
S
, Camilleri
M
, Linker Nord
SJ
, Burton
DD
, Castenada
L
, Croop
R
, et al. Do corticotropin releasing factor-1 receptors influence colonic transit and bowel function in women with irritable bowel syndrome
. Am J Physiol Gastrointest Liver Physiol
. 2009
;296
(6
):G1299
–306
. 14.
Camilleri
M
, McKinzie
S
, Fox
J
, Foxx-Orenstein
A
, Burton
D
, Thomforde
G
, et al. Effect of renzapride on transit in constipation-predominant irritable bowel syndrome
. Clin Gastroenterol Hepatol
. 2004
;2
(10
):895
–904
. 15.
Lembo
AJ
, Cremonini
F
, Meyers
N
, Hickling
R
. Clinical trial: renzapride treatment of women with irritable bowel syndrome and constipation - a double-blind, randomized, placebo-controlled, study
. Aliment Pharmacol Ther
. 2010
;31
(9
):979
–90
. 16.
Manini
ML
, Camilleri
M
, Goldberg
M
, Sweetser
S
, McKinzie
S
, Burton
D
, et al. Effects of Velusetrag (TD-5108) on gastrointestinal transit and bowel function in health and pharmacokinetics in health and constipation
. Neurogastroenterol Motil
. 2010
;22
(1
):42
–e8
. 17.
Chedid
V
, Brandler
J
, Arndt
K
, Vijayvargiya
P
, Wang
XJ
, Burton
D
, et al. Randomised study: effects of the 5-HT4 receptor agonist felcisetrag vs placebo on gut transit in patients with gastroparesis
. Aliment Pharm Ther
. 2021
;53
(9
):1010
–20
. 18.
Prather
CM
, Camilleri
M
, Zinsmeister
AR
, McKinzie
S
, Thomforde
G
. Tegaserod accelerates orocecal transit in patients with constipation-predominant irritable bowel syndrome
. Gastroenterology
. 2000
;118
(3
):463
–8
. 19.
Saito
YA
, Locke
GR
3rd, Zimmerman
JM
, Holtmann
G
, Slusser
JP
, de Andrade
M
, et al. A genetic association study of 5-HTT LPR and GNbeta3 C825T polymorphisms with irritable bowel syndrome
. Neurogastroenterol Motil
. 2007
;19
(6
):465
–70
. 20.
Tillisch
K
, Labus
J
, Kilpatrick
L
, Jiang
Z
, Stains
J
, Ebrat
B
, et al. Consumption of fermented milk product with probiotic modulates brain activity
. Gastroenterology
. 2013
;144
(7
):1394
–401.e14014
. 21.
Jacka
FN
, O'Neil
A
, Opie
R
, Itsiopoulos
C
, Cotton
S
, Mohebbi
M
, et al. A randomised controlled trial of dietary improvement for adults with major depression (the ‘SMILES’ trial)
. BMC Med
. 2017
;15
(1
):23
. 22.
Delgado-Aros
S
, Camilleri
M
, Cremonini
F
, Ferber
I
, Stephens
D
, Burton
DD
. Contributions of gastric volumes and gastric emptying to meal size and postmeal symptoms in functional dyspepsia
. Gastroenterology
. 2004
;127
(6
):1685
–94
. 23.
Algera
JP
, Magnusson
MK
, Öhman
L
, Störsrud
S
, Simrén
M
, Törnblom
H
. Randomised controlled trial: effects of gluten-free diet on symptoms and the gut microenvironment in irritable bowel syndrome
. Aliment Pharmacol Ther
. 2022
;56
(9
):1318
–27
. 24.
Algera
JP
, Demir
D
, Törnblom
H
, Nybacka
S
, Simrén
M
, Störsrud
S
. Low FODMAP diet reduces gastrointestinal symptoms in irritable bowel syndrome and clinical response could be predicted by symptom severity: a randomized crossover trial
. Clin Nutr
. 2022
;41
(12
):2792
–800
. 25.
Nybacka
S
, Törnblom
H
, Josefsson
A
, Hreinsson
JP
, Böhn
L
, Frändemark
Å
, et al. A low FODMAP diet plus traditional dietary advice versus a low-carbohydrate diet versus pharmacological treatment in irritable bowel syndrome (CARIBS): a single-centre, single-blind, randomised controlled trial
. Lancet Gastroenterol Hepatol
. 2024
;9
(6
):507
–20
. 26.
Li
B
, Liang
L
, Deng
H
, Guo
J
, Shu
H
, Zhang
L
. Efficacy and safety of probiotics in irritable bowel syndrome: a systematic review and meta-analysis
. Front Pharmacol
. 2020
;11
:332
. 27.
McMaster
JJ
, Rich
GG
, Shanahan
ER
, Do
AT
, Fletcher
LM
, Kutyla
MJ
, et al. Induction of meal-related symptoms as a novel mechanism of action of the duodenal-jejunal bypass sleeve
. J Clin Gastroenterol
. 2020
;54
(6
):528
–35
. 28.
Dong
TS
, Guan
M
, Mayer
EA
, Stains
J
, Liu
C
, Vora
P
, et al. Obesity is associated with a distinct brain-gut microbiome signature that connects Prevotella and Bacteroides to the brain’s reward center
. Gut Microbes
. 2022
;14
(1
):2051999
. 29.
Potter
M
, Jones
MP
, Walker
MM
, Koloski
NA
, Keely
S
, Holtmann
G
, et al. Incidence and prevalence of self-reported non-coeliac wheat sensitivity and gluten avoidance in Australia
. Med J Aust
. 2020
;212
(3
):126
–31
. 30.
Shah
A
, Kang
S
, Talley
NJ
, Do
A
, Walker
MM
, Shanahan
ER
, et al. The duodenal mucosa associated microbiome, visceral sensory function, immune activation and psychological comorbidities in functional gastrointestinal disorders with and without self-reported non-celiac wheat sensitivity
. Gut Microbes
. 2022
;14
(1
):2132078
. 31.
Baik
JH
. Stress and the dopaminergic reward system
. Exp Mol Med
. 2020
;52
(12
):1879
–90
. 32.
Marques
A
, Marconcin
P
, Werneck
AO
, Ferrari
G
, Gouveia
ÉR
, Kliegel
M
, et al. Bidirectional association between physical activity and dopamine across adulthood-A systematic review
. Brain Sci
. 2021
;11
(7
):829
. 33.
Handschin
C
, Spiegelman
BM
. The role of exercise and PGC1alpha in inflammation and chronic disease
. Nature
. 2008
;454
(7203
):463
–9
. 34.
Clarke
SF
, Murphy
EF
, O'Sullivan
O
, Lucey
AJ
, Humphreys
M
, Hogan
A
, et al. Exercise and associated dietary extremes impact on gut microbial diversity
. Gut
. 2014
;63
(12
):1913
–20
. 35.
Yamamoto
Y
, Furukawa
S
, Miyake
T
, Watanabe
J
, Kato
A
, Kusumoto
K
, et al. Exercise habits that include exercise partners and irritable bowel syndrome in a young Japanese population: a cross-sectional study
. Eur J Gastroen Hepat
. 2023
;35
(6
):641
–5
. 36.
Sadeghian
M
, Sadeghi
O
, Hassanzadeh Keshteli
A
, Daghaghzadeh
H
, Esmaillzadeh
A
, Adibi
P
. Physical activity in relation to irritable bowel syndrome among Iranian adults
. PLoS One
. 2018
;13
(10
):e0205806
. 37.
Zhou
C
, Zhao
E
, Li
Y
, Jia
Y
, Li
F
. Exercise therapy of patients with irritable bowel syndrome: a systematic review of randomized controlled trials
. Neurogastroenterol Motil
. 2019
;31
(2
):e13461
. 38.
Rane
SV
, Asgaonkar
B
, Rathi
P
, Contractor
Q
, Chandnani
S
, Junare
P
, et al. Effect of moderate aerobic exercises on symptoms of functional dyspepsia
. Indian J Gastroenterol
. 2021
;40
(2
):189
–97
. 39.
Li
J
, Liu
H
, Guo
F
, Guo
R
, Zhang
H
, He
X
, et al. Increased GABAergic projections in the paraventricular nucleus regulate colonic hypersensitivity via oxytocin in a rat model of irritable bowel syndrome
. Neuroreport
. 2023
;34
(2
):108
–15
. 40.
Han
A
, Hudson-Paz
C
, Robinson
BG
, Becker
L
, Jacobson
A
, Kaltschmidt
JA
, et al. Temperature-dependent differences in mouse gut motility are mediated by stress
. Lab Anim
. 2024
;53
(6
):148
–59
. 41.
Maillot
C
, Million
M
, Wei
JY
, Gauthier
A
, Taché
Y
. Peripheral corticotropin-releasing factor and stress-stimulated colonic motor activity involve type 1 receptor in rats
. Gastroenterology
. 2000
;119
(6
):1569
–79
. 42.
Larauche
M
, Bradesi
S
, Million
M
, McLean
P
, Taché
Y
, Mayer
EA
, et al. Corticotropin-releasing factor type 1 receptors mediate the visceral hyperalgesia induced by repeated psychological stress in rats
. Am J Physiol Gastrointest Liver Physiol
. 2008
;294
(4
):G1033
–40
. 43.
Greenwood-Van Meerveld
B
, Johnson
AC
, Cochrane
S
, Schulkin
J
, Myers
DA
. Corticotropin-releasing factor 1 receptor-mediated mechanisms inhibit colonic hypersensitivity in rats
. Neurogastroenterol Motil
. 2005
;17
(3
):415
–22
. 44.
Million
M
, Grigoriadis
DE
, Sullivan
S
, Crowe
PD
, McRoberts
JA
, Zhou
H
, et al. A novel water-soluble selective CRF1 receptor antagonist, NBI 35965, blunts stress-induced visceral hyperalgesia and colonic motor function in rats
. Brain Res
. 2003
;985
(1
):32
–42
. 45.
Jeong
EJ
, Chung
SY
, Hong
HN
, Oh
SW
, Sim
JY
. The novel, potent and highly selective 5-HT4 receptor agonist YH12852 significantly improves both upper and lower gastrointestinal motility
. Br J Pharmacol
. 2018
;175
(3
):485
–500
. 46.
Cheng
S
, Li
B
, Ding
Y
, Hou
B
, Hung
W
, He
J
, et al. The probiotic fermented milk of Lacticaseibacillus paracasei JY062 and Lactobacillus gasseri JM1 alleviates constipation via improving gastrointestinal motility and gut microbiota
. J Dairy Sci
. 2024
;107
(4
):1857
–76
. 47.
Zhu
H
, Tian
P
, Qian
X
, Gu
L
, Zhao
J
, Wang
G
, et al. Perinatal transmission of a probiotic Bifidobacterium strain protects against early life stress-induced mood and gastrointestinal motility disorders
. Food Funct
. 2022
;13
(14
):7520
–8
. 48.
Lee
A
, Kim
SY
, Kang
S
, Kang
SH
, Kim
DW
, Choe
JW
, et al. Effect of probiotics in stress-associated constipation model in zebrafish (Danio rerio) larvae
. Int J Mol Sci
. 2024
;25
(7
):3669
. 49.
El Oufir
L
, Flourié
B
, Bruley des Varannes
S
, Barry
JL
, Cloarec
D
, Bornet
F
, et al. Relations between transit time, fermentation products, and hydrogen consuming flora in healthy humans
. Gut
. 1996
;38
(6
):870
–7
. 50.
Vandeputte
D
, Falony
G
, Vieira-Silva
S
, Tito
RY
, Joossens
M
, Raes
J
. Stool consistency is strongly associated with gut microbiota richness and composition, enterotypes and bacterial growth rates
. Gut
. 2016
;65
(1
):57
–62
. 51.
Ke
S
, Guimond
AJ
, Tworoger
SS
, Huang
T
, Chan
AT
, Liu
YY
, et al. Gut feelings: associations of emotions and emotion regulation with the gut microbiome in women
. Psychol Med
. 2023
;53
(15
):7151
–60
. 52.
Shanahan
ER
, Zhong
L
, Talley
NJ
, Morrison
M
, Holtmann
G
. Characterisation of the gastrointestinal mucosa-associated microbiota: a novel technique to prevent cross-contamination during endoscopic procedures
. Aliment Pharmacol Ther
. 2016
;43
(11
):1186
–96
. 53.
Zhong
L
, Shanahan
ER
, Raj
A
, Koloski
NA
, Fletcher
L
, Morrison
M
, et al. Dyspepsia and the microbiome: time to focus on the small intestine
. Gut
. 2017
;66
(6
):1168
–9
. 54.
Shanahan
ER
, Kang
S
, Staudacher
H
, Shah
A
, Do
A
, Burns
G
, et al. Alterations to the duodenal microbiota are linked to gastric emptying and symptoms in functional dyspepsia
. Gut
. 2023
;72
(5
):929
–38
. 55.
Shanahan
ER
, Shah
A
, Koloski
N
, Walker
MM
, Talley
NJ
, Morrison
M
, et al. Influence of cigarette smoking on the human duodenal mucosa-associated microbiota
. Microbiome
. 2018
;6
(1
):150
. 56.
Sternes
PR
, Shah
A
, Ayala Pintos
C
, Fairlie
T
, Koloski
N
, Kang
S
, et al. The biogeography of the mucosa-associated microbiome in health and disease
. Front Microbiol
. 2024
;15
:1454910
. 57.
Shah
A
, Talley
NJ
, Jones
M
, Kendall
BJ
, Koloski
N
, Walker
MM
, et al. Small intestinal bacterial overgrowth in irritable bowel syndrome: a systematic review and meta-analysis of case-control studies
. Am J Gastroenterol
. 2020
;115
(2
):190
–201
. 58.
Gurusamy
SR
, Shah
A
, Talley
NJ
, Koloski
N
, Jones
MP
, Walker
MM
, et al. Small intestinal bacterial overgrowth in functional dyspepsia: a systematic review and meta-analysis
. Am J Gastroenterol
. 2021
;116
(5
):935
–42
. 59.
Nichols
B
, Russell
RK
, Short
B
, Papadopoulou
R
, Focht
G
, Ijaz
UZ
, et al. Gut microbial signatures in pediatric crohn’s disease vary according to disease activity measures and are influenced by proxies of gastrointestinal transit time: an ImageKids study
. Inflamm Bowel Dis
. 2024
:izae199
. 60.
Gschossmann
JM
, Adam
B
, Liebregts
T
, Buenger
L
, Ruwe
M
, Gerken
G
, et al. Effect of transient chemically induced colitis on the visceromotor response to mechanical colorectal distension
. Eur J Gastroenterol Hepatol
. 2002
;14
(10
):1067
–72
. 61.
Gschossmann
JM
, Liebregts
T
, Adam
B
, Buenger
L
, Ruwe
M
, Gerken
G
, et al. Long-term effects of transient chemically induced colitis on the visceromotor response to mechanical colorectal distension
. Dig Dis Sci
. 2004
;49
(1
):96
–101
. 62.
Liebregts
T
, Adam
B
, Bertel
A
, Lackner
C
, Neumann
J
, Talley
NJ
, et al. Psychological stress and the severity of post-inflammatory visceral hyperalgesia
. Eur J Pain
. 2007
;11
(2
):216
–22
. 63.
Liebregts
T
, Adam
B
, Bredack
C
, Röth
A
, Heinzel
S
, Lester
S
, et al. Immune activation in patients with irritable bowel syndrome
. Gastroenterology
. 2007
;132
(3
):913
–20
. 64.
Liebregts
T
, Adam
B
, Bredack
C
, Gururatsakul
M
, Pilkington
KR
, Brierley
SM
, et al. Small bowel homing T cells are associated with symptoms and delayed gastric emptying in functional dyspepsia
. Am J Gastroenterol
. 2011
;106
(6
):1089
–98
. 65.
Hughes
PA
, Moretta
M
, Lim
A
, Grasby
DJ
, Bird
D
, Brierley
SM
, et al. Immune derived opioidergic inhibition of viscerosensory afferents is decreased in Irritable Bowel Syndrome patients
. Brain Behav Immun
. 2014
;42
:191
–203
. 66.
Shah
A
, Fairlie
T
, Brown
G
, Jones
MP
, Eslick
GD
, Duncanson
K
, et al. Duodenal eosinophils and mast cells in functional dyspepsia: a systematic review and meta-analysis of case-control studies
. Clin Gastroenterol Hepatol
. 2022
;20
(10
):2229
–42.e29
. 67.
Lucas
A
, Cobelens
PM
, Kavelaars
A
, Heijnen
CJ
, Holtmann
G
, Haag
S
, et al. Disturbed in vitro adrenergic modulation of cytokine production in inflammatory bowel diseases in remission
. J Neuroimmunol
. 2007
;182
(1–2
):195
–203
. 68.
Mikocka-Walus
AA
, Turnbull
DA
, Moulding
NT
, Wilson
IG
, Andrews
JM
, Holtmann
GJ
. Controversies surrounding the comorbidity of depression and anxiety in inflammatory bowel disease patients: a literature review
. Inflamm Bowel Dis
. 2007
;13
(2
):225
–34
. 69.
Mikocka-Walus
AA
, Turnbull
DA
, Andrews
JM
, Moulding
NT
, Holtmann
GJ
. The effect of functional gastrointestinal disorders on psychological comorbidity and quality of life in patients with inflammatory bowel disease
. Aliment Pharmacol Ther
. 2008
;28
(4
):475
–83
. 70.
Gray
MA
, Chao
CY
, Staudacher
HM
, Kolosky
NA
, Talley
NJ
, Holtmann
G
. Anti-TNFα therapy in IBD alters brain activity reflecting visceral sensory function and cognitive-affective biases
. PLoS One
. 2018
;13
(3
):e0193542
. 71.
Liebregts
T
, Adam
B
, Bertel
A
, Jones
S
, Schulze
J
, Enders
C
, et al. Effect of E. coli Nissle 1917 on post-inflammatory visceral sensory function in a rat model
. Neurogastroenterol Motil
. 2005
;17
(3
):410
–4
. 72.
Fairlie
T
, Shah
A
, Talley
NJ
, Chey
WD
, Koloski
N
, Yeh Lee
Y
, et al. Overlap of disorders of gut-brain interaction: a systematic review and meta-analysis
. Lancet Gastroenterol Hepatol
. 2023
;8
(7
):646
–59
. 73.
Shah
A
, Lee
YY
, Suzuki
H
, Tan-Loh
J
, Siah
KTH
, Gwee
KA
, et al. A pathophysiologic framework for the overlap of disorders of gut-brain interaction and the role of the gut microbiome
. Gut Microbes
. 2024
;16
(1
):2413367
. 74.
Fairlie
T
, Shah
A
, Wong
RK
, Fang
X
, Ghoshal
UC
, Kashyap
PC
, et al. A multifaceted ecological approach to explore links between environmental factors and the epidemiology of disorders of gut-brain interaction
. Neurogastroenterol Motil
. 2024
;36
(9
):e14866
. © 2025 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2025
You do not currently have access to this content.
