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Abstract
Introduction: To offer valuable insights into potential dietary influences on bladder health, the study investigated the relationship between urinary caffeine metabolites and overactive bladder (OAB) syndrome. Methods: The data for this investigation consisted of individuals who were 20 years old or older, obtained from the National Health and Nutrition Examination Survey (NHANES) database. To assess the correlation between urinary caffeine metabolites and OAB, logistic regression analyses were utilized. In addition, quantile g-computation model (Qgcomp) and Bayesian kernel machine regression (BKMR) model were used to determine the combined effect of urine caffeine metabolites on OAB risk. Results: In the analyses of a dataset comprising 4,354 participants, 815 were diagnosed with OAB. After adjusting for various covariates, logistic regression analyses revealed the highest tertiles of caffeine metabolites and ln-transformed caffeine metabolites were negatively associated with OAB risk. Subsequent analyses using the Qgcomp demonstrated that an increase in the quartiles of caffeine metabolites mixture was associated with a decreased risk of developing OAB. The OR was 0.89 (95% confidence interval: 0.81, 0.99). Moreover, such negative correlation was primarily driven by 1,3-dimethylxanthine (1,3-DMX) and 1-methylxanthine (1-MX). The BKMR model confirmed a strong inverse link between urinary caffeine metabolites and OAB. Conclusion: Our work demonstrates a strong inverse relationship between urine caffeine metabolites and the occurrence of OAB. Among these metabolites, 1,3-DMX and 1-MX have the most pronounced impact on the combined effect. These findings suggest that the way caffeine is metabolized in the body could play a crucial role in the development of OAB.
References
1.
Miller
J
, Hoffman
E
. The causes and consequences of overactive bladder
. J Womens Health
. 2006
;15
(3
):251
–60
. 2.
Henderson
E
, Drake
M
. Overactive bladder
. Maturitas
. 2010
;66
(3
):257
–62
. 3.
Hashitani
H
. Interaction between interstitial cells and smooth muscles in the lower urinary tract and penis
. J Physiol
. 2006
;576
(Pt 3
):707
–14
. 4.
Birder
LA
, de Groat
WC
. Mechanisms of disease: involvement of the urothelium in bladder dysfunction
. Nat Clin Pract Urol
. 2007
;4
(1
):46
–54
. 5.
Kervinio
F
, Teng
M
, Miget
G
, Moutounaïck
M
, Charlanes
A
, Chesnel
C
, et al. Menthol in the control of bladder activity: a review
. Prog Urol
. 2018
;28
(11
):523
–9
. 6.
Araki
I
, Du
S
, Kobayashi
H
, Sawada
N
, Mochizuki
T
, Zakoji
H
, et al. Roles of mechanosensitive ion channels in bladder sensory transduction and overactive bladder
. Int J Urol
. 2008
;15
(8
):681
–7
. 7.
Andersson
KE
, Gratzke
C
, Hedlund
P
. The role of the transient receptor potential (TRP) superfamily of cation-selective channels in the management of the overactive bladder
. BJU Int
. 2010
;106
(8
):1114
–27
. 8.
Li
M
, Sun
Y
, Tomiya
N
, Hsu
Y
, Chai
TC
. Elevated polyamines in urothelial cells from OAB subjects mediate oxotremorine-evoked rapid intracellular calcium rise and delayed acetylcholine release
. Am J Physiol Ren Physiol
. 2013
;305
(4
):F445
–50
. 9.
Yokoyama
O
, Yoshiyama
M
, Namiki
M
, de Groat
WC
. Role of the forebrain in bladder overactivity following cerebral infarction in the rat
. Exp Neurol
. 2000
;163
(2
):469
–76
. 10.
Hubeaux
K
, Jousse
M
, Amarenco
G
. [Female overactive bladder syndrome and autonomic nervous system]
. Prog Urol
. 2012
;22
(4
):199
–206
. 11.
McLeod
JG
, Tuck
RR
. Disorders of the autonomic nervous system: Part 1. Pathophysiology and clinical features
. Ann Neurol
. 1987
;21
(5
):419
–30
. 12.
Aragón
IM
, Herrera-Imbroda
B
, Queipo-Ortuño
MI
, Castillo
E
, Del Moral
JSG
, Gómez-Millán
J
, et al. The urinary tract microbiome in health and disease
. Eur Urol Focus
. 2018
;4
(1
):128
–38
. 13.
Peyronnet
B
, Mironska
E
, Chapple
C
, Cardozo
L
, Oelke
M
, Dmochowski
R
, et al. A comprehensive review of overactive bladder pathophysiology: on the way to tailored treatment
. Eur Urol
. 2019
;75
(6
):988
–1000
. 14.
Sultan
MI
, Ibrahim
SA
, Youssef
RF
. Impact of a Mediterranean diet on prevention and management of urologic diseases
. BMC Urol
. 2024
;24
(1
):48
. 15.
Ding
Y
, Mou
Y
, Wang
D
, Niu
Z
, Xin
P
, Zhou
Y
, et al. Relationship between dietary patterns and overactive bladder: a cross sectional study of NHANES 2013 to 2023
. Front Nutr
. 2025
;12
:1554794
. 16.
Robinson
D
, Giarenis
I
, Cardozo
L
. You are what you eat: the impact of diet on overactive bladder and lower urinary tract symptoms
. Maturitas
. 2014
;79
(1
):8
–13
. 17.
Selo-Ojeme
D
, Pathak
S
, Aziz
A
, Odumosu
M
. Fluid and caffeine intake and urinary symptoms in the UK
. Int J Gynaecol Obstet
. 2013
;122
(2
):159
–60
. 18.
Nehlig
A
. Interindividual differences in caffeine metabolism and factors driving caffeine consumption
. Pharmacol Rev
. 2018
;70
(2
):384
–411
. 19.
Tettamanti
G
, Altman
D
, Pedersen
NL
, Bellocco
R
, Milsom
I
, Iliadou
AN
. Effects of coffee and tea consumption on urinary incontinence in female twins
. BJOG Int J Obstet Gynaecol
. 2011
;118
(7
):806
–13
. 20.
Hannestad
YS
, Rortveit
G
, Daltveit
AK
, Hunskaar
S
. Are smoking and other lifestyle factors associated with female urinary incontinence? The Norwegian EPINCONT Study
. BJOG Int J Obstet Gynaecol
. 2003
;110
(3
):247
–54
. 21.
Park
J
, Lee
H
, Kim
Y
, Norton
C
, Woodward
S
, Lee
S
. Effectiveness of fluid and caffeine modifications on symptoms in adults with overactive bladder: a systematic review
. Int Neurourol J
. 2023
;27
(1
):23
–35
. 22.
Rothwell
JA
, Fillâtre
Y
, Martin
JF
, Lyan
B
, Pujos-Guillot
E
, Fezeu
L
, et al. New biomarkers of coffee consumption identified by the non-targeted metabolomic profiling of cohort study subjects
. PLoS One
. 2014
;9
(4
):e93474
. 23.
Ullrich
D
, Compagnone
D
, Münch
B
, Brandes
A
, Hille
H
, Bircher
J
. Urinary caffeine metabolites in man. Age-dependent changes and pattern in various clinical situations
. Eur J Clin Pharmacol
. 1992
;43
(2
):167
–72
. 24.
Crews
HM
, Olivier
L
, Wilson
LA
. Urinary biomarkers for assessing dietary exposure to caffeine
. Food Addit Contam
. 2001
;18
(12
):1075
–87
. 25.
Johnson
CL
, Paulose-Ram
R
, Ogden
CL
, Carroll
, MD
, Kruszon-Moran
, D
, Dohrmann
, SM
, et al. National health and nutrition examination survey: analytic guidelines, 1999-2010
. Vital Health Stat
. 2013
;161
:1
–24
.26.
Weiss
JP
, Blaivas
JG
, Bliwise
DL
, Dmochowski
RR
, Dubeau
CE
, Lowe
FC
, et al. The evaluation and treatment of nocturia: a consensus statement
. BJU Int
. 2011
;108
(1
):6
–21
. 27.
Haylen
BT
, de Ridder
D
, Freeman
RM
, Swift
SE
, Berghmans
B
, Lee
J
, et al. An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction
. Neurourol Urodyn
. 2010
;29
(1
):4
–20
. 28.
Coyne
KS
, Zyczynski
T
, Margolis
MK
, Elinoff
V
, Roberts
RG
. Validation of an overactive bladder awareness tool for use in primary care settings
. Adv Ther
. 2005
;22
(4
):381
–94
. 29.
Homma
Y
, Yoshida
M
, Seki
N
, Yokoyama
O
, Kakizaki
H
, Gotoh
M
, et al. Symptom assessment tool for overactive bladder syndrome--overactive bladder symptom score
. Urology
. 2006
;68
(2
):318
–23
. 30.
Flegal
KM
, Carroll
MD
, Ogden
CL
, Curtin
LR
. Prevalence and trends in obesity among US adults, 1999-2008
. JAMA
. 2010
;303
(3
):235
–41
. 31.
Centers for Disease Control and Prevention (CDC)
. National health interview survey: glossary. U.S. Department of health and human services
. Centers for Disease Control and Prevention
; 2019
.32.
Dawson
DA
, Grant
BF
, Li
TK
. Quantifying the risks associated with exceeding recommended drinking limits
. Alcohol Clin Exp Res
. 2005
;29
(5
):902
–8
. 33.
NHANES 2019-2020 Procedure Manuals
. Centers for Disease Control and Prevention (CDC) National Center for Health Statistics (NCHS)
. Available from online at: https://wwwn.cdc.gov/nchs/nhanes/continuousnhanes/manuals.aspx?BeginYear=201934.
Whelton
PK
, Carey
RM
, Aronow
WS
, Casey
DE
Jr, Collins
KJ
, Dennison Himmelfarb
C
, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart association task force on clinical practice guidelines
. Circulation
. 2018
;138
(17
):e484
–594
. 35.
Carroll
MD
, Lacher
DA
, Wolz
M
, Sorlie
PD
. 30-year trends in serum lipids among United States adults: results from the national health and nutrition examination surveys II, III, and 1999-2006
. Am J Cardiol
. 2011
;107
(12
):1868
–70
. 36.
37.
Keil
AP
, Buckley
JP
, O’Brien
KM
, Ferguson
KK
, Zhao
S
, White
AJ
. A quantile-based g-computation approach to addressing the effects of exposure mixtures
. Environ Health Perspect
. 2020
;128
(4
):47004
. 38.
Carrico
C
, Gennings
C
, Wheeler
DC
, Factor-Litvak
P
. Characterization of weighted quantile Sum regression for highly correlated data in a risk analysis setting
. J Agric Biol Environ Stat
. 2015
;20
(1
):100
–20
. 39.
Bobb
JF
, Valeri
L
, Claus Henn
B
, Christiani
DC
, Wright
RO
, Mazumdar
M
, et al. Bayesian kernel machine regression for estimating the health effects of multi-pollutant mixtures
. Biostatistics
. 2015
;16
(3
):493
–508
. 40.
Little
J
, Higgins
JP
, Ioannidis
JP
, Moher
D
, Gagnon
F
, von Elm
E
, et al. STrengthening the REporting of genetic association studies (STREGA)--an extension of the STROBE statement
. Genet Epidemiol
. 2009
;33
(7
):581
–98
. 41.
Li
H
, Miao
S
, Zhang
M
, Zhang
P
, Li
YB
, Duan
RS
. U-shaped association between serum Klotho and accelerated aging among the middle-aged and elderly US population: a cross-sectional study
. BMC Geriatr
. 2023
;23
(1
):780
. 42.
Calabrese
EJ
, Baldwin
LA
. U-shaped dose-responses in biology, toxicology, and public health
. Annu Rev Public Health
. 2001
;22
:15
–33
. 43.
Fredholm
BB
, Bättig
K
, Holmén
J
, Nehlig
A
, Zvartau
EE
. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use
. Pharmacol Rev
. 1999
;51
(1
):83
–133
. 44.
Kosilov
KV
, Loparev
SA
, Ivanovskaya
MA
, Kosilova
LV
. Caffeine as a probable factor for increased risk of OAB development in elderly people
. Curr Urol
. 2016
;9
(3
):124
–31
. 45.
Dowd
TT
, Campbell
JM
, Jones
JA
. Fluid intake and urinary incontinence in older community-dwelling women
. J Community Health Nurs
. 1996
;13
(3
):179
–86
. 46.
Xu
R
, He
L
, Vatsalya
V
, Ma
X
, Kim
S
, Mueller
EG
, et al. Metabolomics analysis of urine from patients with alcohol-associated liver disease reveals dysregulated caffeine metabolism
. Am J Physiol Gastrointest Liver Physiol
. 2023
;324
(2
):G142
–54
. 47.
Nakabayashi
H
, Hashimoto
T
, Ashida
H
, Nishiumi
S
, Kanazawa
K
. Inhibitory effects of caffeine and its metabolites on intracellular lipid accumulation in murine 3T3-L1 adipocytes
. Biofactors
. 2008
;34
(4
):293
–302
. 
