Association of Dietary P atterns With Risk of Colorectal Cancer
Subtypes Classified by Fusobacterium nucleatum in Tumor Tissue
Raaj S. Mehta, MD; Reiko Nishihara, PhD; Yin Cao, ScD; Mingyang Song, MD, ScD; Kosuke Mima, MD, PhD; Zhi Rong Qian, MD, PhD;
Jonathan A. Nowak, MD, PhD; Keisuke Kosumi, MD, PhD; Tsuyoshi Hamada, MD, PhD; Yohei Masugi, MD, PhD; Susan Bullman, PhD;
David A. Drew, PhD; Aleksandar D. Kostic, PhD; Teresa T. Fung, ScD, RDN; Wendy S. Garrett, MD, PhD; Curtis Huttenhower, PhD;
Kana Wu, MD, PhD; Jeffrey A. Meyerhardt, MD, MPH; Xuehong Zhang, MD, ScD; Walter C. Willett, MD, DrPH; Edward L. Giovannucci, MD, ScD;
Charles S. Fuchs, MD, MPH; Andrew T. Chan, MD, MPH; Shuji Ogino, MD, PhD
IMPORTANCE
Fusobacterium nucleatum appears to play a role in colorectal carcinogenesis
through suppression of the hosts’ immune response to tumor. Evidence also suggests that
diet influences intestinal F nucleatum. However, the role of F nucleatum in mediating the
relationship between diet and the risk of colorectal cancer is unknown.
OBJECTIVE To test the hypothesis that the associations of prudent diets (rich in whole grains
and dietary fiber) and Western diets (rich in red and processed meat, refined grains, and
desserts) with colorectal cancer risk may differ according to the presence of F nucleatum in
tumor tissue.
DESIGN, SETTING, AND PARTICIPANTS A prospective cohort study was conducted using data
from the Nurses’ Health Study (June 1, 1980, to June 1, 2012) and the Health Professionals
Follow-up Study (June 1, 1986, to June 1, 2012) on a total of 121 700 US female nurses and
51 529 US male health professionals aged 30 to 55 years and 40 to 75 years, respectively
(both predominantly white individuals), at enrollment. Data analysis was performed from
March 15, 2015, to August 10, 2016.
EXPOSURES Prudent and Western diets.
MAIN OUTCOMES AND MEASURES Incidence of colorectal carcinoma subclassified by
F nucleatum status in tumor tissue, determined by quantitative polymerase chain reaction.
RESULTS Of the 173 229 individuals considered for the study, 137 217 were included in the
analysis, 47 449 were male (34.6%), and mean (SD) baseline age for men was 54.0 (9.8)
years and for women, 46.3 (7.2) years. A total of 1019 incident colon and rectal cancer cases
with available F nucleatum data were documented over 26 to 32 years of follow-up,
encompassing 3 643 562 person-years. The association of prudent diet with colorectal cancer
significantly differed by tissue F nucleatum status (P = .01 for heterogeneity); prudent diet
score was associated with a lower risk of F nucleatum–positive cancers (P = .003 for trend;
multivariable hazard ratio of 0.43; 95% CI, 0.25-0.72, for the highest vs the lowest prudent
score quartile) but not with F nucleatum–negative cancers (P = .47 for trend, the
corresponding multivariable hazard ratio of 0.95; 95% CI, 0.77-1.17). There was no significant
heterogeneity between the subgroups in relation to Western dietary pattern scores.
CONCLUSIONS AND RELEVANCE Prudent diets rich in whole grains and dietary fiber are
associated with a lower risk for F nucleatum–positive colorectal cancer but not
F nucleatum–negative cancer, supporting a potential role for intestinal microbiota in
mediating the association between diet and colorectal neoplasms.
JAMA Oncol. 2017;3(7):921-927. doi:10.1001/jamaoncol.2016.6374
Published online January 26, 2017. Corrected on March 7, 2019.
Supplemental content
Author Affiliations: Author
affiliations are listed at the end of this
article.
Corresponding Author: Shuji Ogino,
MD, PhD, Division of MPE Molecular
Pathological Epidemiology, Brigham
and Women’s Hospital and Harvard
Medical School, 450 Brookline Ave,
DFCI Room SM1036,
Boston, MA 02215
(shuji_ogino@dfci.harvard.edu).
Research
JAMA Oncology | Original Investigation
(Reprinted) 921
© 2017 American Medical Association. All rights reserved.
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A
ccumulating evidence suggests that the human gut mi-
crobiome is linked to colorectal cancer development.
1-4
Fusobacterium nucleatum has been found to be en-
riched in colorectal cancer tissue relative to normal adjacent
colonic tissue and is detected at higher levels in stool among
individuals with colorectal cancer compared with those
without cancer.
1,5-10
Recent experimental data suggest that
F nucleatum may contribute to colorectal carcinogenesis
through modulation of host immunity and activation of path-
ways associated with cellular proliferation.
9,11,12
Further-
more, a higher amount of F nucleatum in colorectal cancer
tissue has been linked to shorter survival, proximal tumor lo-
cation, and specific tumor molecular features, such as high-
level CpG island methylator phenotype and microsatellite
instability.
13-15
Prudent dietary patterns—rich in fruits, vegetables, and
whole grains—have been associated with a lower risk of colo-
rectal cancer and adenoma
16-21
as reviewed in a recent sys-
tematic meta-analysis.
22
In contrast, Western dietary patterns—
dominated by red and processed meats—have been linked with
colorectal carcinogenesis.
16,22
Although mechanisms under-
lying these diet-cancer associations remain unclear, it is pos-
tulated that the gut microbiota may play a mediating role.
23
Recently, in a dietary intervention study, stool F nucleatum
levels markedly increased after participants were switched
from a prudent-style, high-fiber, low-fat diet to a low-fiber,
high-fat diet.
24
In addition, accumulating data suggest that
low fiber consumption and high meat intake may be associ-
ated with altered bacterial and metagenomic profiles as well
as an inflammatory phenotype determined by serum levels of
metabolites.
25-28
Based on these findings, we hypothesized that the in-
verse association between prudent diets and risk of colorec-
tal cancer might be more evident for a cancer subgroup en-
riched with tissue F nucleatum than for a subgroup without
detectable tissue F nucleatum. To test this hypothesis, we used
2 US nationwide, prospective cohort studies: the Nurses’ Health
Study (NHS) (June 1, 1980, to June 1, 2012) and the Health
Professional Follow-up Study (HPFS). These 2 studies offered
a unique opportunity to integrate prospectively collected,
regularly updated dietary intake data with tissue microbial
features in incident colorectal cancers that occurred over long-
term follow-up.
Methods
Study Population
We used data drawn from 2 ongoing prospective cohort stud-
ies, the NHS and the HPFS. The NHS began in 1976 among
121 700 US female nurses aged 30 to 55 years at enrollment.
The HPFS began in 1986 among 51 529 US male health profes-
sionals aged 40 to 75 years at enrollment. In both cohorts, par-
ticipants have returned questionnaires every 2 years, with
follow-up rates exceeding 90%, to provide information about
lifestyle and dietary factors, medication use, and diagnoses
of colorectal cancer and other diseases. The institutional re-
view board at the Brigham and Women’s Hospital and Harvard
T.H. Chan School of Public Health approved this study, and in-
formed consent was obtained from all participants. The study
was conducted from June 1, 1980, to June 1, 2012.
Of 173 229 individuals considered for the study, a total of
137 217 individuals (47 449 men and 89 768 women) were in-
cluded in this analysis. We excluded participants with implau-
sibly high or low caloric intakes (ie, <600 or >3500 kcal/d for
women and <800 or >4200 kcal/d for men), missing dietary
pattern data, or those with a history of ulcerative colitis or can-
cer (except for nonmelanoma skin cancer) before baseline
(1980 for the NHS and 1986 for the HPFS) (eMethods in the
Supplement).
Assessment of Diet
Participants reported average food intake over the preceding
year (of each questionnaire return) through semiquantitative
food frequency questionnaires, which have been previously
validated and described.
29
Total nutrient intake was calcu-
lated by summing intakes from all foods and adjusted for total
energy intake by the residual method. As previously de-
scribed, total dietary fiber was calculated according to meth-
ods from the Association of Official Analytic Chemists.
30
For
this analysis, we used information from food frequency ques-
tionnaires administered in the following years: 1980, 1984,
1986, 1990, 1994, 1998, 2002, 2006, and 2010 for the NHS and
1986, 1990, 1994, 1998, 2002, 2006, and 2010 for the HPFS.
Assessment of Colorectal Cancer Cases
In both cohorts, incident cases of colorectal cancer were
reported by participants through the 2012 follow-up for the
HPFS and NHS. We identified and confirmed lethal colorec-
tal cancer cases through information from various sources
including next of kin, the National Death Index, death cer-
tificates, and medical records. A study physician (including
J.A.M. and C.S.F.), blinded to exposure information,
reviewed records and extracted data on histologic type, ana-
tomical location, and stage. The cohort study groups
attempted to collect formalin-fixed, paraffin-embedded
(FFPE) tissue specimens from hospitals throughout the
United States as previously detailed.
9
Cases with available
tissue data (n = 1019) for the present study were similar to
those without tissue data (n = 2241) regarding patient and
clinical characteristics (eMethods in the Supplement).
Key Points
Question Does the association between prudent diets (rich in
whole grains and dietary fiber) and risk of colorectal cancer vary by
presence of the bacterial species Fusobacterium nucleatum in
tumor tissue?
Findings In this cohort study of 137 217 adults, the association of a
prudent diet with colorectal cancer was more evident for a cancer
subgroup enriched with tumor F nucleatum than a subgroup
without detectable tumor F nucleatum.
Meaning There may be a potential role for intestinal microbiota,
such as F nucleatum, in mediating the complex association
between diet and the development of colorectal cancer.
Research Original Investigation Diet and Risk of Colorectal Cancer Subtypes Classified by F nucleatum
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F nucleatum Analysis
We extracted DNA from colorectal cancer tissue obtained from
sections of FFPE tumor blocks (QIAamp DNA FFPE tissue kits;
Qiagen). We performed a real-time polymerase chain reaction
(PCR) assay using custom TaqMan primer/probe sets
(Applied Biosystems) for the nusG gene of F nucleatum.
9
The in-
terassay coefficient of variation of cycle threshold values from
each of 5 selected specimens in 5 different batches was less than
1% for all targets in the validation study.
14
Fusobacterium nu-
cleatum positivity was defined as a detectable level of F nuclea-
tumDNA within 45 PCR cycles, and F nucleatum negativity was
defined as an undetectable level with a proper amplification of
human reference gene SLCO2A1 (HGNC: 10955).
Statistical Analysis
All statistical tests were 2-sided. To account for multiple testing
for the 2 primary hypotheses (related to prudent and Western di-
etary scores) associated with the 2 tumor subtype variables, we
adjusted the 2-sided α level to .01(approximately .05/4) by simple
Bonferroni correction in our primary and secondary analysis.
Two maximally uncorrelated dietary patterns—one named
prudent and another named Western—were derived by prin-
cipal component analysis, as previously described and vali-
dated with good reproducibility.
16,31
Factor loadings were de-
rived based on the correlations between food groups and the
2 derived factors. Each participant was assigned a factor score,
determined by adding the reported frequencies of food group
intakes weighted by the factor loadings. These factor scores
were then standardized to have a mean (SD) of 0 (1). To cap-
ture long-term habitual consumption, we calculated the cu-
mulative mean of the prudent (or Western) dietary pattern
scores from preceding food frequency questionnaires up to
each questionnaire cycle. Then, the cumulative average score
was categorized into sex-specific quartiles and used as the pri-
mary exposure variable.
Using Cox proportional hazards regression models, we
computed hazard ratios (HRs) to examine the association of
the prudent or Western dietary score with incidence of colo-
rectal cancer. To test for trend with the Wald test, partici-
pants were assigned to the median score of their sex-specific
dietary pattern quartile, and then this variable was entered into
the models as a continuous term. The covariates included in
the multivariable models are described in the Table and the
eMethods in the Supplement. All analyses were adjusted for
total caloric intake (kilocalories per day) and stratified by age
(in months), year of questionnaire return, and sex (in the analy-
sis using combined cohorts). In multivariable analysis, we ad-
justed for potential confounders, including body mass index
(calculated as weight in kilograms divided by height in me-
ters squared), pack-years of smoking (never, 0-4 pack-years,
5-19 pack-years, 20-39 pack-years, or >40 pack-years), family
history of colorectal cancer in any first-degree relative (yes or
no), previous lower gastrointestinal endoscopy (yes or no),
postmenopausal hormone use (for women only: never,
past, or current), physical activity (quintiles of metabolic-
equivalent task hours per week), and regular use of aspirin or
nonsteroidal anti-inflammatory agents (≥2 tablets per week:
yesorno).
To examine whether the association between dietary pat-
terns and incidence of colorectal cancer subgroups differed ac-
cording to tissue F nucleatum status, we used Cox propor-
tional hazards regression models with a duplication method
for competing risks data. As our primary hypothesis testing,
we tested for heterogeneity by using a likelihood ratio test,
comparing a model that allows for separate associations of di-
etary patterns and risk of cancer subgroups according to
F nucleatum status with a model that assumes a common
association.
32
In secondary analyses, we examined heteroge-
neity of the associations with cancer subgroups in relation to
dominant factor loadings for the prudent dietary pattern using
cumulative average intakes of fruits, vegetables, legumes, and
whole grains as well as energy-adjusted intakes of fat, fiber,
and protein, all of which were categorized into quartiles. We
used SAS software, version 9.3 (SAS Institute Inc) for all sta-
tistical analyses. Data analysis was performed from March 15,
2015, to August 10, 2016.
Results
Of the 137 217 individuals included in the analysis, 47 449 were
male (34.6%); mean (SD) baseline age for men was 54.0 (9.8)
years and for women, 46.3 (7.2) years. Two major, uncorre-
lated dietary patterns were identified by factor analysis. The
prudent dietary pattern was characterized by high intake of
vegetables, fruits, whole grains, and legumes, and the West-
ern dietary pattern was characterized by red and processed
meats, refined grains, and desserts (eTable 1 in the Supple-
ment). Consistent with prior analyses,
16
participants with high
prudent scores in the HPFS and NHS tended to smoke less, ex-
ercise more, and have greater rates of lower gastrointestinal
endoscopy, whereas Western pattern scores were associated
with behaviors typically considered unhealthy (eTable 2 in the
Supplement).
After 26 years (in HPFS) and 32 years (in NHS) of
follow-up encompassing 3 643 562 person-years, we docu-
mented 1019 incident colorectal cancers with available data on
tissue F nucleatum status. Among these cancer cases, there
were 125 (12.3%) F nucleatum–positive tumors and 894 (87.7%)
F nucleatum–negative tumors. We examined the association
of prudent and Western dietary pattern scores with the inci-
dence of overall colorectal cancer. Western dietary pattern
scores showed a trend toward associations with overall risk of
colorectal cancer in the HPFS (eTable 3 in the Supplement) and
the combined cohort (Table); however, statistical signifi-
cance was not reached with the adjusted α level of .01. We did
not observe significant heterogeneity in the associations of the
dietary scores with colorectal cancer risk between the 2 co-
horts (P ≥ .21). To maximize statistical power, we used the com-
bined cohort for further analyses.
We then tested our primary hypothesis that the associa-
tion of prudent and Western diets with colorectal cancer inci-
dence might differ according to the presence of F nucleatum in
tumor tissue. Notably, the association between prudent di-
etary pattern and risk of colorectal cancer significantly dif-
fered by tumor F nucleatum status (P = .01 for heterogeneity)
Diet and Risk of Colorectal Cancer Subtypes Classified by F nucleatum Original Investigation Research
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(Table). We found a significant inverse association of prudent
dietary scores with F nucleatum–positive cancer risk (P =.003
for trend) but not with F nucleatum–negative cancer risk (P = .47
for trend). Comparing participants in the highest prudent di-
etary score quartile with those in the lowest quartile, the mul-
tivariable HR for F nucleatum–positive tumors was 0.43
(95% CI, 0.25-0.72); in contrast, the corresponding HR for
F nucleatum–negative tumors was 0.95 (95% CI, 0.77-1.17). We
found similar differential associations by F nucleatum status in
men (HPFS) and women (NHS), although statistical power was
limited (eTable 4 in the Supplement). In addition, although sta-
tistical power was limited, we found similar results when lev-
els of F nucleatum were categorized as low or high on the basis
of the median cutoff point among F nucleatum–positive cases
as performed in our previous analyses (eTable 5 in the
Supplement).
9
Because we observed that the fraction of colo-
rectal cancers enriched with F nucleatum gradually decreased
from cecum to rectum,
33
we conducted exploratory analyses
stratified by tumor location (eTable 6 in the Supplement). The
differentialassociation of prudent diet score with colorectal can-
cer by tissue F nucleatum status appeared to be consistent in both
proximal and distal cancer strata.
When we examined the association of the Western di-
etary pattern with colorectal cancer subgroups according to
Table. Hazard Ratios of Incident Colorectal Cancer, Overall and by Fusobacterium nucleatum Status
a
Characteristic Quartile 1 Quartile 2 Quartile 3 Quartile 4
P Value
Trend
b
Heterogeneity
c
Prudent Dietary Pattern
Overall colorectal cancer
Person-years 913 569 907 676 912 395 909 922 NA NA
No. of cases (n = 1019), No. (%) 250 (24.5) 248 (24.3) 268 (26.3) 253 (24.8) NA
Age-adjusted HR (95% CI)
d
1 [Reference] 0.93 (0.77-1.11) 0.90 (0.75-1.08) 0.79 (0.65-0.95) .01 NA
Multivariable HR (95% CI)
e
1 [Reference] 0.95 (0.80-1.14) 0.95 (0.79-1.14) 0.85 (0.69-1.03) .08 NA
F nucleatum–positive
colorectal cancer
No. of cases (n = 125), No. (%) 43 (34.4) 26 (20.8) 34 (27.2) 22 (17.6) NA NA
Age-adjusted HR (95% CI)
d
1 [Reference] 0.54 (0.33-0.89) 0.67 (0.42-1.05) 0.40 (0.24-0.67) <.001 NA
Multivariable HR (95% CI)
e
1 [Reference] 0.56 (0.34-0.92) 0.70 (0.44-1.10) 0.43 (0.25-0.72) .003 NA
F nucleatum–negative
colorectal cancer
NA .01
No. of cases (n = 894), No. (%) 207 (23.2) 222 (24.8) 234 (26.2) 231 (25.8) NA NA
Age-adjusted HR (95% CI)
d
1 [Reference] 1.01 (0.83-1.22) 0.96 (0.79-1.16) 0.88 (0.72-1.08) .15 NA
Multivariable HR (95% CI)
e
1 [Reference] 1.04 (0.86-1.26) 1.00 (0.83-1.22) 0.95 (0.77-1.17) .47 NA
Western Dietary Pattern
Overall colorectal cancer
Person-years 910 656 910 525 910 465 911 916 NA NA
No. of cases (n = 1019), No. (%) 244 (23.9) 275 (27.0) 243 (23.8) 257 (25.2) NA NA
Age-adjusted HR (95% CI)
d
1 [Reference] 1.24 (1.04-1.48) 1.21 (1.00-1.46) 1.46 (1.18-1.82) .001 NA
Multivariable HR (95% CI)
e
1 [Reference] 1.19 (1.00-1.43) 1.12 (0.92-1.36) 1.29 (1.03-1.62) .05 NA
F nucleatum–positive
colorectal cancer
NA
No. of cases (n = 125), No. (%) 25 (20.0) 33 (26.4) 33 (26.4) 34 (27.2) NA NA
Age-adjusted HR (95% CI)
d
1 [Reference] 1.42 (0.84-2.40) 1.59 (0.94-2.69) 1.92 (1.12-3.29) .01 NA
Multivariable HR (95% CI)
e
1 [Reference] 1.37 (0.81-2.31) 1.49 (0.88-2.53) 1.69 (0.98-2.90) .05 NA
F nucleatum–negative
colorectal cancer
NA .23
No. of cases (n = 894), No. (%) 219 (24.5) 242 (27.1) 210 (23.5) 223 (24.9) NA NA
Age-adjusted HR (95% CI)
d
1 [Reference] 1.25 (1.03-1.50) 1.16 (0.95-1.42) 1.42 (1.13-1.78) .006 NA
Multivariable HR (95% CI)
e
1 [Reference] 1.20 (0.99-1.44) 1.08 (0.88-1.33) 1.25 (0.99-1.58) .12 NA
Abbreviations: HR, hazard ratio; NA, not applicable.
a
According to prudent or Western dietary score quartiles in the combined
cohort of the Health Professionals Follow-up Study (1986-2012) and the
Nurses’ Health Study (1980-2012).
b
Tests for trend were conducted using the median value of each quartile
category as a continuous variable.
c
We tested for heterogeneity by using a likelihood ratio test comparing a model
that allows separate associations for the 2 colorectal cancer subgroups (ie,
F nucleatum–positive and F nucleatum–negative subgroups) with a model that
assumes a common association.
d
Stratified by age, calendar year, and sex and adjusted for total caloric intake
(kilocalories per day).
e
Stratified as listed in the above footnote and additionally adjusted for family
history of colorectal cancer in any first-degree relative, history of previous
endoscopy, pack-years of smoking (never, 0-4, 5-19, 20-39, or ⱖ40), body
mass index, physical activity (metabolic-equivalent task hours per week), and
regular aspirin or nonsteroidal anti-inflammatory drug use (ⱖ2 tablets/wk).
Research Original Investigation Diet and Risk of Colorectal Cancer Subtypes Classified by F nucleatum
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tumor F nucleatum status, although Western dietary pattern
scores appeared to be more strongly associated with F nuclea-
tum–positive cancer risk, there was no significant heteroge-
neity between the subgroups (P = .23 for heterogeneity) (Table).
In a secondary analysis, we sought to determine whether
specific food groups might explain the observed differential
associations between prudent dietary patterns and risk of co-
lorectal cancer according to F nucleatum status. We exam-
ined the top 4 dominantly contributing food groups to the pru-
dent diet pattern (vegetables, fruits, legumes, and whole grains)
in relation to the risk of colorectal cancer according to
F nucleatum status (eTable 7 in the Supplement). We ob-
served no significant heterogeneity (with the adjusted α of .01).
Finally, to further determine whether any specific mac-
ronutrient components of the prudent dietary pattern might
explain the observed differential associations according to
F nucleatum status, we explored associations of fiber, fat,
and protein intake with colorectal cancer subgroups (eTable
8intheSupplement). There appeared to be heterogeneity in
the differential association of fiber intake with cancer sub-
groups classified by F nucleatum status (P = .02 for heteroge-
neity), similar to the findings for prudent dietary pattern
scores. Comparing participants in the highest quartile of
fiber intake (>26 g/d for men and >19 g/d for women) with
those in the lowest quartile (<18 g/d for men and <13 g/d for
women), the multivariable HR for F nucleatum–positive
tumors was 0.54 (95% CI, 0.32-0.92); in contrast, the corre-
sponding HR for F nucleatum–negative tumors was 1.13 (95%
CI, 0.92-1.40). In further exploratory analyses, we found that
intakes of cereal-derived fiber might be differentially associ-
ated with colorectal cancer according to F nucleatum status
(P = .01 for heterogeneity) (eTable 9 in the Supplement). We
did not observe such heterogeneity for fat or protein.
Discussion
In the 2 US nationwide prospective cohorts, we found that
participants with higher long-term prudent dietary pattern
scores were associated with a lower risk of F nucleatum–
positive colorectal cancers but not F nucleatum–negative
cancers. Our data also suggest that higher intakes of dietary
fiber, one of the components of the prudent diet, may be
associated with a lower risk of F nucleatum–positive colorec-
tal cancer but not F nucleatum–negative cancer. These find-
ings support the hypothesis that the possible cancer-
preventive effects of prudent diets rich in dietary fiber may
be mediated by modulation of specific species in the gut
microbiota and subsequent alteration of the amount of
F nucleatum in local colonic tissue. To our knowledge, our
study represents the first to examine the intersection of diet
and incidence of colorectal cancer subgroups according to
microbial status in human tumor tissue.
The potential role of diet in modulating the risk of a vari-
ety of diseases, including colorectal cancer, has been widely
recognized.
23,34
According to the World Cancer Research Fund
and American Institute for Cancer Research, foods with fiber
including whole grains are one of the strongest factors linked
to decreasing the risk of colorectal cancer.
35
However, there
has been considerable heterogeneity in the epidemiologic data
associating prudent dietary patterns and the major compo-
nents of the prudent diet with colorectal cancer.
36
Our re-
sults here suggest that the inconsistency in the association of
prudent dietary patterns (and components of the diet) with
lower colorectal cancer risk may be in part attributable to dif-
ferential associations with cancer subgroups according to
F nucleatum in tumor tissue. In addition, given recent find-
ings between increasing amounts of F nucleatum DNA in co-
lorectal cancer tissue and worsened survival,
14
our data lend
additional support to the promotion of healthy diets to re-
duce mortality from colorectal cancer.
The precise mechanism by which prudent diets rich in di-
etary fiber may lower F nucleatum–enriched cancer incidence
remains unclear. Accumulating evidence suggests that long-
term dietary fiber intake has a profound effect on the gut mi-
crobiome, specifically through promotion of microbial diver-
sity and by lowering levels of inflammatory metabolites.
25,37-40
A recent study showed that a 2-week feeding intervention
switching rural-dwelling South Africans from a high-fiber,
low-fat diet to a low-fiber, high-fat diet was associated with an
increase in F nucleatum measured by PCR in the stool.
24
In ad-
dition, some have hypothesized that the variation observed in
F nucleatum levels in colorectal cancers collected from Spain,
Vietnam, Japan, and the United States may be attributable to
differences in dietary practices in these countries.
5,41
Further-
more, in a cross-sectional study, participants with advanced ad-
enoma were associated with lower dietary fiber intakes as well
as distinct fecal microbiome communities compared with
healthy controls.
42
It is plausible that an abundance of micro-
biota-accessible carbohydrates from prudent diets may influ-
ence bacterial fermentation of dietary fiber, resulting in al-
tered levels of short-chain fatty acids. These changes may alter
pH, increase transit time of gut contents, or lead to differences
in local immune surveillance, which are less hospitable
for nonnative species, such as F nucleatum, to establish
themselves in the colonic niche and potentiate colorectal
carcinogenesis.
24,25,43,44
Taken together, these data provide evi-
dence of substantial influences of diet on the gut microbiome,
which may in turn influence tumorigenesis.
There are several strengths in this study. First, our di-
etary data were prospectively collected and have been well
validated.
29
Second, our data were detailed and updated such
that we could examine long-term effects of overall dietary pat-
terns, specific food groups, and macronutrients in relation to
colorectal cancer risk. Third, we collected detailed data on mul-
tiple potential confounders, although residual confounding
cannot be excluded. Finally, our molecular pathological epi-
demiology (MPE) research
45
provides refined risk estimates for
specific cancer subgroups, such as F nucleatum–positive
cancer, and thereby offers insights into pathogenesis and cau-
sality. Molecular subtyping in the MPE approach can gather
pathogenetically similar cases, and thus can enhance statis-
tical inference (even with a relatively small number of cases).
46
The present study represents emerging unique microbial MPE
research
47
in which the microbial feature in tumor tissue can
serve as a pathogenic signature.
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