A case-control study of the association between the gut microbiota and colorectal cancer: exploring the roles of diet, stress, and race.

BACKGROUND: The gut microbiota is associated with risk for colorectal cancer (CRC), a chronic disease for which racial disparities persist with Black Americans having a higher risk of CRC incidence and mortality compared to other groups. Given documented racial differences, the gut microbiota may offer some insight into previously unexplained racial disparities in CRC incidence and mortality. A case-control analysis comparing 11 women newly diagnosed with CRC with 22 cancer-free women matched on age, BMI, and race in a 1:2 ratio was conducted. Information about participants' diet and perceived stress levels were obtained via 24-h Dietary Recall and Perceived Stress Scale-10 survey, respectively. Participants provided stool samples from which microbial genomic DNA was extracted to reveal the abundance of 26 genera chosen a priori based on their previously observed relevance to CRC, anxiety symptoms, and diet. RESULTS: Significantly lower alpha diversity was observed among cancer-free Black women compared to all other race-cancer status combinations. No group differences were observed when comparing beta diversity. Non-Hispanic White CRC cases tended to have higher relative abundance of Fusobacteria, Gemellaceae, and Peptostreptococcus compared to all other race-cancer combination groups. Perceived stress was inversely associated with alpha diversity and was associated with additional genera. CONCLUSIONS: Our findings suggest that microbiome-CRC associations may differ by racial group. Additional large, racially diverse population-based studies are needed to determine if previously identified associations between characteristics of the gut microbiome and CRC are generalizable to Black women and other racial, ethnic, and gender groups.

Associations of serum trimethylamine N-oxide and its precursors with colorectal cancer risk in the Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort.

BACKGROUND: Dietary intake influences gut microbiome composition, which in turn may be associated with colorectal cancer (CRC). Associations of the gut microbiome with colorectal carcinogenesis may be mediated through bacterially regulated, metabolically active metabolites, including trimethylamine N-oxide (TMAO) and its precursors, choline, L-carnitine, and betaine. METHODS: Prospective associations of circulating TMAO and its precursors with CRC risk were investigated. TMAO, choline, betaine, and L-carnitine were measured in baseline serum samples from 761 incident CRC cases and 1:1 individually matched controls in the prospective Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort using targeted fully quantitative liquid chromatography tandem mass spectrometry panels. Prospective associations of the metabolites with CRC risk, using multivariable conditional logistic regression, were measured. Associations of a priori-selected dietary exposures with the four metabolites were also investigated. RESULTS: TMAO and its precursors were not associated with CRC risk overall, but TMAO and choline were positively associated with higher risk for distal CRC (continuous ORQ90 vs. Q10 [95% CI] = 1.90 [CI, 1.24-2.92; p = .003] and 1.26 [1.17-1.36; p < .0001], respectively). Conversely, choline was inversely associated with rectal cancer (ORQ90 vs. Q10 [95% CI] = 0.77 [0.76-0.79; p < .001]). Red meat, which was previously associated with CRC risk in the Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort , was positively associated with TMAO (Spearman rho = 0.10; p = .0003). CONCLUSIONS: Serum TMAO and choline may be associated with higher risk of distal CRC, and red meat may be positively associated with serum TMAO. These findings provide insight into a potential microbially mediated mechanism underlying CRC etiology.

Associations of Circulating Estrogens and Estrogen Metabolites with Fecal and Oral Microbiome in Postmenopausal Women in the Ghana Breast Health Study.

The human fecal and oral microbiome may play a role in the etiology of breast cancer through modulation of endogenous estrogen metabolism. This study aimed to investigate associations of circulating estrogens and estrogen metabolites with the fecal and oral microbiome in postmenopausal African women. A total of 117 women with fecal (N = 110) and oral (N = 114) microbiome data measured by 16S rRNA gene sequencing, and estrogens and estrogen metabolites data measured by liquid chromatography tandem mass spectrometry were included. The outcomes were measures of the microbiome and the independent variables were the estrogens and estrogen metabolites. Estrogens and estrogen metabolites were associated with the fecal microbial Shannon index (global P < 0.01). In particular, higher levels of estrone (ß = 0.36, P = 0.03), 2-hydroxyestradiol (ß = 0.30, P = 0.02), 4-methoxyestrone (ß = 0.51, P = 0.01), and estriol (ß = 0.36, P = 0.04) were associated with higher levels of the Shannon index, while 16alpha-hydroxyestrone (ß = -0.57, P < 0.01) was inversely associated with the Shannon index as indicated by linear regression. Conjugated 2-methoxyestrone was associated with oral microbial unweighted UniFrac as indicated by MiRKAT (P < 0.01) and PERMANOVA, where conjugated 2-methoxyestrone explained 2.67% of the oral microbial variability, but no other estrogens or estrogen metabolites were associated with any other beta diversity measures. The presence and abundance of multiple fecal and oral genera, such as fecal genera from families Lachnospiraceae and Ruminococcaceae, were associated with several estrogens and estrogen metabolites as indicated by zero-inflated negative binomial regression. Overall, we found several associations of specific estrogens and estrogen metabolites and the fecal and oral microbiome. IMPORTANCE Several epidemiologic studies have found associations of urinary estrogens and estrogen metabolites with the fecal microbiome. However, urinary estrogen concentrations are not strongly correlated with serum estrogens, a known risk factor for breast cancer. To better understand whether the human fecal and oral microbiome were associated with breast cancer risk via the regulation of estrogen metabolism, we conducted this study to investigate the associations of circulating estrogens and estrogen metabolites with the fecal and oral microbiome in postmenopausal African women. We found several associations of parent estrogens and several estrogen metabolites with the microbial communities, and multiple individual associations of estrogens and estrogen metabolites with the presence and abundance of multiple fecal and oral genera, such as fecal genera from families Lachnospiraceae and Ruminococcaceae, which have estrogen metabolizing properties. Future large, longitudinal studies to investigate the dynamic changes of the fecal and oral microbiome and estrogen relationship are needed.

The intratumor microbiome is associated with microsatellite instability.

Intratumoral microbes may have multifunctional roles in carcinogenesis. Microsatellite instability (MSI) is associated with higher tumor immunity and mutational burden. Using whole transcriptome and whole genome sequencing microbial abundance data, we investigated associations of intratumoral microbes with MSI, survival, and MSI-relevant tumor molecular characteristics across multiple cancer types including colorectal cancer (CRC), stomach adenocarcinoma, and endometrial carcinoma. Among 451 CRC patients, our key finding was strong associations of multiple CRC-associated genera, including Dialister and Casatella, with MSI. Dialister and Casatella abundance was associated with improved overall survival (hazard ratiomortality = 0.56, 95% confidence interval = 0.34 to 0.92, and hazard ratiomortality = 0.44, 95% confidence interval = 0.27 to 0.72), respectively, comparing higher relative to lower quantiles. Multiple intratumor microbes were associated with immune genes and tumor mutational burden. Diversity of oral cavity-originating microbes was also associated with MSI among CRC and stomach adenocarcinoma patients. Overall, our findings suggest the intratumor microbiota may differ by MSI status and play a role in influencing the tumor microenvironment.

Gut microbiome and cancer implications: Potential opportunities for fermented foods.

There is a critical opportunity to improve response to immunotherapies and overall cancer survivorship via dietary interventions targeted to modify the gut microbiome, and in turn, potentially enhance anti-cancer immunity. A promising dietary intervention is fermented foods, which may alter gut microbiome composition and, in turn, improve immunity. In this article, we summarize the state of the literature pertaining to the gut microbiome and response to immunotherapy and other cancer treatments, potential clinical implications of utilizing a fermented foods dietary approach to improve cancer treatment outcomes, and existing gaps in the literature regarding the implementation of fermented food interventions among individuals with cancer or with a history of cancer. This review synthesizes a compelling rationale across different disciplines to lay a roadmap for future fermented food dietary intervention research aimed at modulating the gut microbiome to reduce cancer burden.

Stability of the Fecal and Oral Microbiome over 2 Years at -80°C for Multiple Collection Methods.

BACKGROUND: In prospective cohorts, biological samples are generally stored over long periods before an adequate number of cases have accrued. We investigated the impact of sample storage at -80°C for 2 years on the stability of the V4 region of the 16S rRNA gene across seven different collection methods (i.e., no additive, 95% ethanol, RNAlater stabilization solution, fecal occult blood test cards, and fecal immunochemical test tubes for feces; OMNIgene ORAL tubes and Scope mouthwash for saliva) among 51 healthy volunteers. METHODS: Intraclass correlation coefficients (ICC) were calculated for the relative abundance of the top three phyla, the 20 most abundant genera, three alpha-diversity metrics, and the first principal coordinates of three beta-diversity matrices. RESULTS: The subject variability was much higher than the variability introduced by the sample collection type, and storage time. For fecal samples, microbial stability over 2 years was high across collection methods (range, ICCs = 0.70-0.99), except for the samples collected with no additive (range, ICCs = 0.23-0.83). For oral samples, most microbiome diversity measures were stable over time with ICCs above 0.74; however, ICCs for the samples collected with Scope mouthwash were lower for two alpha-diversity measures, Faith's phylogenetic diversity (0.23) and the observed number of operational taxonomic units (0.23). CONCLUSIONS: Fecal and oral samples in most used collection methods are stable for microbiome analyses after 2 years at -80°C, except for fecal samples with no additive. IMPACT: This study provides evidence that samples stored for an extended period from prospective studies are useful for microbiome analyses.

A case-control study of the association between the gut microbiota and colorectal cancer: exploring the roles of diet, stress, and race.

Background: The gut microbiota is associated with risk for colorectal cancer (CRC), a chronic disease for which racial disparities persist with Black Americans having a higher risk of CRC incidence and mortality compared to other groups. Given documented racial differences, the gut microbiota may offer some insight into previously unexplained racial disparities in CRC incidence and mortality. A case-control analysis comparing 11 women newly diagnosed with CRC with 22 cancer-free women matched on age, BMI, and race in a 1:2 ratio was conducted. Information about participants' diet and perceived stress levels were obtained via 24-hour Dietary Recall and Perceived Stress Scale-10 survey, respectively. Participants provided stool samples from which microbial genomic DNA was extracted to reveal the abundance of 26 genera chosen a priori based on their previously observed relevance to CRC, anxiety symptoms, and diet. Results: Significantly lower alpha diversity was observed among cancer-free Black women compared to all other race-cancer status combinations. No group differences were observed when comparing beta diversity. Non-Hispanic White CRC cases tended to have higher relative abundance of Fusobacteria, Gemellaceae, and Peptostreptococcus compared to all other race-cancer combination groups. Perceived stress was inversely associated with alpha diversity and was associated with additional genera. Conclusions: Our findings suggest that microbiome-CRC associations may differ by racial group. Additional large, racially diverse population-based studies are needed to determine if previously identified associations between characteristics of the gut microbiome and CRC are generalizable to Black women and other racial, ethnic, and gender groups.

Prospective and Cross-sectional Associations of the Rectal Tissue Microbiome with Colorectal Adenoma Recurrence.

BACKGROUND: The gut microbiome is plausibly associated with colorectal cancer risk; however, previous studies mostly investigated this association cross-sectionally. We investigated cross-sectional and prospective associations of the rectal tissue microbiome with adenoma recurrence in the Polyp Prevention Trial (PPT). METHODS: PPT is a 4-year randomized clinical trial of the effect of a dietary intervention on adenoma recurrence among community members. We extracted DNA from rectal biopsies at baseline, end of year 1, and end of year 4 among 455 individuals and sequenced the V4 region of the 16S rRNA gene. At each timepoint, we investigated associations of alpha diversity, beta diversity, and presence and relative abundance of select taxa with adenoma recurrence using multivariable logistic regression. RESULTS: Variation in beta diversity was primarily explained by subject and minimally by year of collection or time between biopsy and colonoscopy. Cross-sectionally, year 4 alpha diversity was strongly, inversely associated with adenoma prevalence [ORQ3 vs. Q1 Shannon index = 0.40 (95% confidence interval, CI: 0.21-0.76)]. Prospective alpha diversity associations (i.e., baseline/year 1 alpha diversity with adenoma recurrence 3-4 years later) were weak or null, as were cross-sectional and prospective beta diversity-adenoma associations. Bacteroides abundance was more strongly, positively associated with adenoma prevalence cross-sectionally than prospectively. CONCLUSIONS: Rectal tissue microbiome profiles may be associated with prevalent adenomas, with little evidence supporting prospective associations. IMPACT: Additional prospective studies, with serial fecal and tissue samples, to explore microbiome-colorectal cancer associations are needed. Eventually, it may be possible to use microbiome characteristics as intervenable risk factors or screening tools.

Associations of dietary and lifestyle inflammation scores with mortality due to CVD, cancer, and all causes among Black and White American men and women.

One potential mechanism by which diet and lifestyle may affect chronic disease risk and subsequent mortality is through chronic systemic inflammation. In this study, we investigated whether the inflammatory potentials of diet and lifestyle, separately and combined, were associated with all-cause, all-CVD and all-cancer mortality risk. We analysed data on 18 484 (of whom 4103 died during follow-up) Black and White men and women aged ≥45 years from the prospective REasons for Geographic and Racial Differences in Stroke study. Using baseline (2003-2007) Block 98 FFQ and lifestyle questionnaire data, we constructed the previously validated inflammation biomarker panel-weighted, 19-component dietary inflammation score (DIS) and 4-component lifestyle inflammation score (LIS) to reflect the overall inflammatory potential of diet and lifestyle. From multivariable Cox proportional hazards models, the hazards ratios (HR) and their 95 % CI for the DIS-all-cause mortality and LIS-all-cause mortality risk associations were 1·32 (95 % CI (1·18, 1·47); Pfor trend < 0·01) and 1·25 (95 % CI (1·12, 1·38); Pfor trend < 0·01), respectively, among those in the highest relative to the lowest quintiles. The findings were similar by sex and race and for all-cancer mortality, but weaker for all-CVD mortality. The joint HR for all-cause mortality among those in the highest relative to the lowest quintiles of both the DIS and LIS was 1·91 (95 % CI 1·57, 2·33) (Pfor interaction < 0·01). Diet and lifestyle, via their contributions to systemic inflammation, separately, but perhaps especially jointly, may be associated with higher mortality risk among men and women.

Total Energy Intake: Implications for Epidemiologic Analyses.

In 1986, Willett and Stampfer (Am J Epidemiol. 1986;124(1):17-27) propelled the nutritional epidemiology field forward by publishing a commentary emphasizing the importance of analyzing diet in relation to total energy intake in epidemiologic analyses of diet and disease, detailing the value of accounting for body size, physical activity, and metabolic efficiency in diet-disease analyses via energy intake adjustment. Their publication has since been cited over 2,886 times and has inarguably advanced methodology for studying diet-disease associations, with most nutritional epidemiology studies standardly including some form of energy adjustment. However, there remains debate regarding the best scenarios and methods for energy adjustment. The goals of this commentary are to provide an updated review on factors that account for interindividual differences in energy intake, provide a balanced discussion regarding the considerations for or against adjustment for energy intake, and provide an updated examination of the commonly employed methods for the analysis of nutrient-disease associations. The principles of energy adjustment continue to be relevant nearly 25 years later, as it remains a critical method to account for potentially confounding interindividual variations in body size and physical activity.

Circulating Bile Acids and Adenoma Recurrence in the Context of Adherence to a High-Fiber, High-Fruit and Vegetable, and Low-Fat Dietary Intervention.

INTRODUCTION: Diet may affect bile acid (BA) metabolism and signaling. In turn, BA concentrations may be associated with cancer risk. We investigated (i) associations of BA concentrations with adenoma recurrence and (ii) the effect of a high-fiber, high-fruit and vegetable, and low-fat dietary intervention on serum BA concentrations. METHODS: The Polyp Prevention Trial is a 4-year randomized, controlled trial that investigated the effect of a high-fiber, high-fruit and vegetable, and low-fat diet on colorectal adenoma recurrence. Among 170 participants who reported adhering to the intervention and 198 comparable control arm participants, we measured 15 BAs in baseline, year 2, and year 3 serum using targeted, quantitative liquid chromatography-tandem mass spectrometry. We estimated associations of BAs with adenoma recurrence using multivariable logistic regression and the effect of the dietary intervention on BA concentrations using repeated-measures linear mixed-effects models. In a subset (N = 65), we investigated associations of BAs with 16S rRNA gene sequenced rectal tissue microbiome characteristics. RESULTS: Baseline total BA concentrations were positively associated with adenoma recurrence (odds ratio Q3 vs Q1 = 2.17; 95% confidence interval = 1.19-4.04; Ptrend = 0.03). Although we found no effect of the dietary intervention on BA concentrations, pretrial dietary fiber intake was inversely associated with total baseline BAs (Spearman = -0.15; PFDR = 0.02). BA concentrations were associated with potential colorectal neoplasm-related microbiome features (lower alpha diversity and higher Bacteroides abundance). DISCUSSION: Baseline circulating BAs were positively associated with adenoma recurrence. Although the dietary intervention did not modify BA concentrations, long-term fiber intake may be associated with lower concentrations of BAs that are associated with higher risk of adenoma recurrence.

Effects of Green Tea Catechins on Prostate Cancer Chemoprevention: The Role of the Gut Microbiome.

Accumulating evidence supports green tea catechins (GTCs) in chemoprevention for prostate cancer (PCa), a leading cause of cancer morbidity and mortality among men. GTCs include (-)-epigallocatechin-3-gallate, which may modulate the molecular pathways implicated in prostate carcinogenesis. Prior studies of GTCs suggested that they are bioavailable, safe, and effective for modulating clinical and biological markers implicated in prostate carcinogenesis. GTCs may be of particular benefit to those with low-grade PCas typically managed with careful monitoring via active surveillance (AS). Though AS is recommended, it has limitations including potential under-grading, variations in eligibility, and anxiety reported by men while on AS. Secondary chemoprevention of low-grade PCas using GTCs may help address these limitations. When administrated orally, the gut microbiome enzymatically transforms GTC structure, altering its bioavailability, bioactivity, and toxicity. In addition to xenobiotic metabolism, the gut microbiome has multiple other physiological effects potentially involved in PCa progression, including regulating inflammation, hormones, and other known/unknown pathways. Therefore, it is important to consider not only the independent roles of GTCs and the gut microbiome in the context of PCa chemoprevention, but how gut microbes may relate to individual responses to GTCs, which, in turn, can enhance clinical decision-making.

The oral microbiome and breast cancer and nonmalignant breast disease, and its relationship with the fecal microbiome in the Ghana Breast Health Study.

The oral microbiome, like the fecal microbiome, may be related to breast cancer risk. Therefore, we investigated whether the oral microbiome was associated with breast cancer and nonmalignant breast disease, and its relationship with the fecal microbiome in a case-control study in Ghana. A total of 881 women were included (369 breast cancers, 93 nonmalignant cases and 419 population-based controls). The V4 region of the 16S rRNA gene was sequenced from oral and fecal samples. Alpha-diversity (observed amplicon sequence variants [ASVs], Shannon index and Faith's Phylogenetic Diversity) and beta-diversity (Bray-Curtis, Jaccard and weighted and unweighted UniFrac) metrics were computed. MiRKAT and logistic regression models were used to investigate the case-control associations. Oral sample alpha-diversity was inversely associated with breast cancer and nonmalignant breast disease with odds ratios (95% CIs) per every 10 observed ASVs of 0.86 (0.83-0.89) and 0.79 (0.73-0.85), respectively, compared to controls. Beta-diversity was also associated with breast cancer and nonmalignant breast disease compared to controls (P ≤ .001). The relative abundances of Porphyromonas and Fusobacterium were lower for breast cancer cases compared to controls. Alpha-diversity and presence/relative abundance of specific genera from the oral and fecal microbiome were strongly correlated among breast cancer cases, but weakly correlated among controls. Particularly, the relative abundance of oral Porphyromonas was strongly, inversely correlated with fecal Bacteroides among breast cancer cases (r = -.37, P ≤ .001). Many oral microbial metrics were strongly associated with breast cancer and nonmalignant breast disease, and strongly correlated with fecal microbiome among breast cancer cases, but not controls.

Associations of Evolutionary-Concordance Diet and Lifestyle Pattern Scores with Incident, Sporadic Colorectal Adenoma in a Pooled Case-Control Study.

Differences in diet and lifestyle relative to those of our Paleolithic-era ancestors may explain current high incidences of chronic diseases, including colorectal cancer (CRC), in Westernized countries. Previously reported evolutionary-concordance diet and lifestyle pattern scores, reflecting closeness of diet and lifestyle patterns to those of Paleolithic-era humans, were associated with lower CRC incidence. Separate and joint associations of the scores with colorectal adenoma among men and women are unknown. To address this, we pooled data from three case-control studies of incident, sporadic colorectal adenomas (n = 771 cases, 1,990 controls), used participants' responses to food frequency and lifestyle questionnaires to calculate evolutionary-concordance diet and lifestyle pattern scores, and estimated the scores' associations with adenomas using multivariable unconditional logistic regression. The multivariable-adjusted odds ratios comparing those in the highest relative to the lowest diet and lifestyle score quintiles were 0.84 (95% confidence interval [CI] 0.62, 1.12; Ptrend:0.03) and 0.41 (95% CI 0.29, 0.59; Ptrend:<0.0001), respectively. The inverse associations were stronger for high-risk adenomas, and among those with both high relative to those with both low diet and lifestyle scores. These results suggest that more evolutionary-concordant diet and lifestyle patterns, separately and jointly, may be associated with lower risk for incident, sporadic colorectal adenoma.Supplemental data for this article is available online at https://doi.org/10.1080/01635581.2021.2002919 .

Bile Acids, Gut Microbes, and the Neighborhood Food Environment-a Potential Driver of Colorectal Cancer Health Disparities.

Bile acids (BAs) facilitate nutrient digestion and absorption and act as signaling molecules in a number of metabolic and inflammatory pathways. Expansion of the BA pool and increased exposure to microbial BA metabolites has been associated with increased colorectal cancer (CRC) risk. It is well established that diet influences systemic BA concentrations and microbial BA metabolism. Therefore, consumption of nutrients that reduce colonic exposure to BAs and microbial BA metabolites may be an effective method for reducing CRC risk, particularly in populations disproportionately burdened by CRC. Individuals who identify as Black/African American (AA/B) have the highest CRC incidence and death in the United States and are more likely to live in a food environment with an inequitable access to BA mitigating nutrients. Thus, this review discusses the current evidence supporting diet as a contributor to CRC disparities through BA-mediated mechanisms and relationships between these mechanisms and barriers to maintaining a low-risk diet.

Associations of Novel Lifestyle- and Whole Foods-Based Inflammation Scores with Incident Colorectal Cancer Among Women.

BACKGROUND: Chronic inflammation, associated with lifestyle and dietary factors, may contribute to colorectal carcinogenesis. To address this, we investigated associations of previously validated, inflammation biomarker panel-weighted, novel, 4-component lifestyle (LIS) and 19-component predominately whole foods-based dietary (DIS) inflammation scores with incident colorectal cancer (CRC) in the prospective Iowa Women's Health Study (IWHS; 1986-2012; n = 34,254, of whom 1,632 developed CRC). METHODS: We applied the published scores' components' weights, summed the weighted components to constitute the scores (higher scores reflect a higher balance of pro-inflammatory exposures), and investigated LIS- and DIS-CRC associations using multivariable Cox proportional hazards regression. RESULTS: The multivariable-adjusted hazards ratios (HR) and their 95% confidence intervals (CI) for CRC among participants in the highest relative to the lowest LIS and DIS quintiles were 1.47 (1.26, 1.72; Ptrend < 0.01) and 1.07 (0.91, 1.25; Ptrend = 0.22), respectively. The corresponding findings for distal colon cancers were HR 1.78 (1.29, 2.47) and HR 1.34 (0.98, 1.84), respectively. Among those in the highest relative to the lowest joint LIS/DIS quintile, the HR for CRC was 1.60 (95% CI 1.30, 1.98). CONCLUSIONS: Our results suggest that a more pro-inflammatory lifestyle, alone and jointly with a more pro-inflammatory diet, may be associated with higher CRC risk.

An investigation of cross-sectional associations of a priori-selected dietary components with circulating bile acids.

BACKGROUND: A growing body of literature suggests chronically higher bile acid (BA) concentrations may be associated with multiple health conditions. Diet may affect BA metabolism and signaling; however, evidence from human populations is lacking. OBJECTIVES: We systematically investigated cross-sectional associations of a priori-selected dietary components (fiber, alcohol, coffee, fat) with circulating BA concentrations. METHODS: We used targeted, quantitative LC-MS/MS panels to measure 15 circulating BAs in a subset of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC; n = 2224) and Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO; n = 986) comprising Finnish male smokers and United States men and women, respectively. We used multivariable linear regression to estimate associations of each dietary component with log-transformed BAs; exponentiated coefficients estimate proportional differences. We included the median of the dietary component quartile in linear regression models to test for trend. RESULTS: In ATBC, fiber was inversely associated with multiple circulating BAs. The proportional difference was -10.09% (95% CI: -19.29 to 0.16; P-trend = 0.04) when comparing total BAs among those in the highest relative to the lowest fiber quartile. Alcohol, trans fat, and polyunsaturated fat were positively associated with BAs in ATBC. The proportional difference comparing total BAs among those in the highest relative to the lowest alcohol quartile was 8.76% (95% CI: -3.10 to 22.06; P-trend = 0.03). Coffee and monounsaturated fat were inversely associated with BAs. The proportional difference comparing total BAs among those in the highest relative to the lowest coffee quartile was -24.03% (95% CI: -31.57 to -15.66; P-trend < 0.0001). In PLCO, no dietary components were associated with BAs except fiber, which was inversely associated with tauroursodeoxycholic acid. CONCLUSIONS: Alcohol, coffee, certain fat subtypes, and fiber were associated with circulating concentrations of multiple BAs among Finnish male smokers. Given the potential role of BAs in disease risk, further investigation of the effects of diet on BAs in humans is warranted.

Novel Dietary and Lifestyle Inflammation Scores Directly Associated with All-Cause, All-Cancer, and All-Cardiovascular Disease Mortality Risks Among Women.

BACKGROUND: Exogenous exposures collectively may contribute to chronic, low-grade inflammation and increase risks for major chronic diseases and mortality. We previously developed, validated, and reported a novel, FFQ-based and lifestyle questionnaire-based, inflammation biomarker panel-weighted, predominantly whole foods-based 19-component dietary inflammation score (DIS) and 4-component lifestyle inflammation score (LIS; comprising physical activity, alcohol intake, BMI, and current smoking status). Both scores were more strongly associated with circulating biomarkers of inflammation in 3 populations than were previously reported dietary inflammation indices. Associations of the DIS and LIS with mortality risk have not been reported. OBJECTIVES: To investigate separate and joint associations of the DIS and LIS with all-cause, all-cancer, and cardiovascular disease (CVD) mortality risks in the prospective Iowa Women's Health Study (1986-2012; n = 33,155 women, ages 55-69 years, of whom 17,431 died during follow-up, including 4379 from cancer and 6574 from CVD). METHODS: We summed each study participant's scores' components, weighted by their published weights, to yield the participant's inflammation score; a higher score was considered more pro-inflammatory. We assessed DIS and LIS mortality associations using multivariable Cox proportional hazards regression. RESULTS: Among participants in the highest relative to the lowest DIS and LIS quintiles, the adjusted HRs for all-cause mortality were 1.11 (95% CI: 1.05-1.16) and 1.60 (95% CI: 1.53-1.68), respectively; for all-cancer mortality were 1.07 (95% CI: 0.97-1.17) and 1.51 (95% CI: 1.38-1.66), respectively; and for CVD mortality were 1.12 (95% CI: 1.03-1.21) and 1.79 (95% CI: 1.66-1.94), respectively (all Ptrend values < 0.01). Among those in the highest relative to the lowest joint LIS/DIS quintiles, the HRs for all-cause, all-cancer, and all-CVD mortality were 1.88 (95% CI: 1.71-2.08), 1.82 (95% CI: 1.50-2.20), and 1.92 (95% CI: 1.64-2.24), respectively. CONCLUSIONS: More pro-inflammatory diets and lifestyles, separately but especially jointly, may be associated with higher all-cause, all-cancer, and all-CVD mortality risks among women.

Effects of processed meat and drinking water nitrate on oral and fecal microbial populations in a controlled feeding study.

BACKGROUND: One mechanism that can explain the link between processed meat consumption and colorectal cancer (CRC) is the production of carcinogenic N-nitroso compounds (NOCs) in the gastrointestinal tract. Oral and gut microbes metabolize ingested proteins (a source of secondary and tertiary amines and amides) and can reduce nitrate to nitrite, generating potentially carcinogenic NOCs. OBJECTIVE: We evaluated whether nitrate/nitrite in processed meat or water influences the fecal or salivary microbiota. DESIGN: In this dietary intervention study, 63 volunteers consumed diets high in conventional processed meats for two weeks, switched to diets high in poultry for two weeks, and then consumed phytochemical-enriched conventional processed or low-nitrite processed meat diets for two weeks. During the intervention, they drank water with low nitrate concentrations and consumed a healthy diet with low antioxidants. Then the volunteers drank nitrate-enriched water for 1 week, in combination with one of the four different diets. We measured creatinine-adjusted urinary nitrate levels and characterized the oral and fecal microbiota using 16S rRNA amplicon sequencing. RESULTS: Using linear mixed models, we found that, compared to baseline, urinary nitrate levels were reduced during the phytochemical-enriched low-nitrite meat diet (p-value = 0.009) and modestly during the poultry diet (p-value = 0.048). In contrast, urinary nitrate increased after 1-week of drinking nitrate-enriched water (p-value<10-5). Nitrate-enriched water, but not processed meats with or without phytochemicals, altered the saliva microbial population (p-value ≤0.001), and significantly increased abundance of 8 bacterial taxa, especially genus Neisseria and other nitrate-reducing taxa. Meats, phytochemicals and nitrate-enriched water had no significant effects on saliva alpha diversity or any diversity parameter measured for the fecal microbiota. CONCLUSION: These findings support the hypothesis that drinking high nitrate water increases oral nitrate-reducing bacteria, which likely results in increased NOC. However, meat nitrate/nitrite at the levels tested had no effect on either the gut or oral bacteria. CLINICALTRIALS. GOV IDENTIFIER: NCT04138654.

Associations of fecal microbial profiles with breast cancer and nonmalignant breast disease in the Ghana Breast Health Study.

The gut microbiota may play a role in breast cancer etiology by regulating hormonal, metabolic and immunologic pathways. We investigated associations of fecal bacteria with breast cancer and nonmalignant breast disease in a case-control study conducted in Ghana, a country with rising breast cancer incidence and mortality. To do this, we sequenced the V4 region of the 16S rRNA gene to characterize bacteria in fecal samples collected at the time of breast biopsy (N = 379 breast cancer cases, N = 102 nonmalignant breast disease cases, N = 414 population-based controls). We estimated associations of alpha diversity (observed amplicon sequence variants [ASVs], Shannon index, and Faith's phylogenetic diversity), beta diversity (Bray-Curtis and unweighted/weighted UniFrac distance), and the presence and relative abundance of select taxa with breast cancer and nonmalignant breast disease using multivariable unconditional polytomous logistic regression. All alpha diversity metrics were strongly, inversely associated with odds of breast cancer and for those in the highest relative to lowest tertile of observed ASVs, the odds ratio (95% confidence interval) was 0.21 (0.13-0.36; Ptrend < .001). Alpha diversity associations were similar for nonmalignant breast disease and breast cancer grade/molecular subtype. All beta diversity distance matrices and multiple taxa with possible estrogen-conjugating and immune-related functions were strongly associated with breast cancer (all Ps < .001). There were no statistically significant differences between breast cancer and nonmalignant breast disease cases in any microbiota metric. In conclusion, fecal bacterial characteristics were strongly and similarly associated with breast cancer and nonmalignant breast disease. Our findings provide novel insight into potential microbially-mediated mechanisms of breast disease.