e24126 Background: Head and neck squamous cancer (HNSCC) patients often face challenges with adequate nutritional intake due to the location of their disease and treatment-related adverse effects. As many as 60% of HNSCC patients present with malnutrition at diagnosis due to tumor location and burden. Currently, there are no specific nutrient guidelines for HNC patients. This study aimed to examine changes in nutrient intake and diet quality in patients with HNSCC before and after completion of radiation therapy (RT) or chemoradiation (CRT). Methods: This study used data from an ongoing longitudinal observational study that included newly diagnosed HNSCC patients receiving RT or CRT at Emory Winship Cancer Institute and MD Anderson Cancer Center. Adults aged ≥ 21 years with non-recurrent, non-metastatic HNSCC were enrolled. Dietary intake was assessed using the Automated Self-Administered 24-Hour Dietary Assessment Tool (ASA24) before treatment initiation and one-month post-treatment. Two dietary interviews were completed at each time point and averaged to estimate nutrient intake using the USDA Food and Nutrient Database and diet quality using Healthy Eating Index-2020 (HEI) scores. Macronutrients were expressed as % of kcal, and other nutrients were energy-adjusted per 1000 kcal. Linear mixed models assessed pre- to post-treatment changes, adjusting for age, BMI, sex, HPV status, treatment, and time, with false discovery rate (FDR) correction for multiple testing. Results: Among the 103 patients analyzed, 83.3% were male, with a mean age of 59.2 yrs (SD = 10.5 yrs). 76.5% were HPV positive, and 66.7% received CRT. Pre-treatment, the mean BMI was 29.4 kg/m 2 (SD = 6.43 kg/m 2 ); the mean total energy intake was 2010 kcal/day (SD = 752 kcal/day), and the mean HEI total score was 48.0 (SD = 48.5). Overall, total energy intake did not change significantly pre- and post-treatment (FDR = 0.198). However, there was a decrease in % kcal from total fat (FDR < 0.01), solid fats (FDR = 0.0144), saturated fat (FDR < 0.01), and monounsaturated fat (FDR = 0.0154). Additionally, % kcal from carbohydrates increased (FDR < 0.01). For micronutrients, iron, Vitamin B1, Vitamin B2, Vitamin B6, Vitamin B9, Vitamin B12, Vitamin D, magnesium, and calcium intake all significantly increased (all FDR < 0.05). Total HEI score did not significantly change (FDR = 0.813), but whole fruit (FDR = 0.013) and total fruit (FDR < 0.01) intake significantly decreased. Conclusions: Despite stable energy intake and diet quality, treatment was associated with decreased fat and fruit intake and increased carbohydrate and certain micronutrient intake. These changes in diet could be attributed to treatment side effects, which can alter food preferences. Further research is warranted to examine the association between treatment side effects and nutritional intake. The findings may inform the development of clinical nutrition guidelines for HNSCC patients.

Background and aims Recent data suggest a role for the gut microbiome in the development of hepatocellular carcinoma. We investigated associations of gut microbiome abundances and concentrations of circulating bacteria-associated metabolites with hepatocellular carcinoma using Mendelian randomisation. Methods Two-sample Mendelian randomisation was conducted using summary statistics from release 11 of FinnGen (609 cases and 473,046 controls) and The North American Hepatocellular Cancer Epidemiology Consortium (1872 cases and 2907 controls). Inverse variance-weighted analyses were performed as well as several sensitivity analyses. Results In the FinnGen analyses, acetoacetate, ascorbate and asparagine were nominally associated with decreased risk. Alanine, hippuric acid and taurocholic acid were nominally associated with increased risk. The Barnesiella, Catenibacterium, Enterorhabdus and Eubacterium oxidoreducens genera were nominally associated with increased risk. Escherichia-Shigella was nominally associated with decreased risk. In the North American Hepatocellular Cancer Epidemiology Consortium analyses, the circulating bacteria-associated metabolites taurochenodeoxycholic acid and threonate were nominally associated with decreased risk. Five genera were nominally associated with increased risk; Eubacterium rectale group, Hungatella, Sellimonas and the unknown genus 1000005472. Conclusion These results, based on genetically predicted gut microbiome characteristics and circulating gut bacteria-related metabolite concentrations, suggest a putative causal role in hepatic carcinogenesis.

Cancer-related inflammation and metabolic alterations extend beyond the tumor microenvironment, exerting systemic effects that disrupt energy homeostasis and contribute to reduced physical function and chronic fatigue. The cGAS-STING pathway has emerged as a key regulator of innate immunity and inflammation; however, its role in cancer-associated fatigue remains poorly understood. In this study, we investigated the contribution of cGAS-STING-mediated inflammation to cancer- and/or its treatment-induced fatigue using a mouse model of human papillomavirus-related head and neck cancer. Wheel running activity, along with inflammatory and metabolic changes in tumor, liver tissues, and plasma, was assessed following chemoradiotherapy and pharmacological inhibition of STING in tumor-bearing and tumor-free control mice. The results revealed that tumor growth and chemoradiotherapy activated the cGAS-STING pathway, together with an upregulation of proinflammatory mediators in the plasma and alterations of mitochondrial and metabolic gene expression in the liver. To inhibit STING activation, mice were administered H-151, a specific STING antagonist. This intervention did not alter mitochondrial stress but attenuated hepatic and plasma inflammatory signatures and mitigated tumor- and/or chemoradiotherapy-associated behavioral fatigue, as measured by decreased voluntary wheel running. These findings implicate for the first time the cGAS-STING signaling pathway and metabolic homeostasis in cancer- and cancer therapy-related fatigue.

We assessed hepatocellular carcinoma (HCC) risk associated with smoking and alcohol consumption and their interactions, using both questionnaire data and objective serum biomarkers. Information on smoking and alcohol consumption was collected at baseline from 450,112 participants of the EPIC cohort, among whom 255 developed HCC after a median follow‐up of 14 years. In a nested case–control subset of 108 HCC cases and 108 matched controls, known biomarkers of smoking (cotinine, nicotine) and habitual alcohol consumption (2‐hydroxy‐3‐methylbutyric acid) were annotated from untargeted metabolomics features. Multivariable‐adjusted hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were computed, and multiplicative and additive interaction parameters were calculated. Compared to never smokers, current smokers had a higher HCC risk (HR = 2.46, 95% CI = 1.77–3.43) dose‐dependently with the number of cigarettes smoked per day ( P trend <.001). Compared to light drinkers, HCC risk was higher in former (HR = 3.20, 95% CI = 1.70–6.03), periodically heavy (HR = 1.98, 95% CI = 1.11–3.54), and always heavy (HR = 5.51, 95% CI = 2.39–12.7) drinkers. Higher HCC risk was also observed in the highest versus the lowest tertiles of cotinine (OR = 4.88, 95% CI = 1.52–15.70), nicotine (OR = 5.80, 95% CI = 1.33–25.30) and 2‐hydroxy‐3‐methylbutyric acid (OR = 5.89, 95% CI = 1.33–26.12). Questionnaire‐assessed smoking and alcohol exposures did not demonstrate an HCC risk interaction at the multiplicative (MI = 0.88, 95% CI = 0.40–1.96) or additive (RERI = 0.71, 95% CI = −10.1 to 23.6; attributable proportion = 0.17, 95% CI = −0.52 to 1.16; synergy index = 1.27, 95% CI = 0.98–1.66) scales. Similar analyses with cotinine, nicotine, and 2‐hydroxy‐3‐methylbutyric acid also did not show interactions between smoking and alcohol consumption on HCC risk. Smoking and alcohol consumption are strong independent risk factors for HCC and do not appear to synergistically impact its risk, but larger studies are needed.

The gut barrier is a multi-later system consisting of two main components: 1) a physical barrier comprised of a thick mucus layer and the epithelium providing defense against microbes and foreign antigens, and 2) a mucosal immune system differentiating between pathogenic and commensal microorganisms, and responsible for the immune response to pathogens and pathogen-associated molecular patterns such as lipopolysaccharide (LPS). Gut barrier dysfunction and related inflammation are known to be associated with and contribute to the development and progression of colorectal cancer (CRC). Whether this association is modified by genetic variation in the genes related to intestinal mucosal and immune function has not been well studied in humans. Therefore, we investigated 292 functional and tagging single-nucleotide polymorphisms (SNPs) in 27 genes encoding proteins in the pathways related to endotoxins/LPS sensing and tolerance, inflammation, Crohn’s disease, and colon mucus synthesis in 1,420 incident CRC cases matched 1:1 to control participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Previously measured serum flagellin- and LPS-specific IgA and IgG levels, considered as biomarkers of exposure to bacterial products and intestinal permeability, were available for a subset of matched case-control pairs. Multivariable odds ratios and 95% confidence intervals were calculated using unconditional logistic regression, with Benjamini-Hochberg (BH) adjustment for multiple comparison testing. The adaptive rank-truncated product (ARTP) method implemented in R-package PIGE was used for gene- and pathway-level analyses. Thirty one SNPs in 16 genes related to LPS response and tolerance (TLR4, TNFRSF1B, LBP, CD38, CD14), colon mucosal function (ABCB1, MUC6/MUC2, CAMP/ZNF589), inflammation (ALOX5, IL10, IL12B, IL2/IL21, IL6, NFKB1), and Crohn’s disease (rs3197999, rs762421) were statistically significantly associated with CRC risk (raw P-values < 0.05), but lost significance after correction for multiple testing. Among controls (n = 692), 10 SNPs in 4 genes (ABCB1, MUC6/MUC2, NFKB1, IL1A/IL1B) were statistically significantly associated with biomarkers of intestinal permeability (raw P-values < 0.05; all non-significant after multiple testing correction). Pathway analyses showed no statistically significant effects on CRC risk for either individual genes or genes grouped into distinct pathways. However, the data suggested possible associations between CRC risk and the genes in the LPS pathway (P = 0.18) and genetic variants previously associated with Crohn’s disease (P = 0.08). This large and comprehensive study has identified gut barrier function-related genes and pathways possibly contributing to CRC risk in European populations. Additional studies in large populations and consortia are needed to confirm our findings.Citation Format: Hannah Mandle, Mazda Jenab, David Hughes, Marc Gunter, Elio Riboli, Veronika Fedirko. Gut barrier function-related genes and colorectal cancer risk in Western European populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1581.

This cohort study examines the association of neighborhood disadvantage with outcomes in patients with head and neck cancer.

Human fatty acid binding protein-4 (FABP-4), a protein elevated in obesity that promotes colon cancer cell invasiveness and metastasis, may be associated with higher mortality in individuals with colorectal cancer (CRC) and may serve as a mediator of the obesity-mortality association in these individuals. We used a causal diagram to inform covariate selection and applied Cox proportional hazards models to estimate hazard ratios (HRs) for CRC-specific, non-CRC-specific, and all-cause mortality by FABP-4 levels measured in baseline blood samples from 1371 incident CRC cases from the European Prospective Investigation into Cancer and Nutrition cohort. Competing risk analyses were adapted for CRC and non-CRC deaths. Mediation analyses were conducted to estimate total effects (TEs), direct effects (DEs), and mediation proportions (MPs) by FABP-4 of pre-diagnostic body mass index (BMI) on mortality. In the fully adjusted model including BMI, higher circulating FABP-4 concentrations were associated with higher CRC mortality (HRQ4vsQ1 = 1.49; 95% CI: 1.11-2.00) and all-cause mortality (HRQ4vsQ1 = 1.49; 95% CI: 1.15-1.93), but not statistically associated with non-CRC mortality (HRQ4vsQ1 = 1.51; 95% CI: 0.82-2.76). The TE and DE per 5 kg/m2 of BMI on all-cause mortality were 1.21; 95% CI: 1.10-1.34, and 1.13; 95% CI: 1.02-1.26, respectively, with a MP of 34.5% (p = .002) by FABP-4. For CRC-specific and non-CRC-specific mortality, MPs by FABP-4 were 33.7% (p = .03) and 36.1% (p = .02), respectively. In conclusion, higher concentrations of FABP-4 were associated with higher CRC-specific and all-cause mortality in individuals with CRC. FABP-4 was a significant partial mediator of the adiposity-mortality relationship in individuals with CRC.

The most widely used technologies for profiling microbial communities are 16S marker-gene sequencing and shotgun metagenomic sequencing. Interestingly, many microbiome studies have performed both sequencing experiments on the same cohort of samples. The two sequencing datasets often reveal consistent patterns of microbial signatures, highlighting the potential for an integrative analysis to improve power of testing these signatures. However, differential experimental biases, partially overlapping samples, and differential library sizes pose tremendous challenges when combining the two datasets. Currently, researchers either discard one dataset entirely or use different datasets for different objectives. In this article, we introduce the first method of this kind, named Com-2seq, that combines the two sequencing datasets for the objective of testing differential abundance at the genus and community levels while overcoming these difficulties. We demonstrate that Com-2seq substantially improves statistical efficiency over analysis of either dataset alone and works better than two ad hoc approaches.

Introduction: Recent experimental evidence shows that intestinal barrier disruption initiates colon inflammation, which may promote colorectal carcinogenesis. In experimental models, vitamin D and calcium improved gut barrier function; however, this has not been assessed in humans. Method: To test the effects of supplemental calcium and vitamin D3 on circulating biomarkers of intestinal mucosal damage (intestinal fatty-acid binding protein, IFABP) and exposure to bacterial products due to impaired gut barrier (lipopolysaccharide-binding protein, LBP), we conducted an “adjunct biomarker study” to a larger 11-center, randomized, placebo-controlled, partial 2 × 2 factorial chemoprevention clinical trial, the Vitamin D/Calcium Polyp Prevention Study. Participants were randomized into four different treatment groups: placebo, 1,200 mg/day calcium, 1,000 IU/day vitamin D3, and 1,200 mg/day calcium plus 1,000 IU/day vitamin D3. Circulating concentrations of LBP and IFABP were measured at baseline and 1-year follow-up using the Meso Scale Discovery electrochemiluminescence assays in a subset of 118 participants included in the adjunct biomarker study. Result: Following one year of vitamin D3 treatment, in the vitamin D3 plus calcium and vitamin D3 groups versus placebo and calcium groups, LBP decreased 10% (316 ng/ml; P=0.23) and IFABP 18% (77 ng/ml; P=0.06). A similar decrease of 20% (P=0.10) was observed for IFABP, but not LBP, in the vitamin D3 plus calcium versus the calcium group. There were no appreciable biomarker changes with calcium treatment. In stratified analyses, we found possible effect modifications by baseline serum 25-OH-vitamin D, total calcium intake, body mass index, and interleukin 6 (IL-6) concentration on estimated vitamin D3 treatment effects on LBP and/or IFABP. Conclusion: These preliminary results are consistent with vitamin D’s potential protective effects on intestinal mucosal barrier and support further research of vitamin D against gut barrier disruption and colorectal neoplasms. Citation Format: Sangji Lee, Veronika Fedirko, Roberd M. Bostick, Bradley Pearce, Elizabeth L. Barry, Robin E. Rutherford, March E. Seabrook. Effects of supplemental calcium and vitamin D on circulating biomarkers of gut barrier function in colorectal adenoma patients: A randomized controlled trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 766.

Advanced glycation end-products (AGEs), formed endogenously or obtained exogenously from diet, may contribute to chronic inflammation, intracellular signaling alterations, and pathogenesis of several chronic diseases including colorectal cancer (CRC). However, the role of AGEs in CRC survival is less known. The associations of pre-diagnostic circulating AGEs and their soluble receptor (sRAGE) with CRC-specific and overall mortality were estimated using multivariable-adjusted Cox proportional hazards regression among 1369 CRC cases in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Concentrations of major plasma AGEs, Nε-[carboxy-methyl]lysine (CML), Nε-[carboxy-ethyl]lysine (CEL) and Nδ-[5-hydro-5-methyl-4-imidazolon-2-yl]-ornithine (MG-H1), were measured using ultra-performance liquid chromatography mass-spectrometry. sRAGE was assessed by enzyme-linked immunosorbent assay. Over a mean follow-up period of 96 months, 693 deaths occurred of which 541 were due to CRC. Individual and combined AGEs were not statistically significantly associated with CRC-specific or overall mortality. However, there was a possible interaction by sex for CEL (Pinteraction = .05). Participants with higher sRAGE had a higher risk of dying from CRC (HRQ5vs.Q1 = 1.67, 95% CI: 1.21-2.30, Ptrend = .02) or any cause (HRQ5vs.Q1 = 1.38, 95% CI: 1.05-1.83, Ptrend = .09). These associations tended to be stronger among cases with diabetes (Pinteraction = .03) and pre-diabetes (Pinteraction <.01) before CRC diagnosis. Pre-diagnostic AGEs were not associated with CRC-specific and overall mortality in individuals with CRC. However, a positive association was observed for sRAGE. Our findings may stimulate further research on the role of AGEs and sRAGE in survival among cancer patients with special emphasis on potential effect modifications by sex and diabetes.

Resistin is a protein involved in inflammation and angiogenesis processes and may play a role in the progression of colorectal cancer (CRC). However, it remains unclear whether resistin is associated with increased mortality after CRC diagnosis. We examined pre-diagnostic serum resistin concentrations in relation to CRC-specific and all-cause mortality among 1343 incident CRC cases from the European Prospective Investigation into Cancer and Nutrition cohort. For CRC-specific mortality as the primary outcome, hazard ratios (HRs) and 95% confidence intervals (95% CI) were estimated from competing risk analyses based on cause-specific Cox proportional hazards models and further in sensitivity analyses using Fine-Gray proportional subdistribution hazards models. For all-cause mortality as the secondary outcome, Cox proportional hazards models were used. Subgroup analyses were performed by sex, tumor subsite, tumor stage, body mass index and time to CRC diagnosis. Resistin was measured on a median of 4.8 years before CRC diagnosis. During a median follow-up of 8.2 years, 474 deaths from CRC and 147 deaths from other causes were observed. Resistin concentrations were not associated with CRC-specific mortality (HRQ4vsQ1  = 0.95, 95% CI: 0.73-1.23; Ptrend  = .97; and HRper doubling of resistin concentration  = 1.00; 95% CI: 0.84-1.19; P = .98) or all-cause mortality. Results from competing risk (sensitivity) analysis were similar. No associations were found in any subgroup analyses. These findings suggest no association between pre-diagnostic circulating resistin concentrations and CRC-specific or all-cause mortality among persons with CRC, and the potential insignificance of resistin in CRC progression.

The aim of the study was to assess associations between intake of combined soft drinks (sugar sweetened and artificially sweetened) and fruit and vegetable juices and the risk of hepatocellular carcinoma (HCC), intrahepatic bile duct (IHBC) and biliary tract cancers (GBTC) using data from the European Prospective Investigation into Cancer and Nutrition cohort of 477,206 participants from 10 European countries.After 11.4 years of follow-up, 191 HCC, 66 IHBC and 236 GBTC cases were identified. Hazard ratios and 95% confidence intervals (HR; 95% CI) were estimated with Cox regression models with multivariable adjustment (baseline total energy intake, alcohol consumption and intake pattern, body mass index, physical activity, level of educational attainment and self-reported diabetes status).No risk associations were observed for IHBC or GBTC. Combined soft drinks consumption of >6 servings/week was positively associated with HCC risk: HR 1.83; 95% CI 1.11-3.02, p trend = 0.01 versus non-consumers. In sub-group analyses available for 91% of the cohort artificially sweetened soft drinks increased HCC risk by 6% per 1 serving increment (HR 1.06, 95% CI 1.03-1.09, n cases = 101); for sugar-sweetened soft drinks, this association was null (HR 1.00, 95% CI 0.95-1.06; n cases = 127, p heterogeneity = 0.07). Juice consumption was not associated with HCC risk, except at very low intakes (<1 serving/week: HR 0.60; 95% CI 0.38-0.95; p trend = 0.02 vs. non-consumers).Daily intake of combined soft drinks is positively associated with HCC, but a differential association between sugar and artificially sweetened cannot be discounted. This study provides some insight into possible associations of HCC with sugary drinks intake. Further exploration in other settings is required.

AbstractGut barrier dysfunction promotes chronic inflammation, contributing to several gastrointestinal diseases, including colorectal cancer. Preliminary evidence suggests that vitamin D and calcium could prevent colorectal carcinogenesis, in part, by influencing gut barrier function. However, relevant human data are scarce. We tested the effects of supplemental calcium (1,200 mg/day) and/or vitamin D3 (1,000 IU/day) on circulating concentrations of biomarkers of gut permeability (anti-flagellin and anti-lipopolysaccharide IgA and IgG, measured via ELISA) from baseline to 1 and 3 or 5 years postbaseline among 175 patients with colorectal adenoma in a randomized, double-blinded, placebo-controlled clinical trial. We also assessed factors associated with baseline concentrations of these biomarkers. We found no appreciable effects of supplemental vitamin D3 and/or calcium on individual or aggregate biomarkers of gut permeability. At baseline, a combined permeability score (the summed concentrations of all four biomarkers) was 14% lower among women (P = 0.01) and 10% higher among those who consumed >1 serving per day of red or processed meats relative to those who consumed none (Ptrend = 0.03). The permeability score was estimated to be 49% higher among participants with a body mass index (BMI) > 35 kg/m2 relative to those with a BMI < 22.5 kg/m2 (Ptrend = 0.17). Our results suggest that daily supplemental vitamin D3 and/or calcium may not modify circulating concentrations of gut permeability biomarkers within 1 or 3–5 years, but support continued investigation of modifiable factors, such as diet and excess adiposity, that could affect gut permeability.Prevention Relevance:Calcium and vitamin D may be involved in regulating and maintaining the integrity of the intestinal mucosal barrier, the dysfunction of which results in exposure of the host to luminal bacteria, endotoxins, and antigens leading to potentially cancer-promoting endotoxemia and chronic colon inflammation. While our results suggest that daily supplementation with these chemopreventive agents does not modify circulating concentrations of gut permeability biomarkers, they support continued investigation of other potential modifiable factors, such as diet and excess adiposity, that could alter gut barrier function, to inform the development of treatable biomarkers of risk for colorectal neoplasms and effective colon cancer preventive strategies.

Table S1. pIKKα/β, TLR4, and TLR5 Expression in the Full Length of Crypts and Stroma in the Differentiation Zone (Upper 40%) in the Normal-Appearing Rectal Mucosa of the Adjunct Biomarker Study Table S2. pIKKα/β, TLR4, and TLR5 Expression in the Full Length of Crypts and Stroma in the Proliferation Zone (Lower 60%) of Normal-Appearing Rectal Mucosa of the Adjunct Biomarker Study Participants (n = 105) During the Triala. Table S3. pIKKα/β, TLR4, and TLR5 Expression in the Ratio (ϕh) of the Differentiation Zone over the Full Length of the Crypt in Normal-Appearing Rectal Mucosa of the Adjunct Biomarker Study Participants (n = 105) During the Triala. Table S4. The Ratios of (pIKKα/β)/TLR4 and (pIKKα/β)/TLR5 in the Crypts in the Normal-Appearing Rectal Mucosa of the Adjunct Biomarker Study Participants (n=105)a. Table S5. Geometric Means, 95% CIs, and Proportional Differences in pIKKα/β, TLR4 and TLR5 Expression in the Full Length of the Crypts and Stroma, by Categories of Baseline Participant Characteristics (n = 105)a.

Fatigue among patients with head and neck cancer (HNC) has been associated with higher inflammation. Shortchain fatty acids (SCFAs) have been shown to have anti-inflammatory and immunoregulatory effects. Therefore, this study aimed to examine the association between SCFAs and fatigue among patients with HNC undergoing treatment with radiotherapy with or without concurrent chemotherapy. Plasma SCFAs and the Multidimensional Fatigue Inventory-20 were collected prior to and one month after the completion of treatment in 59 HNC patients. The genome-wide gene expression profile was obtained from blood leukocytes prior to treatment. Lower butyrate concentrations were significantly associated with higher fatigue (p = 0.013) independent of time of assessment, controlling for covariates. A similar relationship was observed for iso/valerate (p = 0.025). Comparison of gene expression in individuals with the top and bottom 33% of butyrate or iso/valerate concentrations prior to radiotherapy revealed 1,088 and 881 significantly differentially expressed genes, respectively (raw p < 0.05). The top 10 Gene Ontology terms from the enrichment analyses revealed the involvement of pathways related to cytokines and lipid and fatty acid biosynthesis. These findings suggest that SCFAs may regulate inflammatory and immunometabolic responses and, thereby, reduce inflammatory-related symptoms, such as fatigue.

Supplemental Table S1: ORs (95% CI) for risk of CRC by quartiles of baseline biomarkers of anti-LPS- and antiflagellin- IgA and IgG. Supplemental Table S2: ORs (95% CI) for risk of CRC by increasing levels of total bacterial exposure and high sensitivity C-reactive protein, waist circumference, BMI, total dietary fat, and alcohol intake; stratified by sex. Supplemenetal Table S3: ORs (95% CI) for risk of CRC by quartile of baseline biomarkers of anti-LPS- and antiflagellin- IgA and IgG after excluding cases and controls that occurred in the first 2 years of follow-up, stratified by sex

Background and Aims: Tea and coffee are widely consumed beverages worldwide. We evaluated their association with biliary tract cancer (BTC) incidence. Approach and Results: We pooled data from 15 studies in the Biliary Tract Cancers Pooling Project to evaluate associations between tea and coffee consumption and biliary tract cancer development. We categorized participants as nondrinkers (0 cup/day), moderate drinkers (>0 and <3 cups/day), and heavy drinkers (≥3 cups/day). We estimated multivariable HRs and 95% CIs using Cox models. During 29,911,744 person-years of follow-up, 851 gallbladder, 588 intrahepatic bile duct, 753 extrahepatic bile duct, and 458 ampulla of Vater cancer cases were diagnosed. Individuals who drank tea showed a statistically significantly lower incidence rate of gallbladder cancer (GBC) relative to tea nondrinkers (HR=0.77; 95% CI, 0.64–0.91), and intrahepatic bile duct cancer (IHBDC) had an inverse association (HR=0.81; 95% CI, 0.66–1.00). However, no associations were observed for extrahepatic bile duct cancer (EHBDC) or ampulla of Vater cancer (AVC). In contrast, coffee consumption was positively associated with GBC, with a higher incidence rate for individuals consuming more coffee (HR <3 cups/day =1.29; 95% CI, 1.01–1.66; HR ≥3 cups/day =1.49; 95% CI, 1.11–1.99, P trend =0.01) relative to coffee nondrinkers. However, there was no association between coffee consumption and GBC when restricted to coffee drinkers. There was little evidence of associations between coffee consumption and other biliary tract cancers. Conclusions: Tea consumption was associated with a lower incidence of GBC and possibly IHBDC. Further research is warranted to replicate the observed positive association between coffee and GBC.

Perspective on this Article from Effects of Vitamin D and Calcium Supplementation on Markers of Apoptosis in Normal Colon Mucosa: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Supplementary Figure Legends 1-4 from A Randomized Clinical Trial of the Effects of Supplemental Calcium and Vitamin D3 on Markers of Their Metabolism in Normal Mucosa of Colorectal Adenoma Patients