Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps.

Colorectal cancers (CRCs) arise from precursor polyps whose cellular origins, molecular heterogeneity, and immunogenic potential may reveal diagnostic and therapeutic insights when analyzed at high resolution. We present a single-cell transcriptomic and imaging atlas of the two most common human colorectal polyps, conventional adenomas and serrated polyps, and their resulting CRC counterparts. Integrative analysis of 128 datasets from 62 participants reveals adenomas arise from WNT-driven expansion of stem cells, while serrated polyps derive from differentiated cells through gastric metaplasia. Metaplasia-associated damage is coupled to a cytotoxic immune microenvironment preceding hypermutation, driven partly by antigen-presentation differences associated with tumor cell-differentiation status. Microsatellite unstable CRCs contain distinct non-metaplastic regions where tumor cells acquire stem cell properties and cytotoxic immune cells are depleted. Our multi-omic atlas provides insights into malignant progression of colorectal polyps and their microenvironment, serving as a framework for precision surveillance and prevention of CRC.

Racial Disparities in Associations of Alcohol Consumption With Liver Disease Mortality in a Predominantly Low-Income Population: A Report From the Southern Community Cohort Study.

Consistent with previous cross-sectional studies, in the Southern Community Cohort Study, the largest cohort for Black Americans conducted in a predominantly low-income population with 81,694 participants, we found that moderate alcohol drinking was associated with a significantly increased risk of mortality due to liver disease in Black Americans (hazard ratio = 2.06; 95% confidence interval: 1.08-3.94) but not in White Americans (hazard ratio = 0.87; 95% confidence interval: 0.52-1.44). We found that heavy drinking was significantly associated with an increased risk of mortality due to liver disease in both Black and White Americans. Future studies are warranted to understand the mechanism involving such racial disparity.

Magnesium Depletion Score (MDS) Predicts Risk of Systemic Inflammation and Cardiovascular Mortality among US Adults.

BACKGROUND: Kidney reabsorption of magnesium (Mg) is essential for homeostasis. OBJECTIVES: We developed and validated models with the kidney reabsorption-related magnesium depletion score (MDS) to predict states of magnesium deficiency and disease outcomes. METHODS: MDS was validated in predicting body magnesium status among 77 adults (aged 62 ± 8 y, 51% men) at high risk of magnesium deficiency in the Personalized Prevention of Colorectal Cancer Trial (PPCCT) (registered at clinicaltrials.gov as NCT01105169) using the magnesium tolerance test (MTT). We then validated MDS for risk stratification and for associations with inflammation and mortality among >10,000 US adults (weighted: aged 48 ± 0.3 y, 47% men) in the NHANES, a nationally representative study. A proportional hazards regression model was used for associations between magnesium intake and the MDS with risks of total and cardiovascular disease (CVD) mortality. RESULTS: In the PPCCT, the area under the receiver operating characteristic (ROC) curve (AUC) for magnesium deficiency was 0.63 (95% CI: 0.50, 0.76) for the model incorporating the MDS with sex and age compared with 0.53 (95% CI: 0.40, 0.67) for the model with serum magnesium alone. In the NHANES, mean serum C-reactive protein significantly increased with increasing MDS (P-trend < 0.01) after adjusting for age and sex and other covariates, primarily among individuals with magnesium intake less than the Estimated Average Requirement (EAR; P-trend < 0.05). Further, we found that low magnesium intake was longitudinally associated with increased risks of total and CVD mortality only among those with magnesium deficiency predicted by MDS. MDS was associated with increased risks of total and CVD mortality in a dose-response manner only among those with magnesium intake less than the EAR. CONCLUSIONS: The MDS serves as a promising measure in identifying individuals with magnesium deficiency who may benefit from increased intake of magnesium to reduce risks of systemic inflammation and CVD mortality. This lays a foundation for precision-based nutritional interventions.

Physical activity, dietary calcium to magnesium intake and mortality in the National Health and Examination Survey 1999-2006 cohort.

Calcium and magnesium affect muscle mass and function. Magnesium and calcium are also important for optimal vitamin D status. Vitamin D status modifies the associations between physical activity and risk of incident cardiovascular disease (CVD) and CVD mortality. However, no study examined whether levels of magnesium and calcium and the ratio of dietary calcium to magnesium (Ca:Mg) intake modify the relationship between physical activity and mortality. We included 20,295 National Health and Nutrition Examination Survey participants (1999-2006) aged >20 years with complete dietary, physical activity and mortality data (2,663 deaths). We assessed physical activity based on public health guidelines and sex-specific tertiles of MET-minutes/week. We used Cox proportional hazards models adjusted for potential confounding factors and stratified by the intakes of magnesium, calcium, Ca:Mg ratio. We found higher physical activity was significantly associated with reduced risk of total mortality and cause-specific mortality, regardless of Ca:Mg ratio, magnesium or calcium intake. In contrast, both moderate and high physical activity were significantly associated with substantially reduced risks of mortality due to cancer when magnesium intake was above the RDA level. We also found higher physical activity was significantly associated with a reduced risk of mortality due to cancer only when Ca:Mg ratios were between 1.7 and 2.6, although the interaction was not significant. Overall, dietary magnesium and, potentially, the Ca:Mg ratio modify the relationship between physical activity and cause-specific mortality. Further study is important to understand the modifying effects of the balance between calcium and magnesium intake on physical activity for chronic disease prevention.

Associations between calcium and magnesium intake and the risk of incident gastric cancer: A prospective cohort analysis of the National Institutes of Health-American Association of Retired Persons (NIH-AARP) Diet and Health Study.

Gastric cancer remains a leading cause of cancer-related mortality. Identifying dietary and other modifiable disease determinants has important implications for risk attenuation in susceptible individuals. Our primary aim was to estimate the association between dietary and supplemental intakes of calcium and magnesium and the risk of incident gastric cancer. We conducted a prospective cohort analysis of the National Institutes of Health-American Association of Retired Persons Diet and Health Study. We used Cox proportional hazard modeling to estimate the association between calcium and magnesium intakes with risk of incident gastric adenocarcinoma (GA) overall and by anatomic location, noncardia GA (NCGA) and cardia GA (CGA). A total of 536,403 respondents (59% males, 41% females) were included for analysis, among whom 1,518 incident GAs (797 NCGA and 721 CGA) occurred. Increasing calcium intake was associated with lower risk of GA overall (p-trend = 0.05), driven primarily by the association with NCGA, where the above median calcium intakes were associated with a 23% reduction in risk compared to the lowest quartile (p-trend = 0.05). This magnitude of NCGA risk reduction was greater among nonwhite ethnic group and Hispanics (hazard ratio [HR] 0.51, 95% confidence interval [CI]: 0.24-1.07, p-trend = 0.04), current/former smokers (HR 0.58, 95% CI: 0.41-0.81), obese individuals (HR 0.54, 95% CI: 0.31-0.96) and those with high NCGA risk scores (HR 0.50, 95% CI: 0.31-0.80). Among men only, increasing magnesium intake was associated with 22-27% reduced risk of NCGA (p-trend = 0.05), while for the cohort, dietary magnesium intake in the highest vs. lowest quartile was associated with a 34% reduced risk of NCGA (HR 0.66, 95% CI: 0.48-0.90). These findings have important implications for risk factor modification. Future investigations are needed not only to confirm our results, but to define mechanisms underlying these associations.

Associations between calcium and magnesium intake and the risk of incident oesophageal cancer: an analysis of the NIH-AARP Diet and Health Study prospective cohort.

BACKGROUND: Risk reduction through dietary modifications is an adjunct strategy for prevention of oesophageal cancer, a leading cause of cancer-related mortality and morbidity worldwide. We aimed to estimate the association between calcium and magnesium intakes and incident oesophageal cancer (OC). METHODS: We conducted a retrospective analysis of the NIH-AARP Diet and Health Study prospective cohort. We used multivariable Cox proportional hazard modeling to estimate the association between total intakes and incident OC overall and by histology (oesophageal squamous cell carcinoma (OSCC) and adenocarcinoma (OAC)). Sensitivity and stratified analyses were performed. RESULTS: Among 536,359 included respondents, 1414 incident OCs occurred over 6.5 million person-years follow-up time. Increasing dietary calcium intake was associated with an adjusted 32-41% lower risk of OSCC compared to the lowest quartile (p-trend 0.01). There was a positive association between increasing magnesium intake and OAC risk, but only among participants with low calcium:magnesium intake ratios (p-trend 0.04). There was a significant interaction with smoking status. CONCLUSIONS: Based on a retrospective analysis of the NIH-AARP Diet and Health Study prospective cohort, dietary intakes of calcium and magnesium were significantly associated with risk of OSCC and, among certain participants, OAC, respectively. If validated, these findings could inform dietary modifications among at-risk individuals. Mechanistic investigations would provide additional insight.

Yogurt consumption and colorectal polyps.

Diet modifies the risk of colorectal cancer (CRC), and inconclusive evidence suggests that yogurt may protect against CRC. We analysed the data collected from two separate colonoscopy-based case-control studies. The Tennessee Colorectal Polyp Study (TCPS) and Johns Hopkins Biofilm Study included 5446 and 1061 participants, respectively, diagnosed with hyperplastic polyp (HP), sessile serrated polyp, adenomatous polyp (AP) or without any polyps. Multinomial logistic regression models were used to derive OR and 95 % CI to evaluate comparisons between cases and polyp-free controls and case-case comparisons between different polyp types. We evaluated the association between frequency of yogurt intake and probiotic use with the diagnosis of colorectal polyps. In the TCPS, daily yogurt intake v. no/rare intake was associated with decreased odds of HP (OR 0·54; 95 % CI 0·31, 0·95) and weekly yogurt intake was associated with decreased odds of AP among women (OR 0·73; 95 % CI 0·55, 0·98). In the Biofilm Study, both weekly yogurt intake and probiotic use were associated with a non-significant reduction in odds of overall AP (OR 0·75; 95 % CI 0·54, 1·04) and (OR 0·72; 95 % CI 0·49, 1·06) in comparison with no use, respectively. In summary, yogurt intake may be associated with decreased odds of HP and AP and probiotic use may be associated with decreased odds of AP. Further prospective studies are needed to verify these associations.

Calcium: magnesium intake ratio and colorectal carcinogenesis, results from the prostate, lung, colorectal, and ovarian cancer screening trial.

BACKGROUND: We aimed to evaluate the associations between calcium and various stages of colorectal carcinogenesis and whether these associations are modified by the calcium to magnesium (Ca:Mg) ratio. METHODS: We tested our hypotheses in the prostate lung, colorectal and ovarian cancer screening trial. RESULTS: Calcium intake did not show a dose-response association with incident adenoma of any size/stage (P-trend = 0.17), but followed an inverse trend when restricted to synchronous/advanced adenoma cases (P-trend = 0.05). This inverse trend was mainly in participants with Ca:Mg ratios between 1.7 and 2.5 (P-trend = 0.05). No significant associations were observed for metachronous adenoma. Calcium intake was inversely associated with CRC (P-trend = 0.03); the association was primarily present for distal CRC (P-trend = 0.01). The inverse association between calcium and distal CRC was further modified by the Ca:Mg ratio (P-interaction < 0.01); significant dose-response associations were found only in participants with a Ca:Mg ratio between 1.7 and 2.5 (P-trend = 0.04). No associations for calcium were found in the Ca:Mg ratio above 2.5 or below 1.7. CONCLUSION: Higher calcium intake may be related to reduced risks of incident advanced and/or synchronous adenoma and incident distal CRC among subjects with Ca:Mg intake ratios between 1.7 and 2.5.

Is there a relationship between chocolate consumption and symptoms of depression? A cross-sectional survey of 13,626 US adults.

OBJECTIVE: To examine associations between chocolate consumption and depressive symptoms in a large, representative sample of US adults. METHODS: The data were from 13,626 adults (≥20 years) participating in the National Health and Nutrition Examination Survey between 2007-08 and 2013-14. Daily chocolate consumption was derived from two 24-hr dietary recalls. Depressive symptoms were assessed using the Patient Health Questionnaire (PHQ-9), with scores ≥10 indicating the presence of clinically relevant symptoms. We used multivariable logistic regression to test associations of chocolate consumption (no chocolate, non-dark chocolate, dark chocolate) and amount of chocolate consumption (grams/day, in quartiles) with clinically relevant depressive symptoms. Adults with diabetes were excluded and models controlled for relevant sociodemographic, lifestyle, health-related, and dietary covariates. RESULTS: Overall, 11.1% of the population reported any chocolate consumption, with 1.4% reporting dark chocolate consumption. Although non-dark chocolate consumption was not significantly associated with clinically relevant depressive symptoms, significantly lower odds of clinically relevant depressive symptoms (OR = 0.30, 95%CI 0.21-0.72) were observed among those who reported consuming dark chocolate. Analyses stratified by the amount of chocolate consumption showed participants reporting chocolate consumption in the highest quartile (104-454 g/day) had 57% lower odds of depressive symptoms than those who reported no chocolate consumption (OR = 0.43, 95%CI 0.19-0.96) after adjusting for dark chocolate consumption. CONCLUSIONS: These results provide some evidence that consumption of chocolate, particularly dark chocolate, may be associated with reduced odds of clinically relevant depressive symptoms. Further research capturing long-term chocolate consumption and using a longitudinal design are required to confirm these findings and clarify the direction of causation.

The modifying effect of kidney function on the association of cadmium exposure with blood pressure and cardiovascular mortality: NHANES 1999-2010.

OBJECTIVE: We hypothesized that the associations of urinary Cd with blood pressure and cardiovascular disease (CVD) mortality may be modified by renal function. METHODS: We tested these hypotheses using data from the National Health and Nutrition Examination Survey (NHANES, 1999-2010). RESULTS: Both systolic blood pressure (SBP) and diastolic blood pressure (DBP) were positively associated with blood Cd. DBP was positively related to urinary Cd whereas SBP was inversely associated with urinary Cd. In the stratified analyses by level of eGFR, the associations between SBP and urinary Cd were not statistically significant among those with normal renal function and those with mildly reduced renal function whereas SBP significantly positively associated with urinary Cd among those with moderately or severely decreased renal function (p for trend, 0.0004). Renal function appeared to be a modifying factor of the association between urinary Cd and mortality. CVD mortality risks (p for trend, 0.04) were significantly increased with increasing urinary Cd with hazard ratios (HRs) (95% CIs) of 2.18 (0.68-7.01) for the highest quartile of urinary Cd compared to the lowest. The association between urinary Cd and CVD mortality became stronger in the stratified analyses by renal function and these associations became more consistent in those who never smoked. CONCLUSIONS: The inverse association between urinary Cd and blood pressure observed in previous studies may be due to lack of consideration of renal function as an effect modifier. The strength of the association between urinary Cd and CVD mortality may be underestimated without considering renal function.

Intakes of magnesium, calcium and risk of fatty liver disease and prediabetes.

OBJECTIVE: Obesity and insulin resistance play important roles in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Mg intake is linked to a reduced risk of metabolic syndrome and insulin resistance; people with NAFLD or alcoholic liver disease are at high risk of Mg deficiency. The present study aimed to investigate whether Mg and Ca intakes were associated with risk of fatty liver disease and prediabetes by alcohol drinking status. DESIGN: We analysed the association between Ca or Mg intake and fatty liver disease, prediabetes or both prediabetes and fatty liver disease in cross-sectional analyses. SETTING: Third National Health and Nutrition Examination Survey (NHANES III) follow-up cohort of US adults. SUBJECTS: Nationally representative sample of US adults in NHANES (n 13 489). RESULTS: After adjusting for potential confounders, Mg intake was associated with approximately 30 % reduced odds of fatty liver disease and prediabetes, comparing the highest intake quartile v. the lowest. Mg intake may only be related to reduced odds of fatty liver disease and prediabetes in those whose Ca intake is less than 1200 mg/d. Mg intake may also only be associated with reduced odds of fatty liver disease among alcohol drinkers. CONCLUSIONS: The study suggests that high intake of Mg may be associated with reduced risks of fatty liver disease and prediabetes. Further large studies, particularly prospective cohort studies, are warranted to confirm the findings.

Interactions between calcium intake and polymorphisms in genes essential for calcium reabsorption and risk of colorectal neoplasia in a two-phase study.

The SLC8A1 (solute carrier family 8, member 1) gene, encoding Na+ /Ca2+ exchanger, is essential in regulating calcium reabsorption and homeostasis. Calcium homeostasis plays a key role in cell proliferation and apoptosis. We hypothesized that polymorphisms in five calcium-regulating genes (SLC8A1, ATP2B1, CALB1, CALB2, and CABP1) interact with calcium intake in relation to the risk of colorectal neoplasia. A two-phase (discovery and replication) study was conducted within the Tennessee Colorectal Polyp Study, including a total of 1275 cases and 2811 controls. In Phase I, we identified six out of 135 SNPs that significantly interacted with calcium intake in relation to adenoma risk. In Phase II, the calcium intake by rs4952490 (SLC8A1) interaction was replicated (Pinteraction = 0.048). We found an inverse association between calcium intake (1000-2000 mg/day) and colorectal adenomas, particularly for multiple/advanced adenomas, among the G-allele carriers but not among homozygous carriers of the common variant (A) in rs4952490. In the joint analysis of SLC8A1, KCNJ1, and SLC12A1 SNPs, carriers of variant alleles in at least two genes and with calcium intake above the DRI (1000 mg/day) were approximately 30-57% less likely to have adenomas than those whose calcium intake was below the DRI. The association was stronger for multiple/advanced adenomas. No association was found among those who did not carry any variant alleles in these genes when calcium intake was below 2500 mg/day. These findings, if confirmed, may provide a new avenue for the personalized prevention of colorectal adenoma and cancer.

Calcium/magnesium intake ratio, but not magnesium intake, interacts with genetic polymorphism in relation to colorectal neoplasia in a two-phase study.

Some studies suggest that the calcium to magnesium ratio intakes modify the associations of calcium or magnesium with risk of colorectal adenoma, adenoma recurrence, and cancer. Parathyroid hormone (PTH) plays a key role in the regulation of homeostasis for both calcium and magnesium. We hypothesized that polymorphisms in PTH and 13 other genes may modify the association between the calcium/magnesium intake ratio and colorectal neoplasia risk. We conducted a two-phase study including 1336 cases and 2891 controls from the Tennessee Colorectal Polyp Study. In Phase I, we identified 19 SNPs that significantly interacted with the calcium/magnesium intake ratio in adenoma risk. In Phase II, rs11022858 in PTH was replicated. In combined analysis of phases I and II, we found high calcium/magnesium intake ratio tended to be associated with a reduced risk of colorectal adenoma (P for trend, 0.040) among those who carried the TT genotype in rs11022858. In stratified analyses, calcium intake (≥ 1000 mg/d) was significantly associated with 64% reduced adenoma risk (OR = 0.36 (95% CI : 0.18-0.74)) among those homozygous for the minor allele (TT genotype) (P for trend, 0.012), but not associated with risk in other genotypes (CC/TC). Conversely, we found that highest magnesium intake was significantly associated with 27% reduced risk (OR = 0.73 (95% CI : 0.54-0.97)) of colorectal adenoma (P for trend, 0.026) among those who possessed the CC/TC genotypes, particularly among those with the TC genotype, whereas magnesium intake was not linked to risk among those with the TT genotype. These findings, if confirmed, will help for the development of personalized prevention strategies for colorectal cancer. © 2015 Wiley Periodicals, Inc.

Calcium intake and ion transporter genetic polymorphisms interact in human colorectal neoplasia risk in a 2-phase study.

BACKGROUND: The kidney-specific sodium-potassium-chloride cotransporter (NKCC2) protein encoded by solute carrier family 12 member 1 (SLC12A1) is the direct downstream effector of the inward-rectifier potassium channel (ROMK) encoded by potassium inwardly-rectifying channel, subfamily J, member 1 (KCNJ1), both of which are critical for calcium reabsorption in the kidney. OBJECTIVE: We hypothesized that polymorphisms in KCNJ1, SLC12A1, and 7 other genes may modify the association between calcium intake and colorectal neoplasia risk. METHODS: We conducted a 2-phase study in 1336 cases and 2891 controls from the Tennessee Colorectal Polyp Study. RESULTS: In phase I, we identified 5 single-nucleotide polymorphisms (SNPs) that significantly interacted with calcium intake in adenoma risk. In phase II, rs2855798 in KCNJ1 was replicated. In combined analysis of phases I and II, the P values for interactions between calcium intake and rs2855798 were 1 × 10(-4) for all adenoma and 5 × 10(-3) for multiple/advanced adenoma. The highest calcium intake was not associated with risk among those with no variant allele but was significantly associated with a 41% reduced adenoma risk among those who carried at least 1 variant allele in KCNJ1. The corresponding reduction in risk of multiple or advanced adenomas was 52% among those with at least 1 variant allele. The P values for interactions between calcium intake and combined SNPs from the KCNJ1 and SLC12A1 genes were 7.5 × 10(-5) for adenoma and 9.9 × 10(-5) for multiple/advanced adenoma. The highest calcium intake was not associated with risk among those with nonvariant alleles in 2 genes but was significantly associated with a 34% reduced adenoma risk among those who carried a variant allele in 1 of the genes. The corresponding reduction in risk of multiple or advanced adenomas was 64% among those with variant alleles in both genes. CONCLUSION: These findings, if confirmed, will be critical for the development of personalized prevention strategies for colorectal cancer.

Dietary medium-chain fatty acids and risk of incident colorectal cancer in a predominantly low-income population: a report from the Southern Community Cohort Study.

BACKGROUND: No prospective observational study has specifically examined the associations between dietary intakes of medium-chain fatty acids and risk of colorectal cancer. OBJECTIVES: This study examined the association between dietary intakes of medium-chain fatty acids and colorectal cancer risk overall and by racial subgroups in a predominantly low-income United States population. METHODS: This prospective study included 71,599 eligible participants aged 40 to 79 who were enrolled in the Southern Community Cohort Study between 2002 and 2009 in 12 southeastern United States states. Incident colorectal cancer cases were ascertained via linkage to state cancer registries, which was completed through 31 December, 2016. The dietary intakes of medium-chain fatty acids were assessed using a validated 89-item food frequency questionnaire. Multivariable Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between intakes of medium-chain fatty acids and risk for incident colorectal cancer. RESULTS: Among 71,599 participants, 48,008 (67.3%) were Black individuals and 42,260 (59.0%) were female. A total of 868 incident colorectal cancer cases occurred during a median follow-up of 13.7 y. Comparing the highest to the lowest quartile, high intake of dodecanoic acid/lauric acid (C12:0) was associated with reduced risk of colorectal cancer among White participants (HR: 0.52; 95% CI: 0.30, 0.91; P-trend = 0.05), but not in Black individuals (HR: 0.92; 95% CI, 0.68, 1.24; P-trend = 0.80) in multivariable-adjusted models. No associations were found between intakes of hexanoic acid/caproic acid (C6:0), octanoic acid/caprylic acid (C8:0), or decanoic acid/capric acid (C10:0) and risk of incident colorectal cancer overall or within racial subgroups. CONCLUSIONS: In a predominantly low-income United States population, an increased dietary C12:0 intake was associated with a substantially reduced risk of colorectal cancer only among White individuals, but not in Black individuals.

Associations of circulating saturated long-chain fatty acids with risk of mild cognitive impairment and Alzheimer's disease in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.

BACKGROUND: No study has examined the associations between peripheral saturated long-chain fatty acids (LCFAs) and conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD). This study aimed to examine whether circulating saturated LCFAs are associated with both risks of incident MCI from cognitively normal (CN) participants and incident AD progressed from MCI in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. METHODS: We conducted analysis of data from older adults aged 55-90 years who were recruited at 63 sites across the USA and Canada. We examined associations between circulating saturated LCFAs (i.e., C14:0, C16:0, C18:0, C20:0) and risk for incident MCI in CN participants, and incident AD progressed from MCI. FINDINGS: 829 participants who were enrolled in ADNI-1 had data on plasma saturated LCFAs, of which 618 AD-free participants were included in our analysis (226 with normal cognition and 392 with MCI; 60.2% were men). Cox proportional-hazards models were used to account for time-to-event/censor with a 48-month follow-up period for the primary analysis. Other than C20:0, saturated LCFAs were associated with an increased risk for AD among participants with MCI at baseline (Hazard ratios (HRs) = 1.3 to 2.2, P = 0.0005 to 0.003 in fully-adjusted models). No association of C20:0 with risk of AD among participants with MCI was observed. No associations were observed between saturated LCFAs and risk for MCI among participants with normal cognition. INTERPRETATION: Saturated LCFAs are associated with increased risk of progressing from MCI to AD. This finding holds the potential to facilitate precision prevention of AD among patients with MCI. FUNDING: National Institutes of Health.

Associations between traditional Chinese medicine body constitution and obesity risk among US adults.

Background: Traditional Chinese medicine (TCM) body constitution (BC), primarily determined by physiological and clinical characteristics, is an important process for clinical diagnosis and treatment and play a critical role in precision medicine in TCM. The purpose of the study was to explore whether the distributions of BC types differed by obesity status. Methods: We conducted a study to evaluate BC type in US population during 2012-2016. A total of 191 White participants from Personalized Prevention of Colorectal Cancer Trial (PPCCT) completed a self-administered Traditional Chinese Medicine Questionnaire (TCMQ, English version). In this study, we further compared the distribution of major types of TCM BC in the PPCCT to those Chinese populations stratified by obesity status. Results: We found the Blood-stasis frequency was higher in US White adults, 22.6% for individuals with BMI <30 and 11.2% for obese individuals, compared to 1.4% and 1.8%, respectively, in Chinese populations. We also found the percentages Inherited-special and Qi-stagnation were higher in US White adults than those in Chinese populations regardless of obesity status. However, the proportions of Yang-deficiency were higher in Chinese populations than those in our study conducted in US White adults regardless of obesity status. Conclusions: These new findings indicate the difference in distribution of BC types we observed between US and Chinese populations cannot be explained by the differences in prevalence of obesity. Further studies are needed to confirm our findings and understand the potential mechanism including genetic background and/or environmental factors.

Ca:Mg ratio, medium-chain fatty acids, and the gut microbiome.

BACKGROUND & AIMS: Ketogenic medium-chain fatty acids (MCFAs) with profound health benefits are commonly found in dairy products, palm kernel oil and coconut oil. We hypothesize that magnesium (Mg) supplementation leads to enhanced gut microbial production of MCFAs and, in turn, increased circulating MCFAs levels. METHODS: We tested this hypothesis in the Personalized Prevention of Colorectal Cancer Trial (PPCCT) (NCT01105169), a double-blind 2 × 2 factorial randomized controlled trial enrolling 240 participants. Six 24-h dietary recalls were performed for all participants at the baseline and during the intervention period. Based on the baseline 24-h dietary recalls, the Mg treatment used a personalized dose of Mg supplementation that would reduce the calcium (Ca): Mg intake ratio to around 2.3. We measured plasma MCFAs, sugars, ketone bodies and tricarboxylic acid cycle (TCA cycle) metabolites using the Metabolon's global Precision Metabolomics™ LC-MS platform. Whole-genome shotgun metagenomics (WGS) sequencing was performed to assess microbiota in stool samples, rectal swabs, and rectal biopsies. RESULTS: Personalized Mg treatment (mean dose 205.58 mg/day with a range from 77.25 to 389.55 mg/day) significantly increased the plasma levels of C7:0, C8:0, and combined C7:0 and C8:0 by 18.45%, 25.28%, and 24.20%, respectively, compared to 14.15%, 10.12%, and 12.62% decreases in the placebo arm. The effects remain significant after adjusting for age, sex, race and baseline level (P = 0.0126, P = 0.0162, and P = 0.0031, respectively) and FDR correction at 0.05 (q = 0.0324 for both C7:0 and C8:0). Mg treatment significantly reduced the plasma level of sucrose compared to the placebo arm (P = 0.0036 for multivariable-adjusted and P = 0.0216 for additional FDR correction model) whereas alterations in daily intakes of sucrose, fructose, glucose, maltose and C8:0 from baseline to the end of trial did not differ between two arms. Mediation analysis showed that combined C7:0 and C8:0 partially mediated the effects of Mg treatment on total and individual ketone bodies (P for indirect effect = 0.0045, 0.0043, and 0.03, respectively). The changes in plasma levels of C7:0 and C8:0 were significantly and positively correlated with the alterations in stool microbiome α diversity (r = 0.51, p = 0.0023 and r = 0.34, p = 0.0497, respectively) as well as in stool abundance for the signatures of MCFAs-related microbiota with acyl-ACP thioesterase gene producing C7:0 (r = 0.46, p = 0.0067) and C8:0 (r = 0.49, p = 0.003), respectively, following Mg treatment. CONCLUSIONS: Optimizing Ca:Mg intake ratios to around 2.3 through 12-week personalized Mg supplementation leads to increased circulating levels of MCFAs (i.e. C7:0 and C8:0), which is attributed to enhanced production from gut microbial fermentation and, maybe, sucrose consumption.

Magnesium intake is associated with a reduced risk of incident liver cancer, based on an analysis of the NIH-American Association of Retired Persons (NIH-AARP) Diet and Health Study prospective cohort.

BACKGROUND: Liver cancer incidence and mortality are escalating globally. Magnesium intake has been studied extensively in nonmalignant liver pathology, but the association between dietary intake of magnesium and primary liver malignancy has not been previously evaluated. OBJECTIVES: We aimed to determine the association between total magnesium intake and primary liver cancer risk. METHODS: Using the NIH-American Association of Retired Persons (NIH-AARP) Diet and Health Study prospective cohort, we estimated the association between magnesium intake and the risk of incident primary liver cancer using Cox proportional hazard modeling adjusted for relevant confounders. Comprehensive stratified and sensitivity analyses were performed. RESULTS: During 6.4 million person-years of follow-up time, 1067 primary liver cancers occurred in 536,359 participants. Higher magnesium intake was independently associated with a lower risk of liver cancer (P-trend = 0.005), with intakes in the highest compared with lowest quartile associated with 35% lower risk (HR: 0.65; 95% CI: 0.48, 0.87). The dose-related inverse association was more pronounced in moderate and heavy alcohol users (HR: 0.54; 95% CI: 0.35, 0.82; P-trend = 0.006), and this interaction was statistically significant (P-interaction = 0.04). CONCLUSIONS: Based on a prospective cohort analysis, we demonstrated that magnesium intake is associated with a lower risk of primary liver cancer, which was more pronounced among moderate and heavy alcohol users. Robust experimental and mechanistic data provide a biological basis to support these findings.

Magnesium and imidazole propionate.

BACKGROUND & AIMS: Circulating levels of imidazole propionate (ImP), a microbial metabolite of histidine, were higher in participants with type 2 diabetes (T2D) compared to those without and also induced insulin resistance. We hypothesize that low intake of magnesium (Mg) and/or low body Mg status in humans may lead to low Mg concentrations in gut microbiota, and, in turn, elevated microbial production of ImP and increased levels of circulating ImP. METHODS: We tested this hypothesis in the Personalized Prevention of Colorectal Cancer Trial (PPCCT) (registered at clinicaltrials.gov as NCT01105169), a double-blind 2 × 2 factorial randomized controlled trial enrolling 240 participants at high risk of Mg deficiency. Among 68 participants (34 each in the treatment and placebo arms), we measured plasma metabolites using the untargeted Metabolon's global Precision Metabolomics™ LC-MS platform. RESULTS: Mg treatment significantly reduced ImP by 39.9% compared to a 6.0% increase in the placebo arm (P = 0.02). We found the correlation coefficients were -0.12 (P = 0.32) and -0.31 (P < 0.01) between the change in ImP and changes in serum Mg and urinary Mg, respectively. In addition, we found Mg treatment increased circulating levels of propionic acid (InP) by 27.5% (P = 0.07) and reduced levels of glutarate by 17.9% (P = 0.04) compared to the placebo arm. CONCLUSIONS: Further studies are needed to replicate these findings and to investigate whether Mg treatment specifically changes the production of ImP by microbiota. Also, future studies are warranted to confirm the effect of Mg treatment on glutarate and InP.