Connections between the gut and brain monitor the intestinal tissue and its microbial and dietary content
, regulating both physiological intestinal functions such as nutrient absorption and motility
..., and brain-wired feeding behaviour
. It is therefore plausible that circuits exist to detect gut microorganisms and relay this information to areas of the central nervous system that, in turn, regulate gut physiology
. Here we characterize the influence of the microbiota on enteric-associated neurons by combining gnotobiotic mouse models with transcriptomics, circuit-tracing methods and functional manipulations. We find that the gut microbiome modulates gut-extrinsic sympathetic neurons: microbiota depletion leads to increased expression of the neuronal transcription factor cFos, and colonization of germ-free mice with bacteria that produce short-chain fatty acids suppresses cFos expression in the gut sympathetic ganglia. Chemogenetic manipulations, translational profiling and anterograde tracing identify a subset of distal intestine-projecting vagal neurons that are positioned to have an afferent role in microbiota-mediated modulation of gut sympathetic neurons. Retrograde polysynaptic neuronal tracing from the intestinal wall identifies brainstem sensory nuclei that are activated during microbial depletion, as well as efferent sympathetic premotor glutamatergic neurons that regulate gastrointestinal transit. These results reveal microbiota-dependent control of gut-extrinsic sympathetic activation through a gut-brain circuit.
Meat, dairy, and cancer Abid, Zaynah; Cross, Amanda J; Sinha, Rashmi
The American journal of clinical nutrition,
07/2014, Volume:
100
Journal Article
Peer reviewed
Open access
In 2007 the World Cancer Research Fund and American Institute for Cancer Research (WCRF/AICR) report judged that the evidence for an association between red and processed meat consumption and ...colorectal cancer was convincing. In addition, the effect of other animal products on cancer risk has been studied, and the WCRF/AICR report concluded that milk probably decreases the risk of colorectal cancer but diets high in calcium probably increase the risk of prostate cancer, whereas there was limited evidence for an association between milk and bladder cancer and insufficient evidence for other cancers. There are several potential mechanisms relating meat to cancer, including heterocyclic amines, polycyclic aromatic hydrocarbons, N-nitroso compounds, and heme iron. Although the evidence in favor of a link between red and processed meat and colorectal cancer is convincing, the relations with other cancers are unclear. In this review, we summarize cohort studies conducted by the National Cancer Institute on meat and dairy intake in relation to cancer since the 2007 WCRF/AICR report. We also report the findings of meta-analyses published since 2007.
Summary Background Colorectal cancer is the third most common cancer worldwide. Previous analyses have only reported follow-up after flexible sigmoidoscopy for a maximum of 12 years. We aimed to ...examine colorectal cancer incidence and mortality after a single flexible sigmoidoscopy screening and 17 years of follow-up. Methods In this multicentre randomised trial (UK Flexible Sigmoidoscopy Screening Trial), done between Nov 14, 1994, and March 30, 1999, 170 432 eligible men and women, who had indicated on a previous questionnaire that they would probably attend screening if invited, were randomly assigned (1:2) to an intervention group (offered flexible sigmoidoscopy screening) or a control group (not contacted). Randomisation was done centrally in blocks of 12, and stratified by trial centre, general practice, and household type. The nature of the intervention did not allow the staff to be masked to arm of the trial; however, randomisation was done in batches so that the control group and participants not yet randomised were unaware of their allocation status. The primary outcomes were incidence and mortality of colorectal cancer. Hazard ratios (HRs) and 95% CIs for colorectal cancer incidence and mortality were estimated for intention-to-treat and per-protocol analyses. The trial is registered with ISRCTN, number 28352761. Findings Our cohort analysis included 170 034 people: 112 936 in the control group and 57 098 in the intervention group, 40 621 (71%) of whom were screened and 16 477 (29%) were not screened. During screening and a median of 17·1 years' follow-up, colorectal cancer was diagnosed in 1230 individuals in the intervention group and 3253 in the control group, and 353 individuals in the intervention group versus 996 individuals in the control group died from colorectal cancer. In intention-to-treat analyses, colorectal cancer incidence was reduced by 26% (HR 0·74 95% CI 0·70–0·80; p<0·0001) in the intervention group versus the control group and colorectal cancer mortality was reduced by 30% (0·70 0·62–0·79; p<0·0001) in the intervention group versus the control group. In per-protocol analyses, adjusted for non-compliance, colorectal cancer incidence and mortality were 35% (HR 0·65 95% CI 0·59–0·71) and 41% (0·59 0·49–0·70) lower in the screened group. Interpretation A single flexible sigmoidoscopy continues to provide substantial protection from colorectal cancer diagnosis and death, with protection lasting at least 17 years. Funding National Institute for Health Research Efficacy and Mechanism Evaluation.
Background
Older people taking multiple medications represent a large and growing proportion of the population. Managing multiple medications can be challenging, and this is especially the case for ...older people, who have higher rates of comorbidity and physical and cognitive impairment than younger adults. Good medication‐taking ability and medication adherence are necessary to ensure safe and effective use of medications.
Objectives
To evaluate the effectiveness of interventions designed to improve medication‐taking ability and/or medication adherence in older community‐dwelling adults prescribed multiple long‐term medications.
Search methods
We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), PsycINFO, CINAHL Plus, and International Pharmaceutical s from inception until June 2019. We also searched grey literature, online trial registries, and reference lists of included studies.
Selection criteria
We included randomised controlled trials (RCTs), quasi‐RCTs, and cluster‐RCTs. Eligible studies tested interventions aimed at improving medication‐taking ability and/or medication adherence among people aged ≥ 65 years (or of mean/median age > 65 years), living in the community or being discharged from hospital back into the community, and taking four or more regular prescription medications (or with group mean/median of more than four medications). Interventions targeting carers of older people who met these criteria were also included.
Data collection and analysis
Two review authors independently reviewed s and full texts of eligible studies, extracted data, and assessed risk of bias of included studies. We conducted meta‐analyses when possible and used a random‐effects model to yield summary estimates of effect, risk ratios (RRs) for dichotomous outcomes, and mean differences (MDs) or standardised mean differences (SMDs) for continuous outcomes, along with 95% confidence intervals (CIs). Narrative synthesis was performed when meta‐analysis was not possible. We assessed overall certainty of evidence for each outcome using Grades of Recommendation, Assessment, Development and Evaluation (GRADE). Primary outcomes were medication‐taking ability and medication adherence. Secondary outcomes included health‐related quality of life (HRQoL), emergency department (ED)/hospital admissions, and mortality.
Main results
We identified 50 studies (14,269 participants) comprising 40 RCTs, six cluster‐RCTs, and four quasi‐RCTs. All included studies evaluated interventions versus usual care; six studies also reported a comparison between two interventions as part of a three‐arm RCT design.
Interventions were grouped on the basis of their educational and/or behavioural components: 14 involved educational components only, 7 used behavioural strategies only, and 29 provided mixed educational and behavioural interventions. Overall, our confidence in results regarding the effectiveness of interventions was low to very low due to a high degree of heterogeneity of included studies and high or unclear risk of bias across multiple domains in most studies.
Five studies evaluated interventions for improving medication‐taking ability, and 48 evaluated interventions for improving medication adherence (three studies evaluated both outcomes).
No studies involved educational or behavioural interventions alone for improving medication‐taking ability. Low‐quality evidence from five studies, each using a different measure of medication‐taking ability, meant that we were unable to determine the effects of mixed interventions on medication‐taking ability.
Low‐quality evidence suggests that behavioural only interventions (RR 1.22, 95% CI 1.07 to 1.38; 4 studies) and mixed interventions (RR 1.22, 95% CI 1.08 to 1.37; 12 studies) may increase the proportions of people who are adherent compared with usual care. We could not include in the meta‐analysis results from two studies involving mixed interventions: one had a positive effect on adherence, and the other had little or no effect. Very low‐quality evidence means that we are uncertain of the effects of educational only interventions (5 studies) on the proportions of people who are adherent.
Low‐quality evidence suggests that educational only interventions (SMD 0.16, 95% CI ‐0.12 to 0.43; 5 studies) and mixed interventions (SMD 0.47, 95% CI ‐0.08 to 1.02; 7 studies) may have little or no impact on medication adherence assessed through continuous measures of adherence. We excluded 10 studies (4 educational only and 6 mixed interventions) from the meta‐analysis including four studies with unclear or no available results. Very low‐quality evidence means that we are uncertain of the effects of behavioural only interventions (3 studies) on medication adherence when assessed through continuous outcomes.
Low‐quality evidence suggests that mixed interventions may reduce the number of ED/hospital admissions (RR 0.67, 95% CI 0.50 to 0.90; 11 studies) compared with usual care, although results from six further studies that we were unable to include in meta‐analyses indicate that the intervention may have a smaller, or even no, effect on these outcomes. Similarly, low‐quality evidence suggests that mixed interventions may lead to little or no change in HRQoL (7 studies), and very low‐quality evidence means that we are uncertain of the effects on mortality (RR 0.93, 95% CI 0.67 to 1.30; 7 studies).
Moderate‐quality evidence shows that educational interventions alone probably have little or no effect on HRQoL (6 studies) or on ED/hospital admissions (4 studies) when compared with usual care. Very low‐quality evidence means that we are uncertain of the effects of behavioural interventions on HRQoL (1 study) or on ED/hospital admissions (2 studies). We identified no studies evaluating effects of educational or behavioural interventions alone on mortality.
Six studies reported a comparison between two interventions; however due to the limited number of studies assessing the same types of interventions and comparisons, we are unable to draw firm conclusions for any outcomes.
Authors' conclusions
Behavioural only or mixed educational and behavioural interventions may improve the proportion of people who satisfactorily adhere to their prescribed medications, but we are uncertain of the effects of educational only interventions. No type of intervention was found to improve adherence when it was measured as a continuous variable, with educational only and mixed interventions having little or no impact and evidence of insufficient quality to determine the effects of behavioural only interventions. We were unable to determine the impact of interventions on medication‐taking ability. The quality of evidence for these findings is low due to heterogeneity and methodological limitations of studies included in the review. Further well‐designed RCTs are needed to investigate the effects of interventions for improving medication‐taking ability and medication adherence in older adults prescribed multiple medications.
Trends in meat consumption in the USA Daniel, Carrie R; Cross, Amanda J; Koebnick, Corinna ...
Public health nutrition,
04/2011, Volume:
14, Issue:
4
Journal Article
Peer reviewed
Open access
To characterize the trends, distribution, potential determinants and public health implications of meat consumption within the USA.
We examined temporal trends in meat consumption using food ...availability data from the FAO and US Department of Agriculture (USDA), and further evaluated the meat intake by type (red, white, processed) in the National Health and Nutrition Examination Surveys (NHANES) linked to the MyPyramid Equivalents Database (MPED).
Overall meat consumption has continued to rise in the USA and the rest of the developed world. Despite a shift towards higher poultry consumption, red meat still represents the largest proportion of meat consumed in the USA (58 %). Twenty-two per cent of the meat consumed in the USA is processed. According to the NHANES 2003-2004, total meat intake averaged 128 g/d. The type and quantities of meat reported varied by education, race, age and gender.
Given the plausible epidemiological evidence for red and processed meat intake in cancer and chronic disease risk, understanding the trends and determinants of meat consumption in the USA, where meat is consumed at more than three times the global average, should be particularly pertinent to researchers and other public health professionals aiming to reduce the global burden of chronic disease.
Some individuals are diagnosed with colorectal cancer (CRC) despite recent colonoscopy. We examined individuals under colonoscopic surveillance for colonic adenomas to assess possible reasons for ...diagnosing cancer after a recent colonoscopy with complete removal of any identified polyps.
Primary data were pooled from eight large (>800 patients) North American studies in which participants with adenoma(s) had a baseline colonoscopy (with intent to remove all visualised lesions) and were followed with subsequent colonoscopy. We used an algorithm based on the time from previous colonoscopy and the presence, size and histology of adenomas detected at prior exam to assign interval cancers as likely being new, missed, incompletely resected (while previously an adenoma) or due to failed biopsy detection.
9167 participants (mean age 62) were included in the analyses, with a median follow-up of 47.2 months. Invasive cancer was diagnosed in 58 patients (0.6%) during follow-up (1.71 per 1000 person-years follow-up). Most cancers (78%) were early stage (I or II); however, 9 (16%) resulted in death from CRC. We classified 30 cancers (52%) as probable missed lesions, 11 (19%) as possibly related to incomplete resection of an earlier, non-invasive lesion and 14 (24%) as probable new lesions. The cancer diagnosis may have been delayed in three cases (5%) because of failed biopsy detection.
Despite recent colonoscopy with intent to remove all neoplasia, CRC will occasionally be diagnosed. These cancers primarily seem to represent lesions that were missed or incompletely removed at the prior colonoscopy and might be avoided by increased emphasis on identifying and completely removing all neoplastic lesions at colonoscopy.
There is evidence that diet and nutrition are modifiable risk factors for several cancers, but associations may be flawed due to inherent biases. Nutritional epidemiology studies have largely relied ...on a single assessment of diet using food frequency questionnaires. We conduct an umbrella review of meta-analyses of observational studies to evaluate the strength and validity of the evidence for the association between food/nutrient intake and risk of developing or dying from 11 primary cancers. It is estimated that only few single food/nutrient and cancer associations are supported by strong or highly suggestive meta-analytic evidence, and future similar research is unlikely to change this evidence. Alcohol consumption is positively associated with risk of postmenopausal breast, colorectal, esophageal, head & neck and liver cancer. Consumption of dairy products, milk, calcium and wholegrains are inversely associated with colorectal cancer risk. Coffee consumption is inversely associated with risk of liver cancer and skin basal cell carcinoma.
,
, and other members of the Enterobacteriaceae family are common human pathogens that have acquired broad antibiotic resistance, rendering infection by some strains virtually untreatable. ...Enterobacteriaceae are intestinal residents, but generally represent <1% of the adult colonic microbiota. Antibiotic-mediated destruction of the microbiota enables Enterobacteriaceae to expand to high densities in the colon, markedly increasing the risk of bloodstream invasion, sepsis, and death. Here, we demonstrate that an antibiotic-naive microbiota suppresses growth of antibiotic-resistant clinical isolates of
,
, and
by acidifying the proximal colon and triggering short chain fatty acid (SCFA)-mediated intracellular acidification. High concentrations of SCFAs and the acidic environment counter the competitive edge that O
and NO
respiration confer upon Enterobacteriaceae during expansion. Reestablishment of a microbiota that produces SCFAs enhances clearance of
,
, and
from the intestinal lumen and represents a potential therapeutic approach to enhance clearance of antibiotic-resistant pathogens.
The prevalence of diabetes has increased in the UK and other high-income countries alongside a substantial decline in cardiovascular mortality. Yet data are scarce on how these trends have changed ...the causes of death in people with diabetes who have traditionally died primarily of vascular causes. We estimated how all-cause mortality and cause-specific mortality in people with diabetes have changed over time, how the composition of the mortality burden has changed, and how this composition compared with that of the non-diabetes population.
In this epidemiological analysis of primary care records, we identified 313 907 individuals with diabetes in the Clinical Practice Research Datalink, a well described primary care database, between 2001 to 2018, and linked these data to UK Office for National Statistics mortality data. We assembled serial cross sections with longitudinal follow-up to generate a mixed prevalence and incidence study population of patients with diabetes. We used discretised Poisson regression models to estimate annual death rates for deaths from all causes and 12 specific causes for men and women with diabetes. We also identified age-matched and sex matched (1:1) individuals without diabetes from the same dataset and estimated mortality rates in this group.
Between Jan 1, 2001, and Oct 31, 2018, total mortality declined by 32% in men and 31% in women with diagnosed diabetes. Death rates declined from 40·7 deaths per 1000 person-years to 27·8 deaths per 1000 person-years in men and from 42·7 deaths per 1000 person-years to 29·5 deaths per 1000 person-years in women with diagnosed diabetes. We found similar declines in individuals without diabetes, hence the gap in mortality between those with and without diabetes was maintained over the study period. Cause-specific death rates declined in ten of the 12 cause groups, with exceptions in dementia and liver disease, which increased in both populations. The large decline in vascular disease death rates led to a transition from vascular causes to cancers as the leading contributor to death rates in individuals with diagnosed diabetes and to the gap in death rates between those with and without diabetes.
The decline in vascular death rates has been accompanied by a diversification of causes in individuals with diagnosed diabetes and a transition from vascular diseases to cancers as the leading contributor to diabetes-related death. Clinical and preventative approaches must reflect this trend to reduce the excess mortality risk in individuals with diabetes.
Wellcome Trust.
Summary Background Removal of adenomas reduces colorectal cancer incidence and mortality; however, the benefit of surveillance colonoscopy on colorectal cancer risk remains unclear. We examined ...heterogeneity in colorectal cancer incidence in intermediate-risk patients and the effect of surveillance on colorectal cancer incidence. Methods We did this retrospective, multicentre, cohort study using routine lower gastrointestinal endoscopy and pathology data from patients who, after baseline colonoscopy and polypectomy, were diagnosed with intermediate-risk adenomas mostly (>99%) between Jan 1, 1990, and Dec 31, 2010, at 17 hospitals in the UK. These patients are currently offered surveillance colonoscopy at intervals of 3 years. Patients were followed up through to Dec 31, 2014.We assessed the effect of surveillance on colorectal cancer incidence using Cox regression with adjustment for patient, procedural, and polyp characteristics. We defined lower-risk and higher-risk subgroups on the basis of polyp and procedural characteristics identified as colorectal cancer risk factors. We estimated colorectal cancer incidence and standardised incidence ratios (SIRs) using as standard the general population of England in 2007. This trial is registered, number ISRCTN15213649. Findings 253 798 patients who underwent colonic endoscopy were identified, of whom 11 944 with intermediate-risk adenomas were included in this analysis. After a median follow-up of 7·9 years (IQR 5·6–11·1), 210 colorectal cancers were diagnosed. 5019 (42%) patients did not attend surveillance and 6925 (58%) attended one or more surveillance visits. Compared to no surveillance, one or two surveillance visits were associated with a significant reduction in colorectal cancer incidence rate (adjusted hazard ratio 0·57, 95% CI 0·40–0·80 for one visit; 0·51, 0·31–0·84 for two visits). Without surveillance, colorectal cancer incidence in patients with a suboptimal quality colonoscopy, proximal polyps, or a high-grade or large adenoma (≥20 mm) at baseline (8865 74% patients) was significantly higher than in the general population (SIR 1·30, 95% CI 1·06–1·57). By contrast, in patients without these features, colorectal cancer incidence was lower than that of the general population (SIR 0·51, 95% CI 0·29–0·84). Interpretation Colonoscopy surveillance benefits most patients with intermediate-risk adenomas. However, some patients are already at low risk after baseline colonoscopy and the value of surveillance for them is unclear. Funding National Institute for Health Research Health Technology Assessment, Cancer Research UK.
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