Dysbiosis of the gut microbiota in disease

There is growing evidence that dysbiosis of the gut microbiota is associated with the pathogenesis of both intestinal and extra-intestinal disorders. Intestinal disorders include inflammatory bowel disease, irritable bowel syndrome (IBS), and coeliac disease, while extra-intestinal disorders include allergy, asthma, metabolic syndrome, cardiovascular disease, and obesity. In many of these conditions, the mechanisms leading to disease development involve the pivotal mutualistic relationship between the colonic microbiota, their metabolic products, and the host immune system. The establishment of a ‘healthy’ relationship early in life appears to be critical to maintaining intestinal homeostasis. Whilst we do not yet have a clear understanding of what constitutes a ‘healthy’ colonic microbiota, a picture is emerging from many recent studies identifying particular bacterial species associated with a healthy microbiota. In particular, the bacterial species residing within the mucus layer of the colon, either through direct contact with host cells, or through indirect communication via bacterial metabolites, may influence whether host cellular homeostasis is maintained or whether inflammatory mechanisms are triggered. In addition to inflammation, there is some evidence that perturbations in the gut microbiota is involved with the development of colorectal cancer. In this case, dysbiosis may not be the most important factor, rather the products of interaction between diet and the microbiome. High-protein diets are thought to result in the production of carcinogenic metabolites from the colonic microbiota that may result in the induction of neoplasia in the colonic epithelium. Ever more sensitive metabolomics methodologies reveal a suite of small molecules produced in the microbiome which mimic or act as neurosignallers or neurotransmitters. Coupled with evidence that probiotic interventions may alter psychological endpoints in both humans and in rodent models, these data suggest that CNS-related co-morbidities frequently associated with GI disease may originate in the intestine as a result of microbial dysbiosis. This review outlines the current evidence showing the extent to which the gut microbiota contributes to the development of disease. Based on evidence to date, we can assess the potential to positively modulate the composition of the colonic microbiota and ameliorate disease activity through bacterial intervention

Modeling enamel matrix secretion in mammalian teeth

The most mineralized tissue of the mammalian body is tooth enamel. Especially in species with thick enamel, three-dimensional (3D) tomography data has shown that the distribution of enamel varies across the occlusal surface of the tooth crown. Differences in enamel thickness among species and within the tooth crown have been used to examine taxonomic affiliations, life history, and functional properties of teeth. Before becoming fully mineralized, enamel matrix is secreted on the top of a dentine template, and it remains to be explored how matrix thickness is spatially regulated. To provide a predictive framework to examine enamel distribution, we introduce a computational model of enamel matrix secretion that maps the dentine topography to the enamel surface topography. Starting from empirical enamel-dentine junctions, enamel matrix deposition is modeled as a diffusion-limited free boundary problem. Using laboratory microCT and synchrotron tomographic data of pig molars that have markedly different dentine and enamel surface topographies, we show how diffusion-limited matrix deposition accounts for both the process of matrix secretion and the final enamel distribution. Simulations reveal how concave and convex dentine features have distinct effects on enamel surface, thereby explaining why the enamel surface is not a straightforward extrapolation of the dentine template. Human and orangutan molar simulations show that even subtle variation in dentine topography can be mapped to the enamel surface features. Mechanistic models of extracellular matrix deposition can be used to predict occlusal morphologies of teeth. Author summary Teeth of most mammals are covered by a layer of highly mineralized enamel that cannot be replaced or repaired. The enamel layer is not uniform over the underlying dentine, and spatial regulation of enamel formation is critical for making a functional tooth. To explore which kind of mechanisms could underlie the complex patterns of enamel distribution, we present a computational model. Starting from tomography-imaged teeth from which enamel has been digitally removed, enamel is restored on dentine surfaces by simulating diffusion-limited secretion of enamel matrix. Our simulations show how the combination of subtle features of dentine and diffusion-limited secretion of the enamel matrix can substantially increase the complexity of the enamel surface. We propose that the strength of the diffusion-limited process is a key factor in determining enamel distribution among mammalian species.Peer reviewe

Inadequacy of protein intake in older UK adults

The current dietary recommendation for protein intake in the UK is 0.75 g/kg/day, however, this population-wide recommendation does not necessarily reflect altered requirements for older adults to maintain muscle protein synthesis, nor does it encompass the potential impact of intake timing. Optimal muscle protein synthesis in older adults requires both higher intake requirements and a distribution of protein intake above a 25 g threshold, three times across the day. This study aimed to describe the protein intake of older adults in a UK region and compare the results to recommendations. The study re-assessed two existing datasets with rich diet information for older adults in the South Yorkshire area. Data were extracted from food diaries of 256 adults aged between 65 and 89 years old (mean ± SD 72.4 ± 5.3 years). Quantity and timing of intake were coded using Nutritics software and compared to recommendations. The relationship between body mass index (BMI), age, and protein intake was explored. Fewer than 50% of the participants met current UK recommendations (0.75 g/kg/day) and fewer than 15% met the ESPEN 1.2 g/kg/day age-specific recommendation. Only one participant met the 25 g/meal recommendation across three meals. These findings suggest that the older adult population is not achieving recommendations to maintain muscle protein synthesis. Nonetheless it identifies several straightforward opportunities for improvement, notably elevation of morning intake

Short-chain fatty acid level and field cancerization show opposing associations with enteroendocrine cell number and neuropilin expression in patients with colorectal adenoma

BACKGROUND: Previous reports have suggested that the VEGF receptor neuropilin-1 (NRP-1) is expressed in a singly dispersed subpopulation of cells in the normal colonic epithelium, but that expression becomes dysregulated during colorectal carcinogenesis, with higher levels in tumour suggestive of a poor prognosis. We noted that the spatial distribution and morphology if NRP-1 expressing cells resembles that of enteroendocrine cells (EEC) which are altered in response to disease state including cancer and irritable bowel syndrome (IBS). We have shown that NRP-1 is down-regulated by butyrate in colon cancer cell lines in vitro and we hypothesized that butyrate produced in the lumen would have an analogous effect on the colon mucosa in vivo. Therefore we sought to investigate whether NRP-1 is expressed in EEC and how NRP-1 and EEC respond to butyrate and other short-chain fatty acids (SCFA - principally acetate and propionate). Additionally we sought to assess whether there is a field effect around adenomas. METHODOLOGY: Biopsies were collected at the mid-sigmoid, at the adenoma and at the contralateral wall (field) of 28 subjects during endoscopy. Samples were fixed for IHC and stained for either NRP-1 or for chromogranin A (CgA), a marker of EEC. Stool sampling was undertaken to assess individuals' butyrate, acetate and propionate levels. RESULT: NRP-1 expression was inversely related to SCFA concentration at the colon landmark (mid-sigmoid), but expression was lower and not related to SCFA concentration at the field. Likewise CgA+ cell number was also inversely related to SCFA at the landmark, but was lower and unresponsive at the field. Crypt cellularity was unaltered by field effect. A colocalisation analysis showed only a small subset of NRP-1 localised with CgA. Adenomas showed extensive, weaker staining for NRP-1 which contrastingly correlated positively with butyrate level. Field effects cause this relationship to be lost. Adenoma tissue shows dissociation of the co-regulation of NRP-1 and EEC. CONCLUSION: NRP-1 is inversely associated with levels of butyrate and other SCFA in vivo and is expressed in a subset of CgA expressing cells. EEC number is related to butyrate level in the same way

Protein for Life: Review of Optimal Protein Intake, Sustainable Dietary Sources and the Effect on Appetite in Ageing Adults

With an ageing population, dietary approaches to promote health and independence later in life are needed. In part, this can be achieved by maintaining muscle mass and strength as people age. New evidence suggests that current dietary recommendations for protein intake may be insufficient to achieve this goal and that individuals might benefit by increasing their intake and frequency of consumption of high-quality protein. However, the environmental effects of increasing animal-protein production are a concern, and alternative, more sustainable protein sources should be considered. Protein is known to be more satiating than other macronutrients, and it is unclear whether diets high in plant proteins affect the appetite of older adults as they should be recommended for individuals at risk of malnutrition. The review considers the protein needs of an ageing population (>40 years old), sustainable protein sources, appetite-related implications of diets high in plant proteins, and related areas for future research

Is it time we split bowel preparation for all colonoscopies? Outcomes from a national survey of bowel preparation practice in the UK

Introduction: Adequate bowel preparation is a prerequisite for effective colonoscopy. Split bowel preparation results in optimal cleansing. This study assessed the bowel preparation regimes advised by endoscopy units across the UK, and correlated the differences with outcomes. Methods: Trusts in the UK were surveyed, with data requested between January 2018 and January 2019, including: the type and timing of preparation, pre-endoscopy diet, adequacy rates and polyp detection. Trusts were grouped according to the timing of bowel preparation. χ2 test was used to assess for differences in bowel preparation adequacy. Results: Moviprep was the first line bowel preparation in 79% of trusts. Only 7% of trusts advised splitting bowel preparation for all procedures, however, 91% used split bowel preparation for afternoon procedures. Trusts that split preparation for all procedures had an inadequacy rate of 6.7%, compared with 8.5% (p<0.001) for those that split preparation for PM procedures alone and 9.5% (p<0.001) for those that provided day before preparation for all procedures. Morning procedures with day-before preparation had a higher rate of inadequate cleansing than afternoon procedures that received split preparation (7.7% vs 6.5 %, p<0.001). The polyp detection rate for procedures with adequate preparation was 37.1%, compared with 26.4% for those that were inadequate. Conclusion: Most trusts in the UK do not provide instructions optimising the timing of bowel preparation prior to colonoscopy. This correlated with an increased rate of inadequate cleansing. Splitting bowel preparation is likely to reduce the impacts of poor cleansing: missed lesions, repeat colonoscopies and significant costs

The normalisation of Food Aid: What happened to feeding people well?

In the UK, food poverty has increased in the last 15 years and the food aid supply chain that has emerged to tackle it is now roughly 10 years old. In this time, we have seen the food aid supply chain grow at a rate that has astounded many.  Recently that growth has been aided by a grant of £20m from a large supermarket chain. It appears institutionalisation is just around the corner, if not already here. It also appears that there is far greater emphasis on dealing with  the symptoms as opposed to solving the root causes of the problem. As an opinion piece, this paper reflects on some of the prevalent issues, and suggests some ways forward

Vitamin D associates with improved quality of life in participants with irritable bowel syndrome: outcomes from a pilot trial

Background: Vitamin D deficiency has been associated or implicated with the pathophysiology of the gastrointestinal conditions inflammatory bowel disease and colorectal cancer, as well as with depression. No trials or epidemiology studies to date have investigated a link with irritable bowel syndrome (IBS). A single case report has suggested a benefit in IBS of vitamin D supplementation. We hypothesised that IBS participants with vitamin D insufficiency would benefit from repletion in terms of their IBS symptoms. We undertook a pilot trial to provide data to support a power calculation and to justify a full trial. Methods: This was a randomised, double blinded, three-arm parallel design trial of vitamin D, placebo or a combination of vitamin D and probiotics. Participants were further stratified according to whether they were vitamin D replete or insufficient. Vitamin D status was determined by blood test at baseline and exit; IBS symptoms were assessed by validated questionnaire; dietary intakes were assessed by food frequency questionnaire. Results: A significant proportion of the IBS population were vitamin D deficient, such that the replete stratum could not be adequately recruited. There was a significant association in the baseline data between circulating vitamin D level and quality of life (“How much has IBS affected your life?”). Supplementation significantly improved vitamin D level versus placebo. IBS symptoms were not significantly improved in this pilot, although a power calculation was enabled from the intervention data. Conclusions: The IBS population exhibits significant levels of vitamin D insufficiency and would benefit from screening and possible supplementation. The impact of IBS on quality of life may be reduced by vitamin D level. Future trials should have a sample size of over 9