Diarrhoea is a common and serious complication of enteral tube feeding. Its pathogenesis involves antibiotic prescription, enteropathogenic colonization and abnormal colonic responses, all of which involve an interaction with the colonic microbiota. Alterations in the colonic microbiota have been identified in patients receiving enteral tube feeding and these changes may be associated with the incidence of diarrhoea. Preventing negative alterations in the colonic microbiota has therefore been investigated as a method of reducing the incidence of diarrhoea. Probiotics and prebiotics may be effective because of their suppression of enteropathogenic colonization, stimulation of immune function and modulation of colonic metabolism. Randomized controlled trials of probiotics have produced contrasting results, although Saccharomyces boulardii has been shown to reduce the incidence of diarrhoea in patients in the intensive care unit receiving enteral tube feeding. Prebiotic fructo-oligosaccharides have been shown to increase the concentration of faecal bifidobacteria in healthy subjects consuming enteral formula, although this finding has not yet been confirmed in patients receiving enteral tube feeding. Furthermore, there are no clinical trials investigating the effect of a prebiotic alone on the incidence of diarrhoea. Further trials of the efficacy of probiotics and prebiotics, alone and in combination, in preventing diarrhoea in this patient group are warranted.

The major glucocorticoid in man, cortisol, plays important roles in regulating fuel metabolism, energy partitioning and body fat distribution. In addition to the control of cortisol levels in blood by the hypothalamic–pituitary–adrenal axis, intracellular cortisol levels within target tissues can be controlled by local enzymes. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyses the regeneration of active cortisol from inert cortisone, thereby amplifying cortisol levels and glucocorticoid receptor activation in adipose tissue, liver and other tissues. 11β-HSD1 is under complex tissue-specific regulation and there is evidence that it adjusts local cortisol concentrations independently of the plasma cortisol concentrations, e.g. in response to changes in diet. In obesity 11β-HSD1 mRNA and activity in adipose tissue are increased. The mechanism of this up-regulation remains uncertain; polymorphisms in the HSD11B1 gene have been associated with metabolic complications of obesity, including hypertension and type 2 diabetes, but not with obesity per se. Extensive data have been obtained in mice with transgenic over-expression of 11β-HSD1 in liver and adipocytes, targeted deletion of 11β-HSD1, and using novel selective 11β-HSD1 inhibitors; these data support the use of 11β-HSD1 inhibitors to lower intracellular glucocorticoid levels and treat both obesity and its metabolic complications. Moreover, in human subjects the non-selective ‘prototype’ inhibitor carbenoxolone enhances insulin sensitivity. Results of clinical studies with novel potent selective 11β-HSD1 inhibitors are therefore eagerly awaited. The present article focuses on the physiological role of glucocorticoids in regulating energy partitioning, and the evidence that this process is modulated by 11β-HSD1 in human subjects.

Almost anything that is swallowed in pill or potion form that is not a licensed medicine is, by default, legally classified as a dietary supplement. The present paper is an overview of supplement use and is intended to provide a logical framework for their discussion. Five major supplement categories are identified: essential micronutrients; other metabolites that have vitamin-like roles; natural oils; natural plant or animal extracts; antioxidants, which span the other categories. Supplement usage is also classified into broad categories. Examples of each supplement category and usage are briefly discussed. Some potential hazards of supplement use are also outlined; many substances in supplements are either not found in normal UK diets or consumed in much greater amounts than would be found in food. Many supplements are used for pharmaceutical purposes and sold as supplements to avoid the expense of acquiring a medicinal licence and to avoid the stricter quality-control regulations that apply to medicines. The use of supplements to ensure nutritional adequacy and as possible conditionally-essential nutrients is briefly discussed, as is their essentially pharmaceutical use for the prevention and alleviation of disease. There is critical discussion of whether the use of antioxidant supplements is justified or even if it is reasonable to promote a particular food on the basis of antioxidant content alone. Much of the research on supplements is reductionist, commercially sponsored or has other weaknesses; so, despite decades of use and research there is still uncertainty about their efficacy in many cases.

The Diet and Reinfarction Trial (DART) involved 2033 men (mean age 56·5 years) recovering from myocardial infarction. They were randomly allocated to receive advice or to receive no advice on each of three dietary factors: an increase in fatty fish intake; a reduction in fat intake with an increase in polyunsaturated fat:saturated fat; an increased intake of cereal fibre. Compliance was satisfactory with the fish and fibre advice, but less so with the fat advice. The men given fish advice had 29% lower 2-year all-cause mortality; the other forms of advice did not have any significant effects. The Diet and Angina Randomized Trial (DART-2) involved 3114 men (mean age 61·1 years) with stable angina, who were followed up for 3–9 years. Advice to eat oily fish or take fish oil did not affect all-cause mortality, but it was associated with a significant increase in sudden cardiac death (P=0·018), and this effect was largely confined to the subgroup given fish oil capsules. Advice to eat more fruit and vegetables had no effect, probably because of poor compliance. The outcome of DART-2 appears to conflict with that of DART and some other studies; various possible explanations are considered. Nutritional interventions are not equally acceptable and should be tailored to the individuals for whom they are intended. Various distinct groups have a raised risk of CHD, and it cannot be assumed that the same nutritional interventions are appropriate to them all. Nutritional supplements do not necessarily have the same effects as the foods from which they are derived.

Osteoporosis is a common disease with a strong genetic component characterised by reduced bone mass and an increased risk of fragility fractures. Twin and family studies have shown that genetic factors contribute to osteoporosis by influencing bone mineral density (BMD), and other phenotypes that are associated with fracture risk, although the heritability of fracture itself is modest. Linkage studies have identified several quantitative trait loci that regulate BMD but most causal genes remain to be identified. In contrast, linkage studies in monogenic bone diseases have been successful in gene identification, and polymorphisms in many of these genes have been found to contribute to the regulation of bone mass in the normal population. Population-based studies have identified polymorphisms in several candidate genes that have been associated with bone mass or osteoporotic fracture, although individually these polymorphisms only account for a small amount of the genetic contribution to BMD regulation. Environmental factors such as diet and physical activity are also important determinants of BMD, and in some cases specific nutrients have been found to interact with genetic polymorphisms to regulate BMD. From a clinical standpoint, advances in knowledge about the genetic basis of osteoporosis are likely to be important in increasing the understanding of the pathophysiology of the disease; providing new genetic markers with which to assess fracture risk and in identifying genes and pathways that form molecular targets for the design of the next generation of drug treatments.

Human subjects and their enteric microbiota have evolved together to reach a state of mutual tolerance. Mounting evidence from both animal models and human studies suggests that inflammatory bowel disease (IBD) represents a malfunction of this relationship. The enteric microecology therefore represents an attractive therapeutic target with few side effects. Probiotics and prebiotics have been investigated in clinical trials as treatments for IBD, with conflicting results. The evidence for the use of probiotics in the management of pouchitis is persuasive and several studies indicate their effectiveness in ulcerative colitis. Trials of probiotics and prebiotics in Crohn's disease are less convincing. However, methodologies vary widely and a range of probiotic, prebiotic and combination (synbiotic) treatments have been tested in a variety of patient groups with an assortment of end points. Conclusions about any one treatment in a specific patient group can therefore only be drawn on evidence from relatively small numbers of patients. The present article reviews the role of the intestinal microbiota in the pathogenesis of IBD and addresses the clinical evidence for the therapeutic manipulation of bowel microbiota using probiotics, prebiotics and synbiotics in IBD.

Within the last decade there has been a dramatic increase in the sale and use of herbal supplements and food supplements by Western populations and within the UK. This increased usage has coincided with a resurgence of interest in nutritional therapy and complementary and alternative medicine (CAM) therapies, such as herbal medicine, naturopathy and homeopathy, in which therapists may provide dietary advice and advocate the use of food or herbal supplements. The rise in the use of CAM therapies by the UK population can be attributed to several factors, including: promotion via health programmes and the media; a change in public attitudes; training of more nutritional and CAM therapists as a result of the increased availability of courses; a greater use of CAM and food and herbal supplements, particularly by patients with cancer. The aim of the present paper is to identify the pattern of usage of food and herbal supplements in the UK.

The use of complementary medicines in patients suffering from chronic illnesses such as cancer and depression is widely documented. Current studies suggest that the prevalence of the use of complementary medicines in patients with cancer ranges from 7% to 80%. In patients suffering from severe depression the use of complementary medicines may be >40%. The aim of the present review is to systematically explore the main dimensions that clinicians have to consider when advising patients suffering from these conditions. The Medline and Cochrane databases were searched for evidence relating to the benefits and risks of supplements in the treatment of cancer and depression, including the potential interactions with pharmaco- and radiotherapy. Supplements predominantly used by patients with cancer include vitamins A, C and E, β-carotene and ubiquinone 10. Supplements predominantly used by patients with depression include S-adenosylmethionine, l-tryptophan and 5-hydroxytryptophan and inositol. Supplements potentially used by both groups include n-3 fatty acids, Se and folic acid. Four dimensions are identified and discussed: effectiveness; safety; communication; medico-legal aspects. These dimensions have to be addressed in an illness- and case-specific context. This task can be complex given the emerging clinical evidence, patients' own preferences and expectations and current prescribing guidelines.

In their current guidelines cardiac societies recommend the consumption of the two n-3 fatty acids EPA and DHA to prevent cardiovascular complications. Cardiovascular events are reduced by EPA and DHA, because they are antiarrhythmic, mitigate the course of atherosclerosis and stabilise plaque. As atherosclerosis is considered an inflammatory disorder a number of studies have investigated the anti-inflammatory mechanisms of EPA and DHA in a cardiovascular context in human dietary intervention studies. Pro-inflammatory cytokines, or cytokines reflecting inflammatory processes, e.g. IL-1β, IL-2, IL-6, TNFα, platelet-derived growth factor (PDGF)-A and -B and monocyte chemoattractant protein-1 (MCP-1), are reduced by ingestion of EPA and DHA by human subjects. Interestingly, C-reactive protein remains largely unaltered. However, in in vitro and animal models, but less so in human subjects, soluble cytokines reflecting interactions between blood cells and the vessel wall, such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, are reduced. Moreover, in contrast to common expectations, oxidative stress seems to be reduced after ingestion of EPA and DHA, at least as indicated by measurement of urinary F2 isoprostane excretion. Notably, for PDGF-A and -B and for MCP-1 the reduction has been demonstrated to occur at the gene expression level, which indicates that a deliberate change in diet can alter gene expression quantitatively. The precise underlying mechanism, however, remains to be clarified, but might involve PPAR, NF-κB and/or the eicosanoid system. The same holds true for the mechanisms by which levels of other cytokines are altered by EPA and DHA.

The metabolism of critical illness is characterised by a combination of starvation and stress. There is increased production of cortisol, catecholamines, glucagon and growth hormone and increased insulin-like growth factor-binding protein-1. Phagocytic, epithelial and endothelial cells elaborate reactive oxygen and nitrogen species, chemokines, pro-inflammatory cytokines and lipid mediators, and antioxidant depletion ensues. There is hyperglycaemia, hyperinsulinaemia, hyperlactataemia, increased gluconeogenesis and decreased glycogen production. Insulin resistance, particularly in relation to the liver, is marked. The purpose of nutritional support is primarily to save life and secondarily to speed recovery by reducing neuropathy and maintaining muscle mass and function. There is debate about the optimal timing of nutritional support for the patient in the intensive care unit. It is generally agreed that the enteral route is preferable if possible, but the dangers of the parenteral route, a route of feeding that remains important in the context of critical illness, may have been over-emphasised. Control of hyperglycaemia is beneficial, and avoidance of overfeeding is emphasised. Growth hormone is harmful. The refeeding syndrome needs to be considered, although it has been little studied in the context of critical illness. Achieving energy balance may not be necessary in the early stages of critical illness, particularly in patients who are overweight or obese. Protein turnover is increased and N balance is often negative in the face of normal nutrient intake; optimal N intakes are the subject of some debate. Supplementation of particular amino acids able to support or regulate the immune response, such as glutamine, may have a role not only for their potential metabolic effect but also for their potential antioxidant role. Doubt remains in relation to arginine supplementation. High-dose mineral and vitamin antioxidant therapy may have a place.

Patients with irreversible intestinal failure and complications of parenteral nutrition should now be routinely considered for small intestine transplantation. Despite attempts for >40 years immunological graft intolerance presented an impenetrable barrier to successful engraftment until the development in the late 1970s of the powerful calcineurin-inhibitor immunosuppressive agents. Their use over the last 17 years has led to small intestinal transplantation being generally considered as a routine option for patients with irreversible intestinal failure and failing parenteral nutrition. The 1-year patient survival rates (%) are now excellent for renal (95), liver (78), heart (82) and lung (75) transplantation. In contrast, survival rates for small intestinal transplantation have been slow to improve, although they are now approaching those for lung and liver transplantation (intestine 78%, intestine and liver 60%, multivisceral 66%), and well-performing centres report recent 1-year graft survival rates as high as 92%. Patient 5-year survival (%) has also improved (intestine alone 50, intestine and liver 50 and multivisceral 62) and compares increasingly favourably with renal (85), liver (67), heart (67) and lung (46). Currently, small intestinal transplantation is reserved for patients with irreversible small intestinal failure who have a poor prognosis on parenteral nutrition. However, as 5-year patient survival following intestinal transplantation approaches that for parenteral nutrition there will be increasing pressure to offer this modality of treatment as an alternative to parenteral nutrition, especially for those patients who have a poor quality of life as a result of parenteral nutrition.

Anorexia is part of the body's acute-phase response to illness. Microbial products such as lipopolysaccharides (LPS), which are also commonly used to model acute illness, trigger the acute-phase response and cause anorexia mainly through pro-inflammatory cytokines. LPS stimulate cytokine production through the cell-surface structural molecule CD14 and toll-like receptor-4. Cytokines ultimately change neural activity in brain areas controlling food intake and energy balance. The blood–brain barrier endothelial cells (BBB EC) are an important site of cytokine action in this context. BBB EC and perivascular cells (microglia and macrophages) form a complex regulatory interface that modulates neuronal activity by the release of messengers (e.g. PG, NO) in response to peripheral challenges. Serotonergic neurons originating in the raphe nuclei and glucagon-like peptide-1-expressing neurons in the hindbrain may be among the targets of these messengers, because serotonin (5-HT), acting through the 5-HT2C receptor, and glucagon-like peptide-1 have recently emerged as neurochemical mediators of LPS anorexia. The central melanocortin system, which is a downstream target of serotonergic neurons, also appears to be involved in mediation of LPS anorexia. Interestingly, LPS also reduce orexin expression and the activity of orexin neurons in the lateral hypothalamic area of fasted mice. As the eating-stimulatory properties of orexin are apparently related to arousal, the inhibitory effect of LPS on orexin neurons might be involved in LPS-induced inactivity and anorexia. In summary, the immune signalling pathways of LPS-induced, and presumably acute illness-induced, anorexia converge on central neural signalling systems that control food intake and energy balance in healthy individuals.

The use of vitamins, minerals and other supplements has increased considerably during recent years. In the National Diet and Nutrition Survey of British adults aged 19–64 years 40% of those surveyed were taking supplements. In 2005 sales of dietary supplements in the UK were approximately £325·7×106 in ‘bricks and mortar’ shops (excluding health food shops). The physiological effects of vitamins and minerals in amounts approximating to the UK reference nutrient intake or the EU RDA are well understood in terms of reducing the risk of micronutrient deficiency. However, the effects of vitamins, minerals and other supplements in larger amounts have attracted much attention in recent decades, and these effects, some of which may be pharmacological, are not as well categorised. Some of these effects are beneficial, some are not. Although vitamins and minerals and other supplements are generally safe at higher doses, there are some safety issues that are relevant in the context of the wide availability of supplements without a doctor's prescription. Thus, several authorities throughout the world have established upper limits (UL) for the intake of vitamins and minerals, and the EU is in the process of setting maximum permitted levels (MPL) for vitamins and minerals in food supplements. The present paper discusses the potential benefits and safety issues relating to the use of supplements at doses higher than the RDA. The rationale for the establishment of UL is also discussed, explaining the differences between the values set by different authorities and the expected guidance and legislation from the European Commission on MPL for vitamins and minerals in food supplements.

The importance of adipose tissue in health as well as disease has been demonstrated in several studies recently, and it has become appropriate to use the term ‘adipose organ’ when referring to adipose tissue as a whole. The obesity epidemic, with a marked increase in the incidence of the metabolic syndrome leading to diabetes type 2 as well as cardiovascular complications, has stimulated considerable interest in adipose tissue biology. Moreover, several studies in different species have shown that limited energy intake is associated with less inflammation, improved biomarkers of health and a marked increase in longevity. In addition, there is convincing evidence that an optimal amount of adipose tissue is essential for many body functions such as immune response, reproduction and bone quality. Some nutrients and their metabolites are important as energy sources as well as ligands for many transcription factors expressed in adipose tissue, including all energy-providing nutrients both directly and indirectly as well as cholesterol, vitamin E and vitamin D. In particular, fatty acids can be effectively taken up by adipocytes and they can interact with several transcription factors crucial for growth, development and metabolic response, e.g. PPARα, −δ and −γ, sterol regulatory element-binding proteins1 and 2 and liver X receptors α and β). Moreover, glucose is also readily taken up and stored as fatty acids via lipogenesis in adipocytes. It is known that some metabolic signals released as proteins from adipose tissue (adipokines) are important for normal as well as pathological responses to the amount of energy stored in the adipose organ. The future challenge will be to understand the function of adipose tissue in energy homeostasis and the interplay with nutrients in order to be able to give optimal advice for the prevention and treatment of obesity.

In the UK the mental and physical health and well-being of millions of women are influenced by living in poverty. Low educational attainment, unemployment, low pay and poor areas of residence exacerbate the challenges of obtaining optimal food choices, dietary intake and healthy eating patterns. Poorer women are more likely to eat low amounts of fruits and vegetables, whole grains and fish, and higher amounts of sugar and sweetened drinks compared with more affluent women. Diet contributes to the health inequalities evident in high rates of diet-related morbidity (including obesity) and mortality (including IHD and stroke) and in maternal and child health considerations (including breast-feeding and family diet practices). There is a dearth of research on effective interventions undertaken with low-income women, reflecting some of the challenges of engaging and evaluating programmes with this ‘hard to reach’ subpopulation. Intervention programmes from the USA, including WISEWOMAN, the Women's Health Initiative, the American Special Supplemental Food Program for Women, Infants and Children and the Expanded Food and Nutrition Education Program provide models for changing behaviour amongst women in the UK, although overall effects of such programmes are fairly modest. Lack of evidence does not mean that that policy work should be not be undertaken, but it is essential that policy work should be evaluated for its ability to engage with target groups as well as for the behavioural change and health outcomes.

In 2000 an estimated £335×106 was spent on food supplements and herbal remedies in the UK. Until recently, The Trades Description Act 1968, the Food Safety Act 1990 and The Food Labelling Regulations 1996 (amended 2004) were the only form of regulation available to protect the public. The medical community has been concerned about the risk to patients of inaccurate dosages and poor-quality products as well as drug–nutrient and nutrient–nutrient interactions. Following growing concern about the type and quality of food supplements and herbal remedies available in the EU, the European Commission has published directives regulating food supplements (2002/46/EC) and herbal remedies (2004/24/EC and 2004/27/EC) available within the EU. The directives came into force in 2005 and limit the number and quality of permitted food supplements through the creation of a ‘positive list’ of approved supplements. In the present paper the new regulatory frameworks and the implications for the food supplement manufacturers, traditional and complementary therapists, the healthcare professions and patients will be examined. It would appear that there is considerable dissatisfaction with the regulations in their present form. Several questions remain: is regulation the answer; who decides which nutrients go on the positive list; what effect has the regulation had on patient safety and patient choice?

A high dietary fat intake and low physical activity characterize the current Western lifestyle. Dietary fatty acids do not stimulate their own oxidation and a surplus of fat is stored in white adipose tissue, liver, heart and muscle. In these organs intracellular lipids serve as a rapidly-available energy source during, for example, physical activity. However, under conditions of elevated plasma fatty acid levels and high dietary fat intake, conditions implicated in the development of modern diseases such as obesity and type 2 diabetes mellitus, fat accumulation in liver and muscle (intramyocellular lipids; IMCL) is associated with the development of insulin resistance. Recent data suggest that IMCL are specifically harmful when combined with reduced mitochondrial function, both conditions that characterize type 2 diabetes. In the (pre)diabetic state reduced expression of the transcription factor PPARγ co-activator-1α (PGC-1α), which is involved in mitochondrial biogenesis, has been suggested to underlie the reduced mitochondrial function. Importantly, the reduction in PGC-1α may be a result of low physical activity, consumption of high-fat diets and high plasma fatty acid levels. Mitochondrial function can also be impaired as a result of enhanced mitochondrial damage by reactive oxygen species. Fatty acids in the vicinity of mitochondria are particularly prone to lipid peroxidation. In turn, lipid peroxides can induce oxidative damage to mitochondrial RNA, DNA and proteins. The mitochondrial protein uncoupling protein 3, which is induced under high-fat conditions, may serve to protect mitochondria against lipid-induced oxidative damage, but is reduced in the prediabetic state. Thus, muscular lipotoxicity may impair mitochondrial function and may be central to insulin resistance and type 2 diabetes mellitus.

Impairments of sensory perception that occur during a period of critical care can seriously impact on health and nutritional status, activities of daily living, independence, quality of life and the possibility of recovery. It is emphasized from the outset that sensory losses in critically-ill patients may or may not be related to their current medical condition. The present paper provides an overview of all five senses (vision, hearing, taste, smell and touch) and describes the factors that contribute to sensory losses in critically-ill patients, including medications, medical conditions and treatments and the process of aging itself. Cancer and stroke are two critical illnesses in which profound sensory decrements often occur. Many sensory complaints in patients with cancer are related to alteration in sensory signals caused by damage to the sensory receptors. However, some complaints, such as taste aversions in patients with cancer, are not related to altered sensory physiology per se but to learned aversions that arise during the noxious effects of radiotherapy and chemotherapy. The paper also reviews a study in which the sensory performance (of all five senses) was compared in three groups of elderly subjects: (1) patients who had undergone coronary artery bypass surgery; (2) patients with cardiovascular conditions but with no history of surgery; (3) healthy non-medicated age-matched controls. Performance of patients who had undergone coronary artery bypass surgery was worse than that for the other two groups, with taste and smell losses greater than for the other senses. The study demonstrates that critical illness (e.g. coronary artery bypass surgery) can exacerbate sensory losses in an older cohort.

Cardiovascular risk is determined by the complex interactions between genetic and environmental factors. The apoE genotype represents the most-widely-studied single nucleotide polymorphism in relation to CVD risk, with >3600 publications cited in PubMed. Although originally described as a mediator of lipoprotein metabolism, the lipoprotein-independent functions of apoE are being increasingly recognised, with limited data available on the potential impact of genotype on these metabolic processes. Furthermore, although meta-analyses suggest that apoE4 carriers may have a 40–50% increased CVD risk, the associations reported in individual studies are highly heterogeneous and it is recognised that environmental factors such as smoking status and dietary fat composition influence genotype–phenotype associations. However, information is often derived from observational studies or small intervention trials in which retrospective genotyping of the cohort results in small group sizes in the rarer E2 and E4 subgroups. Either larger well-standardised intervention trials or smaller trials with prospective recruitment according to apoE genotype are needed to fully establish the impact of diet on genotype–CVD associations and to establish the potential of dietary strategies such as reduced total fat, saturated fat, or increased antioxidant intakes to counteract the increased CVD burden in apoE4 carriers.