Over the last 30 years it has become apparent that specific dietary fatty acids are capable of regulating, either directly or indirectly through various signal pathways, the expression of numerous genes, either positively or negatively. Such nutrient-gene interactions have important effects on cell metabolism, differentiation and growth, and ultimately on disease processes. The present review describes some of the more important fatty acid-gene interactions in relation to health and disease in mammalian species, and focuses on the underlying cell signal mechanisms, including various transcription factors, affected by fatty acids and some of their oxygenated derivatives, e.g. the eicosanoids. The review also attempts to clarify some of the complexities of the effects of fatty acids by suggesting a possible overriding regulation by the redox status of the cell. The latter will at least stimulate controversy in this exciting area of lipid research.

Physical activity has the potential to modulate appetite control by improving the sensitivity of the physiological satiety signalling system, by adjusting macronutrient preferences or food choices and by altering the hedonic response to food. There is evidence for all these actions. Concerning the impact of physical activity on energy balance, there exists a belief that physical activity drives up hunger and increases food intake, thereby rendering it futile as a method of weight control. There is, however, no evidence for such an immediate or automatic effect. Short (1–2 d)-term and medium (7–16 d)-term studies demonstrate that men and women can tolerate substantial negative energy balances of ≤4MJ energy cost/d when performing physical activity programmes. Consequently, the immediate effect of taking up exercise is weight loss (although this outcome is sometimes difficult to assess due to changes in body composition or fluid compartmentalization). However, subsequently food intake begins to increase in order to provide compensation for about 30% of the energy expended in activity. This compensation (up to 16 d) is partial and incomplete. Moreover, subjects separate into compensators and non-compensators. The exact nature of these differences in compensation and whether it is actually reflective of non-compliance with protocols is yet to be determined. Some subjects (men and women) performing activity with a cost of ≤4 MJ/d for 14 d, show no change in daily energy intake. Conversely, it can be demonstrated that when active individuals are forced into a sedentary routine food intake does not decrease to a lower level to match the reduced energy expenditure. Consequently, this situation creates a substantial positive energy balance accompanied by weight gain. The next stage is to further characterize the compensators and non-compensators, and to identify the mechanisms (physiological or behavioural) that are responsible for the rate of compensation and its limits.

The relationship between intake of dietary fibre and risk of colon cancer has been studied for 30 years and still the data are inconclusive. There are many possible reasons for this outcome, and they include a failure to consider exposure to dietary fibre separately by source, or colon cancers separately by subsite. These potential confounders have been known for at least 20 years. However, the disease is normally considered by epidemiologists as a single entity. More recently, it has become clear that colon cancer can arise via various histological pathways, and by various genetic pathways. There is no reason at all for assuming that risk factors for these possible pathways are the same. There is a need, therefore, for a more detailed approach to the study of diet and colon cancer, with fibre source and cancer subsite, genetic pathway and histological pathway taken into account.

Vitamin K, originally recognised as a factor required for normal blood coagulation, is now receiving more attention in relation to its role in bone metabolism. Vitamin K is a coenzyme for glutamate carboxylase, which mediates the conversion of glutamate to γ-carboxyglutamate (Gla). Gla residues attract Ca2+ and incorporate these ions into the hydroxyapatite crystals. There are at least three Gla proteins associated with bone tissue, of which osteocalcin is the most abundant and best known. Osteocalcin is the major non-collagenous protein incorporated in bone matrix during bone formation. However, approximately 30% of the newly-produced osteocalcin stays in the circulation where it may be used as an indicator of bone formation. Vitamin K deficiency results in an increase in undercarboxylated osteocalcin, a protein with low biological activity. Several studies have demonstrated that low dietary vitamin K intake is associated with low bone mineral density or increased fractures. Additionally, vitamin K supplementation has been shown to reduce undercarboxylated osteocalcin and improve the bone turnover profile. Some studies have indicated that high levels of undercarboxylated osteocalcin (as a result of low vitamin K intake?) are associated with low bone mineral density and increased hip fracture. The current dietary recommendation for vitamin K is 1 μ/kg body weight per d, based on saturation of the coagulation system. The daily dietary vitamin K intake is estimated to be in the range 124–375 μg/d in a European population. Thus, a deficiency based on the hepatic coagulation system would be unusual, but recent data suggest that the requirement in relation to bone health might be higher.

Host-parasite interactions are often seen as an arms race, with parasites attempting to overcome host resistance to infection. Herbivory is a common route of transmission of parasites that represents the most pervasive challenge to mammalian growth and reproduction. The present paper reviews the foraging skills of mammalian herbivores in relation to their ability to exploit plant properties to combat parasites. The starting point is that foraging behaviour may ameliorate the impact of parasitism in three ways; hosts could: (1) avoid foraging in areas contaminated with parasites; (2) select diets which increase their resistance to parasites; (3) select for foods containing anti-parasitic properties (self-medication). Details are given of the pre-requisite skills needed by herbivores if they are to combat parasitism via behaviour, i.e. herbivores are able to: (a) determine their parasitic state and alter their behaviour in relation to that state (behaviours 1, 2 and 3); (b) determine the environmental distribution of parasites (behaviour 1); (c) distinguish plant species or plant parts that increase their resistance to parasites (behaviour 2) or have anti-parasitic properties (behaviour 3). Mammalian herbivores cannot detect the presence of the parasites themselves and must rely on cues such as faeces. Despite the use of these cues contacting parasites may be inevitable and so mechanisms to combat parasitism are necessary. Mammalian herbivores have the foraging skills needed to exploit the heterogeneous distributions of nutrients and parasites in complex foraging environments in order to avoid, and increase their resistance to, parasites. Current evidence for the use of plant secondary metabolites (PSM) by herbivores for self-medication purposes remains equivocal. PSM have both positive (anti-parasitic) and negative (toxic) effects on herbivores. Here details are given of an experimental approach using tri-trophic (plant-herbivore-parasite) interactions that could be used to demonstrate self-medication in animals. There is strong evidence suggesting that herbivore hosts have developed the foraging skills needed to take advantage of plant properties to combat parasites and thus use behaviour as a weapon in the host-parasite arms race.

Short-chain fatty acid (SCFA) formation by intestinal bacteria is regulated by many different host, environmental, dietary and microbiological factors. In broad terms, however, substrate availability, bacterial species composition of the microbiota and intestinal transit time largely determine the amounts and types of SCFA that are produced in healthy individuals. The majority of SCFA in the gut are derived from bacterial breakdown of complex carbohydrates, especially in the proximal bowel, but digestion of proteins and peptides makes an increasing contribution to SCFA production as food residues pass through the bowel. Bacterial hydrogen metabolism also affects the way in which SCFA are made. This outcome can be seen through the effects of inorganic electron acceptors (nitrate, sulfate) on fermentation processes, where they facilitate the formation of more oxidised SCFA such as acetate, at the expense of more reduced fatty acids, such as butyrate. Chemostat studies using pure cultures of saccharolytic gut micro-organisms demonstrate that C availability and growth rate strongly affect the outcome of fermentation. For example, acetate and formate are the major bifidobacterial fermentation products formed during growth under C limitation, whereas acetate and lactate are produced when carbohydrate is in excess. Lactate is also used as an electron sink in Clostridium perfringens and, to a lesser extent, in Bacteroides fragilis. In the latter organism acetate and succinate are the major fermentation products when substrate is abundant, whereas succinate is decarboxylated to produce propionate when C and energy sources are limiting.

Regular physical exercise and endurance training are associated with low body weight and low body fat mass. The relationship between exercise and body-weight control is complex and incompletely understood. Regular exercise may decrease energy balance through an increase in energy expenditure or an increase in fat oxidation. It may also contribute to weight loss by modulating nutrient intake. An intriguing question that remains unresolved is whether changes in nutrient intake or body composition secondarily affect spontaneous physical activity. If this were the case, physical activity would represent a major adaptative mechanism for body-weight control.

Severe vitamin A toxicity is known to have adverse effects on skeletal health. Studies involving animal models and case reports have documented that hypervitaminosis A is associated with bone resorption, hypercalcaemia and bone abnormalities. More recently, some epidemiological studies have suggested that high habitual intake of vitamin A could contribute to low bone mineral content and fracture risk. The evidence relating to the possible deleterious role of vitamin A in bone health is of variable quality and is potentially confounded by collinearity of nutrient intake and difficulties in assessing vitamin A exposure. Furthermore, because intake of vitamin A varies between studies it is not possible to define an intake threshold associated with harm.

Non-exercise activity thermogenesis (NEAT) is the energy expended that is not from sleeping, eating or sports-like exercise. It ranges from the energy expended walking to work, typing, performing yard work, undertaking agricultural tasks and fidgeting. NEAT can be measured by one of two approaches. The first approach is to measure or estimate total NEAT. Here, total daily energy expenditure is measured and from it is subtracted BMR + thermic effect of food. The second is the factoral approach whereby the components of NEAT are quantified and total NEAT calculated by summing these components. The amount of NEAT that human subjects perform represents the product of the amount and types of physical activities and the thermogenic cost of each activity. The factors that affect the NEAT of a human subject are readily divisible into biological factors, such as weight, gender and body composition, and environmental factors, such as occupation or dwelling within a ‘concrete jungle’. The combined impact of these factors explains the substantial variance in human NEAT. The variability in NEAT might be viewed as random but human data contradict this perception. It appears that changes in NEAT subtly accompany experimentally-induced changes in energy balance and are important in the physiology of weight change. NEAT and sedentariness may thus be important in obesity. It then becomes intriguing to dissect mechanistic studies that delineate how NEAT is regulated by neural, peripheral and humoral factors. NEAT may be a carefully-regulated ‘tank’ of physical activity that is crucial for weight control.

Early in the co-evolution of plant-animal relationships, some arthropod species began to utilize the chemical defences of plants to protect themselves from their own predators and parasites. It is likely, therefore, that the origins of herbal medicine have their roots deep within the animal kingdom. From prehistoric times man has looked to wild and domestic animals for sources of herbal remedies. Both folklore and living examples provide accounts of how medicinal plants were obtained by observing the behaviour of animals. Animals too learn about the details of self-medication by watching each other. To date, perhaps the most striking scientific studies of animal self-medication have been made on the African great apes. The great ape diet is often rich in plants containing secondary compounds of non-nutritional, sometimes toxic, value that suggest medicinal benefit from their ingestion. Chimpanzees (Pan troglodytes), bonobos (Pan paniscus) and gorillas (Gorilla gorilla) are known to swallow whole and defecate intact leaves. The habit has been shown to be a physical means of purging intestinal parasites. Chimpanzees and man co-existing in sub-Saharan Africa are also known to ingest the bitter pith of Vernonia amygdalina for the control of intestinal nematode infections. Phytochemical studies have demonstrated a wide array of biologically-active properties in this medicinal plant species. In light of the growing resistance of parasites and pathogens to synthetic drugs, the study of animal self-medication and ethno-medicine offers a novel line of investigation to provide ecologically-sound methods for the treatment of parasites using plant-based medicines in populations and their livestock living in the tropics.

The mechanism of action of probiotics is largely unknown. A potential mechanism should be to increase the production of short-chain fatty acids (SCFA), known modulators of gut functions, by the bacterial ecosystem in the large intestine. The present paper reviews our recent studies in which the capacity of probiotic bacteria to increase the production of SCFA by pig caecal bacteria was investigated using batch-culture and continuous-culture techniques. All four commercial probiotic preparations and three strains of probiotic bacteria dose-dependently accelerated the net production of SCFA, succinic acid and lactic acid without changing the acid profile, and slowed the net production of NH4. Effects on organic acid production did not vary among different probiotic species. Neither probiotic preparations nor probiotic bacteria affected the organic acid production from glucose, gastric mucin, starch or lactose, or organic acids produced:added saccharide. Glucose abolished these effects of probiotic preparations. However, the capacity of probiotics to increase SCFA production was not modified by gastric mucin, starch or lactose. These results indicate that probiotic bacteria increase SCFA production by accelerating the breakdown of carbohydrates that are resistant to indigenous bacteria, and suggest that the concept of prebiotics in terms of SCFA production as a measure of probiotic function is arguable.

Approximately 99% of body Ca is found in bone, where it serves a key structural role as a component of hydroxyapatite. Dietary requirements for Ca are determined by the needs for bone development and maintenance, which vary throughout the life stage, with greater needs during the periods of rapid growth in childhood and adolescence, during pregnancy and lactation, and in later life. There is considerable disagreement between expert groups on the daily Ca intake levels that should be recommended, reflecting the uncertainty in the data for establishing Ca requirements. Inadequate dietary Ca in early life impairs bone development, and Ca supplementation of the usual diet for periods of ≤3 years has been shown to enhance bone mineral status in children and adolescents. However, it is unclear whether this benefit is long term, leading to the optimisation of peak bone mass in early adulthood. In later years inadequate dietary Ca accelerates bone loss and may contribute to osteoporosis. Ca supplementation of the usual diet in post-menopausal women and older men has been shown to reduce the rate of loss of bone mineral density at a number of sites over periods of 1–2 years. However, the extent to which this outcome reduces fracture risk needs to be determined. Even allowing for disagreements on recommended intakes, evidence indicates that dietary Ca intake is inadequate for maintenance of bone health in a substantial proportion of some population groups, particularly adolescent girls and older women.

Plant phenolic compounds are diverse in structure but are characterised by hydroxylated aromatic rings (e.g. flavan-3-ols). They are categorised as secondary metabolites, and their function in plants is often poorly understood. Many plant phenolic compounds are polymerised into larger molecules such as the proanthocyanidins (PA; condensed tannins) and lignins. Only the lignins, PA, oestrogenic compounds and hydrolysable tannins will be considered here. Lignins slow the physical and microbial degradation of ingested feed, because of resilient covalent bonding with hemicellulose and cellulose, rather than any direct effects on the rumen per se. The PA are prevalent in browse and are expressed in the foliage of some legumes (e.g. Lotus spp.), but rarely in grasses. They reduce the nutritive value of poor-quality diets, but can also have substantial benefits for ruminant productivity and health when improved temperate forages are fed. Beneficial effects are dependent on the chemical and physical structure, and concentration of the PA in the diet, but they have been shown to improve live-weight gain, milk yield and protein concentration, and ovulation rate. They prevent bloat in cattle, reduce gastrointestinal nematode numbers, flystrike and CILt production. Some phenolic compounds (e.g. coumestans) cause temporary infertility, whilst those produced by Fusarium fungi found in pasture, silage or stored grains can cause permanent infertility. The HT may be toxic because products of their metabolism can cause liver damage and other metabolic disorders.

Butyrate is a C4 acid produced by microbial fermentation of carbohydrates and protein in the large intestine of all animal species. The factor of prime importance for the production rate of butyrate in the lower gut is type and levels of non-digestible carbohydrates entering the large intestine. It was previously believed that 85–90% of the butyrate produced in the gut was cleared when passing the gut epithelium, but recent studies with catheterised pigs have shown that the concentration of butyrate in the portal vein is strongly influenced by the production rate in the large intestine. Increased gut production of butyrate further raises the circulating level of butyrate. For good reason it is not possible with current technologies to perform direct measurements of the variation in the butyrate concentration in the portal vein of human subjects, but short-chain fatty acid levels in portal blood from sudden-death victims, subjects undergoing emergency surgery or planned surgery have indicated a higher gut production and absolute and relative concentration of butyrate in non-fasted as compared with fasted human subjects. However, despite an expected higher gut production of butyrate when feeding a high-fibre rye-bread-based diet as compared with a low-fibre wheat-bread-based diet, there was no difference in absolute or relative levels of butyrate in the peripheral blood of human subjects.

The accurate measurement of physical activity is fraught with problems in adults, but more especially in children because they have more complex and multi-dimensional activity patterns. In addition, the results of different studies are often difficult to interpret and compare, because of the diversity of methodological approaches, differences in data analysis and reporting, and the adoption of varying definitions of what constitutes an appropriate level of activity. Furthermore, inactivity is seldom quantified directly. Although there exists an extensive literature documenting the health benefits of regular physical activity in adults, activity-health relationships in children are not clear-cut. Current recommendations reinforce the concept of health-related activity, accumulating 30 min moderate-intensity exercise on at least 5 d/week (adults) and 1 h moderate-intensity exercise/d (children). Evidence suggests a high prevalence of inactivity in adults, but whether or not inactivity is increasing cannot be assessed currently. Similarly, no definite conclusions are justified about either the levels of physical activity of children, or whether these are sufficient to maintain and promote health. Data to support the belief that activity levels in childhood track into adulthood are weak. Inactivity is associated with an increased risk of weight gain and obesity, but causality remains to be established. In children there is strong evidence to demonstrate a dose-response relationship between the prevalence and incidence of obesity and time spent viewing television. Future research should focus on refining methodology for physical activity assessment to make it more sensitive to the different dimensions and contexts of activity in different age-groups.

Na-induced calciuria has been well documented and provides a physiological basis for the proposed role of dietary Na (or salt) as a risk factor for osteoporosis. However, the evidence is based primarily on acute salt-loading studies, and there are insufficient data on the effects of high salt intake on net Ca retention to predict long-term effects on bone health. Results of investigations on salt and bone turnover, as assessed by bone biomarkers, are inconsistent, but the large variations in inter-individual response to acute and chronic Na loading may be related to salt sensitivity. Results of cross-sectional and prospective investigations on high salt intake and long-term bone health are inconclusive, probably reflecting the difficulty of conducting such studies in free-living populations. However, the mean urinary Ca loss of 1 mmol/100 mmol Na suggests that chronic changes in salt intake may have large effects on Ca and bone balance, especially in individuals with a reduced capacity to compensate for Na-induced Ca loss. Investigating the relationship between salt intake and bone health requires a greater focus on whole diets (including components such as K, Mg, P and protein), reliable measures of salt intake, appropriate bone health outcome measures, and improved subject characterisation (e.g. salt sensitivity). The reasons for inter-individual variability should be explored using post-genomic techniques.

A new definition of intestinal failure is of reduced intestinal absorption so that macronutrient and/or water and electrolyte supplements are needed to maintain health or growth. Severe intestinal failure is when parenteral nutrition and/or fluid are needed and mild intestinal failure is when oral supplements or dietary modification suffice. Treatment aims to reduce the severity of intestinal failure. In the peri-operative period avoiding the administration of excessive amounts of intravenous saline (9 g NaCl/l) may prevent a prolonged ileus. Patients with intermittent bowel obstruction may be managed with a liquid or low-residue diet. Patients with a distal bowel entero-cutaneous fistula may be managed with an enteral feed absorbed by the proximal small bowel while no oral intake may be needed for a proximal bowel enterocutaneous fistula. Patients undergoing high-dose chemotherapy can usually tolerate jejunal feeding. Rotating antibiotic courses may reduce small bowel bacterial overgrowth in patients with chronic intestinal pseudo-obstruction. Restricting oral hypotonic fluids, sipping a glucose-saline solution (Na concentration of 90–120 mmol/l) and taking anti-diarrhoeal or anti-secretory drugs, reduces the high output from a jejunostomy. This treatment allows most patients with a jejunostomy and >1 m functioning jejunum remaining to manage without parenteral support. Patients with a short bowel and a colon should consume a diet high in polysaccharides, as these compounds are fermented in the colon, and low in oxalate, as 25% of the oxalate will develop as calcium oxalate renal stones. Growth factors normally produced by the colon (e.g. glucagon-like peptide-2) to induce structural jejunal adaptation have been given in high doses to patients with a jejunostomy and do marginally increase the daily energy absorption.

Short-chain fatty acids (SCFA; mainly acetate, propionate and butyrate) are largely produced in non-ruminants during the colonic bacterial fermentation of non-digestible carbohydrates. These intestinal exogenous SCFA pass in part through the splanchnic bed and reach the peripheral bloodstream, mixing with the endogenous circulating SCFA. The whole-body turnover of SCFA is thus composed of an endogenous peripheral turnover and an exogenous production that depends on dietary intake of non-digestible carbohydrates. In the present work methods were developed for determining the SCFA turnover in animals and in human subjects using stable isotopes. The original studies performed to determine endogenous and exogenous metabolism of SCFA in animals and in human subjects are summarised. Using intravenous infusion of 13C-labelled SCFA the whole-body turnover of acetate, propionate and butyrate was assessed in rats in a fasted state. The endogenous turnover of acetate and its oxidation were determined in healthy human subjects in the post-absorptive state, using intravenous infusion of[l-13C]acetate. Intragastric tracer infusions were performed to evaluate the splanchnic first-pass retention of acetate in adults. Finally, an original model was developed in healthy human subjects using intravenous infusion of[l-13C]acetate to determine in vivo the true colonic acetate production after ingestion of a non-digestible disaccharide. These present studies using stable isotopes provide the basis for a novel strategy to evaluate in vivo, in human subjects, the production of SCFA in the large intestine.

There are now concerns that dietary Se intake is inadequate for the population in the UK and parts of Europe. Many different methods can be proposed to deal with this problem. Experience from Finland suggests that the addition of Se to fertiliser is a safe and effective means of increasing the intake of the micronutrient in the human population. However, careful consideration needs to be given to the potential consequences of increasing Se intake. It is important to understand the biochemical and physiological changes that may occur with any increase in Se intake within the UK population. Se is an essential component of at least twenty functional proteins within mammals. These proteins are essential for a range of metabolic functions, including antioxidant activity, thyroid hormone synthesis and immune function. Thus, any increase in Se intake has the potential to influence in a wide range of factors that may impinge on the incidence of chronic disease. Treatment of soil with Se-supplemented fertiliser will certainly increase total Se in food products derived from areas where this treatment is in place. Consumption of such foods will increase Se status in many populations where the existing intake does not meet requirements. If the increases in Se intake are not toxic the overall consequences have the potential to be beneficial.

The effects of dietary protein on bone health are paradoxical and need to be considered in context of the age, health status and usual diet of the population. Over the last 80 years numerous studies have demonstrated that a high protein intake increases urinary Ca excretion and that on average 1 mg Ca is lost in urine for every 1 g rise in dietary protein. This relationship is primarily attributable to metabolism of S amino acids present in animal and some vegetable proteins, resulting in a greater acid load and buffering response by the skeleton. However, many of these early studies that demonstrated the calciuric effects of protein were limited by low subject numbers, methodological errors and the use of high doses of purified forms of protein. Furthermore, the cross-cultural and population studies that showed a positive association between animal-protein intake and hip fracture risk did not consider other lifestyle or dietary factors that may protect or increase the risk of fracture. The effects of protein on bone appear to be biphasic and may also depend on intake of Ca- and alkali-rich foods, such as fruit and vegetables. At low protein intakes insulin-like growth factor production is reduced, which in turn has a negative effect on Ca and phosphate metabolism, bone formation and muscle cell synthesis. Although growth and skeletal development is impaired at very low protein intakes, it is not known whether variations in protein quality affect the achievement of optimal peak bone mass in adolescents and young adults. Prospective studies in the elderly in the USA have shown that the greatest bone losses occur in elderly men and women with an average protein intake of 16–50 g/d. Although a low protein intake may be indicative of a generally poorer diet and state of health, there is a need to evaluate whether there is a lower threshold for protein intake in the elderly in Europe that may result in increased bone loss and risk of osteoporotic fracture.