Denis Burkitt and the origins of the dietary fibre hypothesis.

For more than 200 years the fibre in plant foods has been known by animal nutritionists to have significant effects on digestion. Its role in human nutrition began to be investigated towards the end of the 19th century. However, between 1966 and 1972, Denis Burkitt, a surgeon who had recently returned from Africa, brought together ideas from a range of disciplines together with observations from his own experience to propose a radical view of the role of fibre in human health. Burkitt came late to the fibre story but built on the work of three physicians (Peter Cleave, G. D. Campbell and Hugh Trowell), a surgeon (Neil Painter) and a biochemist (Alec Walker) to propose that diets low in fibre increase the risk of CHD, obesity, diabetes, dental caries, various vascular disorders and large bowel conditions such as cancer, appendicitis and diverticulosis. Simply grouping these diseases together as having a common cause was groundbreaking. Proposing fibre as the key stimulated much research but also controversy. Credit for the dietary fibre hypothesis is given largely to Burkitt who became known as the 'Fibre Man'. This paper sets out the story of the development of the fibre hypothesis, and the contribution to it of these individuals.

Longitudinal analyses of gut mucosal microbiotas in ulcerative colitis in relation to patient age and disease severity and duration.

Bacteria belonging to the normal colonic microbiota are associated with the etiology of ulcerative colitis (UC). Although several mucosal species have been implicated in the disease process, the organisms and mechanisms involved are unknown. The aim of this investigation was to characterize mucosal biofilm communities over time and to determine the relationship of these bacteria to patient age and disease severity and duration. Multiple rectal biopsy specimens were taken from 33 patients with active UC over a period of 1 year. Real-time PCR was used to quantify mucosal bacteria in UC patients compared to 18 noninflammatory bowel disease controls, and the relationship between indicators of disease severity and bacterial colonization was evaluated by linear regression analysis. Significant differences were detected in bacterial populations on the UC mucosa and in the control group, which varied over the study period. High clinical activity indices (CAI) and sigmoidoscopy scores (SS) were associated with enterobacteria, desulfovibrios, type E Clostridium perfringens, and Enterococcus faecalis, whereas the reverse was true for Clostridium butyricum, Ruminococcus albus, and Eubacterium rectale. Lactobacillus and bifidobacterium numbers were linked with low CAI. Only E. rectale and Clostridium clostridioforme had a high age dependence. These findings demonstrated that longitudinal variations in mucosal bacterial populations occur in UC and that bacterial community structure is related to disease severity.

A newly constructed and validated isoflavone database for the assessment of total genistein and daidzein intake.

The principal phyto-oestrogens (PO) in food are isoflavones, lignans, coumestans and prenylated flavonoids, with isoflavones and lignans being the most commonly found in UK diets. Until recently obtaining accurate data on the PO content of foods was hampered by lack of suitable analytical methods and validation techniques. Furthermore, although PO data exist for some foods, these foods may not be available in the UK. The aim of the present study was to construct a new, comprehensive isoflavone (total genistein + daidzein) database. Using data, mainly from recent GC-MS analysis, for approximately 300 foods available in the UK, and extensive recipe calculations, a new database was constructed containing approximately 6000 foods allocated an isoflavone value. By analysing 7 d weighed food diaries, the database was subsequently used to estimate isoflavone intake in two groups of healthy volunteers, omnivores (n 9) and vegetarians (n 10). Mean isoflavone intake in the vegetarian and omnivorous group was 7.4 (sem 3.05) and 1.2 (sem 0.43) mg/d, respectively. Mean intake for the total group was 4.5 (sem 1.89) mg/d. Main food sources of isoflavones for the vegetarian group were soya milk (plain), meat-substitute foods containing textured vegetable protein and soya protein isolate, soya mince, wholemeal bread and rolls, white bread and rolls, croissants and pitta breads, beans, raisins and soya sauce. Main food sources of isoflavones for the omnivorous group were soya yogurts, wholemeal bread and rolls, white bread and rolls, garlic bread, nan bread and brown bread, sultanas and scones.

Coeliac disease: a diverse clinical syndrome caused by intolerance of wheat, barley and rye.

Coeliac disease is a lifelong intolerance to the gluten found in wheat, barley and rye, and some patients are also sensitive to oats. The disease is genetically determined, with 10% of the first-degree relatives affected and 75% of monozygotic twins being concordant. Of the patients with coeliac disease 95% are human leucocyte antigen (HLA)-DQ2 or HLA-DQ8 positive. Characteristically, the jejunal mucosa becomes damaged by a T-cell-mediated autoimmune response that is thought to be initiated by a 33-mer peptide fragment in A2 gliadin, and patients with this disorder have raised levels of anti-endomysium and tissue transglutaminase antibodies in their blood. Coeliac disease is the major diagnosable food intolerance and, with the advent of a simple blood test for case finding, prevalence rates are thought to be approximately 1:100. Classically, the condition presented with malabsorption and failure to thrive in infancy, but this picture has now been overtaken by the much more common presentation in adults, usually with non-specific symptoms such as tiredness and anaemia, disturbance in bowel habit or following low-impact bone fractures. Small intestinal biopsy is necessary for diagnosis and shows a characteristically flat appearance with crypt hypoplasia and infiltration of the epithelium with lymphocytes. Diet is the key to management and a gluten-free diet effectively cures the condition. However, this commitment is lifelong and many aisles in the supermarket are effectively closed to individuals with coeliac disease. Compliance can be monitored by measuring antibodies in blood, which revert to negative after 6-9 months. Patients with minor symptoms, who are found incidentally to have coeliac disease, often ask whether it is necessary to adhere to the diet. Current advice is that dietary adherence is necessary to avoid the long-term complications, which are, principally, osteoporosis and small bowel lymphoma. However, risk of these complications diminishes very considerably in patients who are on a gluten-free diet.

Associations between diet and disease activity in ulcerative colitis patients using a novel method of data analysis.

BACKGROUND: The relapsing nature and varying geographical prevalence of ulcerative colitis (UC) implicates environmental factors such as diet in its aetiology. METHODS: In order to determine which foods might be related to disease activity in UC a new method of dietary analysis was developed and applied. Eighty-one UC patients were recruited at all stages of the disease process. Following completion of a 7 d diet diary, clinical assessment including a sigmoidoscopic examination (scale 0 (normal mucosa) to 6 (very active disease)) was conducted. Food weights for each person were adjusted (divided) by the person's calorific intake for the week. Each food consumed was given a food sigmoidoscopy score (FSS) calculated by summing the products of the (adjusted) weight of food consumed and sigmoidoscopy score for each patient and occurrence of food and dividing by the total (adjusted) weight of the food consumed by all 81 patients. Thus, foods eaten in large quantities by patients with very active disease have high FSSs and vice versa. Foods consumed by <10 people or weighing <1 kg for the whole group were excluded, leaving 75 foods. RESULTS: High FSS foods were characterized by high levels of the anti-thiamin additive sulfite (Mann-Whitney, p < 0.001), i.e. bitter, white wine, burgers, soft drinks from concentrates, sausages, lager and red wine. Caffeine also has anti-thiamin properties and decaffeinated coffee was associated with a better clinical state than the caffeine containing version. Beneficial foods (average intake per week) included pork (210 g), breakfast cereals (200 g), lettuce (110 g), apples and pears (390 g), milk (1250 ml), melon (350 g), bananas (350 g), bacon (120 g), beef and beef products (500 g), tomatoes (240 g), soup (700 g), citrus fruits (300 g), fish (290 g), yogurt (410 g), cheese (110 g), potatoes (710 g) and legumes (120 g). CONCLUSIONS: The dietary analysis method described provides a new tool for establishing relationships between diet and disease and indicates a potentially therapeutic diet for UC.

Chemotaxonomic analysis of bacterial populations colonizing the rectal mucosa in patients with ulcerative colitis.

The etiology of ulcerative colitis (UC) is unknown, but evidence links it to bacteria belonging to the normal colonic microbiota. The aims of this study were to characterize bacteria colonizing the rectal epithelium, and to investigate whether significant differences existed in UC. Rectal biopsy specimens were obtained via endoscopy from 9 patients with active colitis and 10 patients without inflammatory bowel disease. Complex bacterial communities colonized the rectal mucosa in all subjects. Overall, 72 bacterial taxa (18 genera) were detected. Twenty species were common to both groups, but only differences in bifidobacteria were statistically significant (P=.005). Peptostreptococci were only detected in patients with UC. Microscopy showed that bacteria in mucosal biofilms often occurred in microcolonies. Interindividual variations in mucosal biofilms made it difficult to assign a role for specific bacteria in UC etiology. However, differences in bifidobacteria and peptostreptococci may implicate these organisms in this disease.

PASSCLAIM--gut health and immunity.

BACKGROUND: The gut and immune system form a complex integrated structure that has evolved to provide effective digestion and defence against ingested toxins and pathogenic bacteria. However, great variation exists in what is considered normal healthy gut and immune function. Thus, whilst it is possible to measure many aspects of digestion and immunity, it is more difficult to interpret the benefits to individuals of variation within what is considered to be a normal range. Nevertheless, it is important to set standards for optimal function for use both by the consumer, industry and those concerned with the public health. The digestive tract is most frequently the object of functional and health claims and a large market already exists for gut-functional foods worldwide. AIM: To define normal function of the gut and immune system and describe available methods of measuring it. RESULTS: We have defined normal bowel habit and transit time, identified their role as risk factors for disease and how they may be measured. Similarly, we have tried to define what is a healthy gut flora in terms of the dominant genera and their metabolism and listed the many, varied and novel methods for determining these parameters. It has proved less easy to provide boundaries for what constitutes optimal or improved gastric emptying, gut motility, nutrient and water absorption and the function of organs such as the liver, gallbladder and pancreas. The many tests of these functions are described. We have discussed gastrointestinal well being. Sensations arising from the gut can be both pleasant and unpleasant. However, the characteristics of well being are ill defined and merge imperceptibly from acceptable to unacceptable, a state that is subjective. Nevertheless, we feel this is an important area for future work and method development. The immune system is even more difficult to make quantitative judgements about. When it is defective, then clinical problems ensure, but this is an uncommon state. The innate and adaptive immune systems work synergistically together and comprise many cellular and humoral factors. The adaptive system is extremely sophisticated and between the two arms of immunity there is great redundancy, which provides robust defences. New aspects of immune function are discovered regularly. It is not clear whether immune function can be "improved". Measuring aspects of immune function is possible but there is no one test that will define either the status or functional capacity of the immune system. Human studies are often limited by the ability to sample only blood or secretions such as saliva but it should be remembered that only 2% of lymphocytes circulate at any given time, which limits interpretation of data. We recommend assessing the functional capacity of the immune system by: measuring specific cell functions ex vivo. measuring in vivo responses to challenge, e. g. change in antibody in blood or response to antigens. determining the incidence and severity of infection in target populations during naturally occurring episodes or in response to attenuated pathogens.

Contribution of dietary protein and inorganic sulfur to urinary sulfate: toward a biomarker of inorganic sulfur intake.

BACKGROUND: Sulfiting agents are widely used as food additives. Limits are set on their use in foods because they may adversely affect health. Sulfiting agents are excreted in urine as sulfate, which is indistinguishable from sulfate derived from sulfur amino acids. OBJECTIVE: The objective was to assess the contribution of inorganic sulfur to urinary sulfate excretion and of dietary protein to urinary sulfate and nitrogen excretion with the aim of developing a urinary biomarker of inorganic sulfur intake. DESIGN: Nine healthy men were fed a sequence of 3 diets for 15 d (n = 7), 5 diets for 10 d (n = 6), or both. The diets contained 51-212 g protein/d (0.43-1.71 g S/d) and 0.17-0.27 g inorganic S/d; p-aminobenzoic acid-validated 24-h urine samples (n = 47) were analyzed for sulfate and nitrogen. RESULTS: Dietary inorganic sulfur was efficiently excreted as sulfate in urine. Urinary sulfate derived from protein correlated strongly (r(2) = 0.86) with urinary nitrogen. Urinary recovery of protein sulfur and nitrogen decreased from 84% at average protein intakes (72 g/d) to 70% at high protein intakes (212 g/d). The nitrogen:sulfur ratio (in g) of the protein in the study diets was 18.9, which was maintained in urine (18.4 +/- 0.1) after dietary inorganic sulfur intake was subtracted from urinary sulfate. Therefore, inorganic sulfur intake (g/d) = urinary sulfur (g/d) - 0.054 x urinary nitrogen (g/d). For typical UK intakes of inorganic sulfur (0.25 g/d), this biomarker should produce mean (+/- SD) values of 0.24 +/- 0.10 g S/d. CONCLUSION: Twenty-four-hour urinary nitrogen and sulfate values can be used to predict inorganic sulfur intake.

Plasma and urinary phyto-oestrogens as biomarkers of intake: validation by duplicate diet analysis.

Estimating intake of phyto-oestrogens (PO) is difficult because there is inadequate information on the PO content of foods. Development of a biomarker of intake is therefore necessary for carrying out epidemiological studies. We aimed to validate a newly constructed PO database, containing more than 600 values assigned to foods by using duplicate diet analysis, and to investigate the relationships between measured PO intake, urinary excretion and plasma concentrations of PO. Fourteen subjects with estimated dietary intakes of PO ranging from 0 to 44 mg/d, measured by 7 d weighed intake, completed a duplicate diet collection over 24 h. Concurrently, a 24 h urine collection, validated using p-aminobenzoic acid, was obtained and one timed spot plasma sample taken. Duplicate diets, complete urine collections and plasma samples were analysed for total genistein and daidzein using liquid chromatography-MS to determine PO intake. The potential for 24 h urinary excretion and plasma PO concentrations to reflect dietary intake was investigated. Mean estimated and measured dietary PO intakes were 12.3 and 11.0 mg/d respectively. The correlation between estimated intake and measured intake of PO was highly significant (r 0.98, P<0.001). Urinary excretion (24 h) and plasma concentrations of PO were significantly related to measured dietary PO intake (r 0.97, P<0.001 and r 0.92, P<0.001 respectively). The relationship between 24 h urinary PO excretion and timed plasma concentrations was also significant (r 0.99, P<0.001). These findings validate the PO database and indicate that 24 h urinary excretion and timed plasma concentrations can be used as biomarkers of PO intake.

Probiotics, prebiotics and antibiotics in inflammatory bowel disease.

Probiotics and prebiotics are the sort of therapy that most patients with inflammatory bowel disease (IBD) wish for. They are without significant side effects, except possibly an increase in gas with prebiotics, and so far, appear to be entirely safe. However, are they effective? More than a dozen studies using probiotics in IBD have now been reported, and there is dear benefit in pouchitis and possibly also in Crohn's, although there are so many clinical types of this condition that a clear indication has yet to emerge. For ulcerative colitis (UC) more studies are needed. The use of prebiotics in IBD is only just starting, although significant effects on both the luminal and mucosa-associated flora have been demonstrated in healthy subjects. Antibiotics offer more certain hope in IBD treatment, although with a much greater risk of unwanted effects. Their efficacy in clinical studies varies, with Crohn's disease and pouchitis reporting more benefit than ulcerative colitis. However, the ideal combination of antibiotics, and rationale for their use has not been determined.

The effects of bismuth, iron, zinc and nitrate on free sulfide in batch cultures seeded with fecal flora.

BACKGROUND: Hydrogen sulfide (H2S) and methanthiol (CH3SH) have been implicated as bacterially derived toxins which may be damaging to the gut mucosa. The addition of nitrate and metals that bind sulfide could potentially reduce the concentrations of these toxic gases. In this study, the effects of iron, zinc, bismuth and nitrate on free H2S concentrations in fecal batch cultures were investigated. METHODS: Stool samples were collected from six healthy subjects. Ten percent fecal slurries was made up with phosphate buffer. One milliliter of fecal slurry and 1 ml of metal solution were added to 28 ml anaerobic broth in a 30-ml vial giving final metal concentrations of 0.1, 0.5 and 1.0 mmol/l. For a control, the metal iron solution was replaced by 1 ml of water. After 24 h of incubation at 37 degrees C, 1 ml of the supernatant from the broth was distilled by microdistillation and sulfide determined by HPLC using amperometric detection. RESULTS: A significant reduction in H2S (P<0.05) of 57% was seen with 1.0 mmol/l zinc, but not with 0 and 0.5 mmol/l zinc treatments. Iron at 0.1, 0.5 and 1.0 mmol/l significantly reduced H2S concentrations (P<0.05) by 36%, 44% and 58%, respectively. Bismuth, the most effective metal, reduced H2S concentrations by more than 90% for all treatments. Both magnesium citrate and magnesium acetate did not affect sulfide concentrations, while 41% and 68% reductions were seen from the addition of 0.5 and 1.0 mmol/l magnesium nitrate, respectively (P<0.05). CONCLUSIONS: Bismuth, iron, zinc and nitrate are effective at reducing free H2S concentrations in batch cultures. Side effects of these metals may limit their use in vivo. Nitrate is considered toxic because of its contribution to the formation of the carcinogenic nitrite and nitrosamine, though results presented here may indicate a beneficial effect in the large intestine.

The effect of 5-aminosalicylic acid-containing drugs on sulfide production by sulfate-reducing and amino acid-fermenting bacteria.

The toxic, bacterial metabolite sulfide is implicated in ulcerative colitis. Ulcerative colitis patients taking 5-aminosalicylic acid-containing drugs have lower fecal sulfide levels than those not taking these drugs. The effects of sulfasalazine, balsalazide, olsalazine, and 5-aminosalicylic acid on sulfide production were studied in a three-stage chemostat pulsed on days 1 to 3 with 5 g sulfasalazine (40 mM) and in pure cultures of amino acid-fermenting and sulfate-reducing bacteria. By the third day of sulfasalazine addition to the chemostat, sulfide concentrations in vessels 1 through 3 had dropped from 1.73, 1.78, and 1.43 mM to 0.01, 0.15, and 0.9 mM, respectively. In pure cultures, 50% inhibition of sulfide production from amino acids occurred at 2.5 +/- 0.05 mM for sulfasalazine, 5 +/- 0.2 mM for olsalazine, 6 +/- 1 mM for balsalazide, and more than 20 mM for 5-aminosalicylic acid. Fifty percent inhibition of sulfide production from sulfate occurred at 0.25 +/- 0.05 mM for sulfasalazine, 0.7 +/- 0.2 mM for balsalazide, and 9.0 +/- 1.0 mM for 5-aminosalicylic acid. The order of effectiveness of equimolar concentrations of drugs (most effective first) in this assay was sulfasalazine, then olsalazine (though given clinically at half the dose of other 5-aminosalicylic acid prodrugs) and balsalazide, and lastly 5-aminosalicylic acid. Inhibition of sulfide production by 5-aminosalicylic acid-containing drugs may contribute to their therapeutic effect in ulcerative colitis.

Differences in N-acetylation genotypes between Caucasians and Black South Africans: implications for cancer prevention.

Polymorphic N-acetyltransferase genes (NAT1 and NAT2) determine rapid or slow acetylation phenotypes, which are believed to affect cancer risk related to environmental exposure. Black South Africans have a unique incidence pattern of environment-related cancers, but genetic characteristics of this population are mostly unknown. In this study, we compared NAT1 and NAT2 allele distributions in 101 Black South Africans and 112 UK Caucasians. Frequencies of the rapid alleles were significantly higher in Black South Africans for both NAT1 and NA72. Putative rapid NAT1 genotypes due to the presence of either NAT1*10 or NAT1*11 were found in 74.3% of Black South Africans (only NAT1*10) and 42.0% of UK Caucasians (P < 0.0001). Similarly, NAT2 analysis showed that the presence of NA12*4, NAT2*12A, NAT2*12B, NA72*12C, and NAT2*13 alleles provided significantly higher (P = 0.0001) frequency of rapid acetylation genotypes among Black South Africans (60.4%) than in the Caucasian group (33.9%). The rapid acetylation genotype in Caucasians usually depended on the NAT2*4 allele presence. The significant differences in N-acetylation genotypes can be among the factors determining a distinctive cancer morbidity and mortality pattern observed in Black South Africans. Both further genetic characterization of different populations and development of preventive strategies adopted for ethnicities with different genetic backgrounds are needed to deal adequately with the emerging health care problems in developing multiethnic societies.

Probiotics, infection and immunity.

PURPOSE OF REVIEW: Taking live bacteria by mouth to improve health (probiotics) is not intuitively rational yet it is a practice with a long history. As interest in the effects on health of the intestinal flora has developed, along with major advances in the technology for studying it, so has come a new interest in establishing the true benefits of probiotic therapy. This review summarizes the most recent contributions to this rapidly developing area. RECENT FINDINGS: Probiotic bacteria, mainly bifidobacteria and lactobacilli for historical reasons, can prevent or ameliorate some diseases. Many empirical studies have been done, but work to develop the ideal characteristics of probiotics lags behind. Current literature covers survival of probiotics in the gut, mucosal adherence, antibacterial/pathogen mechanisms, effects on immune function and clinical studies. SUMMARY: Probiotic bacteria are effective in preventing and reducing the severity of acute diarrhoea in children. They are also useful in antibiotic associated diarrhoea but not for elimination of Helicobacter pylori. In inflammatory bowel disease, especially ulcerative colitis, probiotics offer a safe alternative to current therapy. Probiotics have been used to prevent urogenital tract infection with benefit and, perhaps more intriguingly, to reduce atopy in children. Probiotics do not invariably work and study of mechanisms is urgently needed.