The essentiality of n-6 polyunsaturated fatty acids (PUFA) is described in relation to a thymus/thymocyte accretion of arachidonic acid (20:4n-6, AA) in early development, and the high requirement of lymphoid and other cells of the immune system for AA and linoleic acid (1 8:2n-6, LA) for membrane phospholipids. Low n-6 PUFA intakes enhance whereas high intakes decrease certain immune functions. Evidence from in vitro and in vivo studies for a role of AA metabolites in immune cell development and functions shows that they can limit or regulate cellular immune reactions and can induce deviation toward a T helper (Th)2-like immune response. In contrast to the effects of the oxidative metabolites of AA, the longer-chain n-6 PUFA produced by gamma-linolenic acid (18:3n-6, GLA) feeding decreases the Th2 cytokine and immunoglobulin (Ig)G1 antibody response. The n-6 PUFA, GLA, dihomo-gamma-linolenic acid (20:3n-6, DHLA) and AA, and certain oxidative metabolites of AA can also induce T-regulatory cell activity, e.g., transforming growth factor (TGF)-beta-producing T cells; GLA feeding studies also demonstrate reduced proinflammatory interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha production. Low intakes of long-chain n-3 fatty acids (fish oils) enhance certain immune functions, whereas high intakes are inhibitory on a wide range of functions, e.g., antigen presentation, adhesion molecule expression, Th1 and Th2 responses, proinflammatory cytokine and eicosanoid production, and they induce lymphocyte apoptosis. Vitamin E has a demonstrable critical role in long-chain n-3 PUFA interactions with immune functions, often reversing the effects of fish oil. The effect of dietary fatty acids on animal autoimmune disease models depends on both the autoimmune model and the amount and type of fatty acids fed. Diets low in fat, essential fatty acid deficient (EFAD), or high in long-chain n-3 PUFA from fish oils increase survival and reduce disease severity in spontaneous autoantibody-mediated disease, whereas high-fat LA-rich diets increase disease severity. In experimentally induced T cell-mediated autoimmune disease, EFAD diets or diets supplemented with long-chain n-3 PUFA augment disease, whereas n-6 PUFA prevent or reduce the severity. In contrast, in both T cell- and antibody-mediated autoimmune disease, the desaturated/elongated metabolites of LA are protective. PUFA of both the n-6 and n-3 families are clinically useful in human autoimmune-inflammatory disorders, but the precise mechanisms by which these fatty acids exert their clinical effects are not well understood. Finally, the view that all n-6 PUFA are proinflammatory requires revision, in part, and their essential regulatory and developmental role in the immune system warrants appreciation.

Food intolerance in irritable bowel syndrome (IBS) is increasingly being recognized, with patients convinced that diet plays a role in symptom induction. Evidence is building to implicate fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) in the onset of abdominal pain, bloating, wind and altered bowel habit through their fermentation and osmotic effects. Hypersensitivity to normal levels of luminal distension is known to occur in patients with IBS, with consideration of food chemical intolerance likely to answer many questions about this physiological process. This paper summarizes the evidence and application of the most common approaches to managing food intolerance in IBS: the low-FODMAP diet, the elimination diet for food chemical sensitivity and others including possible noncoeliac gluten intolerance.

BACKGROUND: Fibromyalgia engulfs patients in a downward, reinforcing cycle of unrestorative sleep, chronic pain, fatigue, inactivity, and depression. In this study we tested whether a mostly raw vegetarian diet would significantly improve fibromyalgia symptoms.

METHODS: Thirty people participated in a dietary intervention using a mostly raw, pure vegetarian diet. The diet consisted of raw fruits, salads, carrot juice, tubers, grain products, nuts, seeds, and a dehydrated barley grass juice product. Outcomes measured were dietary intake, the fibromyalgia impact questionnaire (FIQ), SF-36 health survey, a quality of life survey (QOLS), and physical performance measurements.

RESULTS: Twenty-six subjects returned dietary surveys at 2 months; 20 subjects returned surveys at the beginning, end, and at either 2 or 4 months of intervention; 3 subjects were lost to follow-up. The mean FIQ score (n = 20) was reduced 46% from 51 to 28. Seven of the 8 SF-36 subscales, bodily pain being the exception, showed significant improvement (n = 20, all P for trend < 0.01). The QOLS, scaled from 0 to 7, rose from 3.9 initially to 4.9 at 7 months (n = 20, P for trend 0.000001). Significant improvements (n = 18, P < 0.03, paired t-test) were seen in shoulder pain at rest and after motion, abduction range of motion of shoulder, flexibility, chair test, and 6-minute walk. 19 of 30 subjects were classified as responders, with significant improvement on all measured outcomes, compared to no improvement among non-responders. At 7 months responders' SF-36 scores for all scales except bodily pain were no longer statistically different from norms for women ages 45-54.

CONCLUSION: This dietary intervention shows that many fibromyalgia subjects can be helped by a mostly raw vegetarian diet.

The aims of this study were to evaluate the implication of food allergy as a cause of paediatric constipation and to determine the diet period needed to tolerate the constipation-causing foods. Fifty-four children aged 6 months to 14 years (median, 42 months) suffering from chronic constipation (without anatomic abnormalities, cοeliac disease or hypothyroidism), unresponsive to a 3-month laxative therapy, were prospectively evaluated. All participants were evaluated for allergy to cow's milk, egg, wheat, rice, corn, potato, chicken, beef and soy, using skin tests (SPT), serum specific IgE and atopy patch test (APT). A withdrawal of the APT-positive foods was instructed. Thirty-two children had positive APT; 15 were positive to one; six, to two and 11, to three or more food allergens, wheat and egg being the commonest. After withdrawing the APT-positive foods for an 8-week period, constipation had improved in 28/32 children, but a relapse of constipation was noticed after an oral food challenge, so they continued the elimination diet. Tolerance to food allergens was achieved in only 6/28 after 6 months, compared to 25/28 after 12 months and to all after a 2-year-long elimination. Food allergy seems to be a significant etiologic factor for chronic constipation not responding to treatment, in infants and young children. APT was found to be useful in evaluating non-IgE allergy-mediated constipation, and there was no correlation of APT with IgE detection. Tolerance was adequately achieved after 12 months of strict food allergen elimination.

Recognition of food components that induce functional gut symptoms in patient's functional bowel disorders (FBD) has been challenging. Food directly or indirectly provides considerable afferent input into the enteric nervous system. There is an altered relationship between the afferent input and perception/efferent response in FBD. Defining the nature of food-related stimuli may provide a means of minimizing such an input and gut symptoms. Using this premise, reducing the intake of FODMAPs (fermentable oligo-, di-, and mono-saccharides and polyols)-poorly absorbed short-chain carbohydrates that, by virtue of their small molecular size and rapid fermentability, will distend the intestinal lumen with liquid and gas-improves symptoms in the majority of patients. Well-developed methodologies to deliver the diet via dietician-led education are available. Another abundant source of afferent input is natural and added food chemicals (such as salicylates, amines, and glutamates). Studies are needed to assess the efficacy of the low food chemical dietary approach. A recent placebo-controlled trial of FODMAP-poor gluten provided the first valid evidence that non-celiac gluten intolerance might actually exist, but its prevalence and underlying mechanisms require elucidation. Food choice via the low FODMAP and potentially other dietary strategies is now a realistic and efficacious therapeutic approach for functional gut symptoms.Am J Gastroenterol advance online publication, 10 April 2012; doi:10.1038/ajg.2012.49.

BACKGROUND AND AIM:Food-related symptoms are commonly described by patients with functional bowel disorders, but dietary change as an evidence-based therapy has not been part of routine management strategies. This reviews aims to discuss strategies commonly applied.

METHOD:Published literature was reviewed.

RESULTS:Traditional approaches involve elimination diets followed by placebo-controlled reintroduction of specific foods, which is tedious at best and not applied in routine practice. Pathogenically-based approaches include determining what food components are inducing food hypersensitivity responses using specific biomarkers, but this is probably applicable to a small proportion of patients only and has met with only limited success. Food bioactive chemicals, such as salicylates, have been targeted, but there is a paucity of quality evidence for or against this approach. In contrast, targeting poorly absorbed dietary components that might induce luminal distension via osmotic effects and rapid fermentation (FODMAPs) has been successful and the efficacy of the dietitian-delivered low FODMAP diet is now supported by high quality evidence. Improvement of all symptoms of FBD in three out of four patients has been achieved. The diet may potentially improve stool frequency in patients with an ileal pouch or a high output ileostomy, or functional symptoms in patients with inflammatory bowel disease. FODMAPs in enteral formulas may also be responsible for diarrhoea induced by enteral nutrition.

CONCLUSION:Dietary restriction of FODMAPs is an effective therapy in the majority of patients with functional bowel symptoms and, provided dietitians are trained in the technique, should be first line therapy.

In the laboratory, food restriction has been shown to induce neuroadaptations in brain reward circuitry which are likely to be among those that facilitate survival during periods of food scarcity in the wild. However, the upregulation of mechanisms that promote foraging and reward-related learning may pose a hazard when food restriction is self-imposed in an ecology of abundant appetitive rewards. For example, episodes of loss of control during weight-loss dieting, use of drugs with addictive potential as diet aids, and alternating fasting with alcohol consumption in order to avoid weight gain, may induce synaptic plasticity that increases the risk of enduring maladaptive reward-directed behavior. In the present mini-review, representative basic research findings are outlined which indicate that food restriction alters the function of mesoaccumbens dopamine neurons, potentiates cellular and behavioral responses to D-1 and D-2 dopamine receptor stimulation, and increases stimulus-induced synaptic insertion of AMPA receptors in nucleus accumbens. Possible mechanistic underpinnings of increased drug reward magnitude, drug-seeking, and binge intake of sucrose in food-restricted animal subjects are discussed and possible implications for human weight-loss dieting are considered.

For adolescents with celiac disease (CD), a gluten-free diet (GFD) is crucial for health, but compliance is problematic and noncompliance is common even among those aware of the risks. To better understand their lives with the disease, Swedish CD adolescents were invited to take part in focus group discussions. Data were analyzed for recurrent stigma-related themes across the groups. Adolescents described an awareness of being different from others that was produced by meal appearance and the poor availability of gluten-free food. The GFD often required discussions and special requests, so eating in public had the effect of making an invisible condition visible, and thereby creating a context for felt or enacted stigma. Maintaining invisibility avoided negative consequences of stigma, and other strategies were used to reduce the costs of visibility. The results of the study show that the GFD can produce stigma experiences in adolescence, and that dietary compliance (or lack thereof) can be understood in terms of dealing with GFD concealment and disclosure.

Celiac disease is increasingly recognized autoimmune enteropathy caused by a permanent gluten intolerance. Gluten is the main storage protein of wheat, in genetically predisposed individuals. Celiac disease risk in first degree relatives is about 10%. Diarrhea and changes of bowel movement, observed as well in celiac disease as in IBS, may lead to misdiagnosis of IBS basing on the Rome criteria or may be associated with coexistence of both diseases. The aim of the study was to assess the celiac disease prevalence in patients with irritable bowel syndrome. The study group comprised 200 patients (120 women and 80 men) aged 18-78 years (mean: 46.7 years) with diarrhoeal form of irritable bowel syndrome (IBS), according to the Rome criteria II. At the beginning and after a three month period anti tissue transglutaminase antibodies (IgA tTG) were estimated. Gastroscopy with biopsy where performed in those with IgA tTG titre above 1/200. 40 patients were immunologically positive and 14 of them have histopathologically proven celiac disease. In the group of patients with detected celiac disease, gluten free diet was applied besides the treatment with trimebutin or mebewerin, recommended for IBS. After 6 months the decrease of IgA tTG titre in the serum was observed. In 5 of these patients IgA tTG level was negative. It was associated with the significant decrease of clinical symptoms, such as diarrhea and flatulence. The remaining symptoms, such as abdominal pain, feeling of incomplete defecation demanded continuation of IBS treatment. With regard to often atypical celiac disease symptoms--adult active searching should be performed to differentiate from irritable bowel syndrome.

BACKGROUND:Prospective studies in non-Mediterranean populations have consistently related increasing nut consumption to lower coronary heart disease mortality. A small protective effect on all-cause and cancer mortality has also been suggested. To examine the association between frequency of nut consumption and mortality in individuals at high cardiovascular risk from Spain, a Mediterranean country with a relatively high average nut intake per person.

METHODS:We evaluated 7,216 men and women aged 55 to 80 years randomized to 1 of 3 interventions (Mediterranean diets supplemented with nuts or olive oil and control diet) in the PREDIMED ('PREvención con DIeta MEDiterránea') study. Nut consumption was assessed at baseline and mortality was ascertained by medical records and linkage to the National Death Index. Multivariable-adjusted Cox regression and multivariable analyses with generalized estimating equation models were used to assess theassociation between yearly repeated measurements of nut consumption and mortality.

RESULTS:During a median follow-up of 4.8 years, 323 total deaths, 81 cardiovascular deaths and 130 cancer deaths occurred. Nut consumption was associated with a significantly reduced risk of all-cause mortality (P for trend<0.05, all). Compared to non-consumers, subjects consuming nuts>3 servings/week (32% of the cohort) had a 39% lower mortality risk (hazard ratio (HR) 0.61; 95% CI 0.45 to 0.83). A similar protective effect against cardiovascular and cancer mortality was observed. Participants allocated to the Mediterranean diet with nuts group who consumed nuts>3 servings/week at baseline had the lowest total mortality risk (HR 0.37; 95% CI 0.22 to 0.66).

CONCLUSIONS:Increased frequency of nut consumption was associated with a significantly reduced risk of mortality in a Mediterranean population at high cardiovascular risk.Please see related commentary: http://www.biomedcentral.com/1741-7015/11/165.

TRIAL REGISTRATION:Clinicaltrials.gov. International Standard Randomized Controlled Trial Number (ISRCTN): 35739639. Registration date: 5 October 2005.

BACKGROUND & AIMS:Celiac disease (CD) patients often complain of symptoms consistent with gastroesophageal reflux disease (GERD). We aimed to assess the prevalence of GERD symptoms at diagnosis and to determine the impact of the gluten-free diet (GFD).

METHODS:We evaluated 133 adult CD patients at diagnosis and 70 healthy controls. Fifty-three patients completed questionnaires every 3 months during the first year and more than 4 years after diagnosis. GERD symptoms were evaluated using a subdimension of the Gastrointestinal Symptoms Rating Scale for heartburn and regurgitation domains.

RESULTS:At diagnosis, celiac patients had a significantly higher reflux symptom mean score than healthy controls (P<.001). At baseline, 30.1% of CD patients had moderate to severe GERD (score>3) compared with 5.7% of controls (P<.01). Moderate to severe symptoms were significantly associated with the classical clinical presentation of CD (35.0%) compared with atypical/silent cases (15.2%; P<.03). A rapid improvement was evidenced at 3 months after initial treatment with a GFD (P<.0001) with reflux scores comparable to healthy controls from this time point onward.

CONCLUSIONS:GERD symptoms are common in classically symptomatic untreated CD patients. The GFD is associated with a rapid and persistent improvement in reflux symptoms that resembles the healthy population.

We are accumulating evidence to suggest that 17(th) century Renaissance foodways -largely based on the old "Mediterranean dietary traditions"- may provide new nutraceutical management strategies against HER2-positive breast cancer disease in the 21st century. Epidemiological and experimental studies begin to support the notion that "The Sacred Law of Salads" (i.e., "raw vegetables... plenty of generous (olive) oil") -originally proposed in 1614 by Giacomo Castelvetro in its book The Fruit, Herbs&Vegetables of Italy- might be considered the first (unintended) example of customised diets for breast cancer prevention based on individual genetic make-up (i.e., nutraceuticals against human breast carcinomas bearing HER2 oncogene amplification/overexpression). First, the so-called salad vegetables dietary pattern (i.e., a high consumption of raw vegetables and olive oil) appears to exert a protective effect mostly confined to the HER2-positive breast cancer subtype, with no significant influence on the occurrence of HER2-negative breast cancers. Second, all the main olive oil constituents (i.e., the omega-9 monounsaturated fatty acid oleic acid and polyphenolic compounds such as the secoiridoid oleuropein or the lignan 1-[+]-acetoxypinoresinol) dramatically reduce HER2 expression and specifically induce apoptotic cell death in cultured HER2- positive breast cancer cells, with marginal effects against HER2-negative cells. Third, an olive oil-rich diet negatively influences experimental mammary tumorigenesis in rats likewise decreasing HER2 expression levels. If early 1600s Castelvetro's salads can be used as dietary protocols capable to protecting women against biologically aggressive HER2-positive breast cancer subtypes is an intriguing prospect that warrants to be evaluated in human pilot studies in the future. Here, at least, we would like to recognise Giacomo Castelvetro as the father of modern nutritional genomics in oncology.

BACKGROUND:We have shown that individually, dietary fiber and protein increase secretion of the anorexigenic and insulinotropic hormone, glucagon-like peptide-1 (GLP-1).

OBJECTIVE:Our objective was to combine, in one diet, high levels of fiber and protein to maximize GLP-1 secretion, improve glucose tolerance, and reduce weight gain.

METHODS AND PROCEDURES:Lean (+/?) and obese (cp/cp) male James C Russell corpulent (JCR:LA-cp) rats lacking a functional leptin receptor were fed one of four experimental diets (control, high protein (HP), high fiber (HF, prebiotic fiber inulin), or combination (CB)) for 3 weeks. An oral glucose tolerance test (OGTT) was performed to evaluate plasma GLP-1, insulin and glucose. Plasma lipids and intestinal proglucagon mRNA expression were determined.

RESULTS:Energy intake was lower with the HF diet in lean and obese rats. Weight gain did not differ between diets. Higher colonic proglucagon mRNA in lean rats fed a CB diet was associated with higher GLP-1 secretion during OGTT. The HP diet significantly reduced plasma glucose area under the curve (AUC) during OGTT in obese rats, which reflected both an increased GLP-1 AUC and higher fasting insulin. Diets containing inulin resulted in the lowest plasma triglyceride and total cholesterol levels.

DISCUSSION:Overall, combining HP with HF in the diet increased GLP-1 secretion in response to oral glucose, but did not improve glucose tolerance or lipid profiles more than the HF diet alone did. We also suggest that glycemic and insulinemic response to prebiotics differ among rat models and future research work should examine their role in improving glucose tolerance in diet-induced vs. genetic obesity with overt hyperleptinemia.

BACKGROUND:It has been suggested that peptides from gluten and casein may have a role in the origins of autism and that the physiology and psychology of autism might be explained by excessive opioid activity linked to these peptides. Research has reported abnormal levels of peptides in the urine and cerebrospinal fluid of persons with autism. If this is the case, diets free of gluten and /or casein should reduce the symptoms associated with autism.

OBJECTIVES:To determine the efficacy of gluten- and/or casein- free diets as an intervention to improve behaviour, cognitive and social functioning in individuals with autism.

SEARCH STRATEGY:Electronic searching of abstracts from the Cochrane Library (Issue 3, 2003), PsycINFO (1971- May 2003), EMBASE (1974- May 2003), CINAHL (1982- May 2003), MEDLINE (1986- May 2003), ERIC (1965-2003), LILACS (to 2003) and the specialist register of the Cochrane Complementary Medicine Field (January 2004). Review bibliographies were also examined to identify potential trials.

SELECTION CRITERIA:All randomised controlled trials involving programmes which eliminated gluten, casein or both gluten and casein from the diets of individuals diagnosed with autistic spectrum disorder.

DATA COLLECTION AND ANALYSIS:Abstracts of studies identified in searches of electronic databases were read and assessed to determine whether they might meet the inclusion criteria. The authors independently selected the relevant studies from the reports identified in this way. As only one trial fitted the inclusion criteria, no meta-analysis is currently possible and data are presented in narrative form.

MAIN RESULTS:The one trial included reported results on four outcomes. Unsurprisingly in such a small-scale study, the results for three of these outcomes (cognitive skills, linguistic ability and motor ability) had wide confidence intervals that spanned the line of nil effect. However, the fourth outcome, reduction in autistic traits, reported a significant beneficial treatment effect for the combined gluten- and casein- free diet.

REVIEWERS' CONCLUSIONS:This is an important area of investigation and large scale, good quality randomised controlled trials are needed.

Gluten exclusion (protein complex present in many cereals) has been proposed as an option for the prevention of diseases other than coeliac disease. However, the effects of gluten-free diets on obesity and its mechanisms of action have not been studied. Thus, our objective was to assess whether gluten exclusion can prevent adipose tissue expansion and its consequences. C57BL/6 mice were fed a high-fat diet containing 4.5% gluten (Control) or no gluten (GF). Body weight and adiposity gains, leukocyte rolling and adhesion, macrophage infiltration and cytokine production in adipose tissue were assessed. Blood lipid profiles, glycaemia, insulin resistance and adipokines were measured. Expression of the PPAR-α and γ, lipoprotein lipase (LPL), hormone sensitive lipase (HSL), carnitine palmitoyl acyltransferase-1 (CPT-1), insulin receptor, GLUT-4 and adipokines were assessed in epidydimal fat. Gluten-free animals showed a reduction in body weight gain and adiposity, without changes in food intake or lipid excretion. These results were associated with up-regulation of PPAR-α, LPL, HSL and CPT-1, which are related to lipolysis and fatty acid oxidation. There was an improvement in glucose homeostasis and pro-inflammatory profile-related overexpression of PPAR-γ. Moreover, intravital microscopy showed a lower number of adhered cells in the adipose tissue microvasculature. The overexpression of PPAR-γ is related to the increase of adiponectin and GLUT-4. Our data support the beneficial effects of gluten-free diets in reducing adiposity gain, inflammation and insulin resistance. The data suggests that diet gluten exclusion should be tested as a new dietary approach to prevent the development of obesity and metabolic disorders.

Eight adult female patients suffering from abdominal pain and chronic diarrhea which was often incapacitating and frequently nocturnal, had dramatic relief on a gluten-free diet and return of symptoms after gluten challenge. Previous nonspecific measures and a milk-free diet were ineffective. Multiple jejunal biopsies showed minor, but significant changes in cellularity which returned to normal on the gluten-free diet. Apart from a slight increase in jejunal cellularity, no immunological abnormalities were found after gluten challenge. Steatorrhea or other biochemical defects, common in celiac disease, were not found. It was concluded that these patients had a gluten-sensitive diarrhea, but had no evidence of celiac disease.