Life Extension Magazine®

Issue: Oct 2015

Florassist, Fish Oil, and Stomach Health

Florassist, Fish Oil, and Stomach Health

By Life Extension.

Florassist

The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice.

Diet and nutritional status are among the most important modifiable determinants of human health. The nutritional value of food is influenced in part by a person’s gut microbial community (microbiota) and its component genes (microbiome). Unraveling the interrelations among diet, the structure and operations of the gut microbiota, and nutrient and energy harvest is confounded by variations in human environmental exposures, microbial ecology, and genotype. To help overcome these problems, we created a well-defined, representative animal model of the human gut ecosystem by transplanting fresh or frozen adult human fecal microbial communities into germ-free C57BL/6J mice. Culture-independent metagenomic analysis of the temporal, spatial, and intergenerational patterns of bacterial colonization showed that these humanized mice were stably and heritably colonized and reproduced much of the bacterial diversity of the donor’s microbiota. Switching from a low-fat, plant polysaccharide-rich diet to a high-fat, high-sugar “Western” diet shifted the structure of the microbiota within a single day, changed the representation of metabolic pathways in the microbiome, and altered microbiome gene expression. Reciprocal transplants involving various combinations of donor and recipient diets revealed that colonization history influences the initial structure of the microbial community but that these effects can be rapidly altered by diet. Humanized mice fed the Western diet have increased adiposity; this trait is transmissible via microbiota transplantation. Humanized gnotobiotic mice will be useful for conducting proof-of-principle “clinical trials” that test the effects of environmental and genetic factors on the gut microbiota and host physiology. Nearly full-length 16S rRNA gene sequences are deposited in GenBank under the accession numbers GQ491120 to GQ493997.

Sci Transl Med . 2009 Nov 11;1(6):6ra14

Nutrition of the critically ill — a 21st-century perspective.

Health care-induced diseases constitute a fast-increasing problem. Just one type of these health care-associated infections (HCAI) constitutes the fourth leading cause of death in Western countries. About 25 million individuals worldwide are estimated each year to undergo major surgery, of which approximately 3 million will never return home from the hospital. Furthermore, the quality of life is reported to be significantly impaired for the rest of the lives of those who, during their hospital stay, suffered life-threatening infections/sepsis. Severe infections are strongly associated with a high degree of systemic inflammation in the body, and intimately associated with significantly reduced and malfunctioning GI microbiota, a condition called dysbiosis. Deranged composition and function of the gastrointestinal microbiota, occurring from the mouth to the anus, has been found to cause impaired ability to maintain intact mucosal membrane functions and prevent leakage of
toxins—bacterial endotoxins, as well as whole bacteria or debris of bacteria, the DNA of which are commonly found in most cells of the body, often in adipocytes of obese individuals or in arteriosclerotic plaques. Foods rich in proteotoxins such as gluten, casein and zein, and proteins, have been observed to have endotoxin-like effects that can contribute to dysbiosis. About 75% of the food in the Western diet is of limited or no benefit to the microbiota in the lower gut. Most of it, comprised specifically of refined carbohydrates, is already absorbed in the upper part of the GI tract, and what eventually reaches the large intestine is of limited value, as it contains only small amounts of the minerals, vitamins and other nutrients necessary for maintenance of the microbiota. The consequence is that the microbiota of modern humans is greatly reduced, both in terms of numbers and diversity when compared to the diets of our paleolithic forebears and the individuals living a rural lifestyle today. It is the artificial treatment provided in modern medical care—unfortunately often the only alternative provided—which constitute the main contributors to a poor outcome. These treatments include artificial ventilation, artificial nutrition, hygienic measures, use of skin-penetrating devices, tubes and catheters, frequent use of pharmaceuticals; they are all known to severely impair the microbiomes in various locations of the body, which, to a large extent, are ultimately responsible for a poor outcome. Attempts to reconstitute a normal microbiome by supply of probiotics have often failed as they are almost always undertaken as a complement to—and not as an alternative to—existing treatment schemes, especially those based on antibiotics, but also other pharmaceuticals.

Nutrients. 2013 Jan 14;5(1):162-207

Gut microbiota and its possible relationship with obesity.

Obesity results from alterations in the body’s regulation of energy intake, expenditure, and storage. Recent evidence, primarily from investigations in animal models, suggests that the gut microbiota affects nutrient acquisition and energy regulation. Its composition has also been shown to differ in lean vs obese animals and humans. In this article, we review the published evidence supporting the potential role of the gut microbiota in the development of obesity and explore the role that modifying the gut microbiota may play in its future treatment. Evidence suggests that the metabolic activities of the gut microbiota facilitate the extraction of calories from ingested dietary substances and help to store these calories in host adipose tissue for later use. Furthermore, the gut bacterial flora of obese mice and humans include fewer Bacteroidetes and correspondingly more Firmicutes than that of their lean counterparts, suggesting that differences in caloric extraction of ingested food substances may be due to the composition of the gut microbiota. Bacterial lipopolysaccharide derived from the intestinal microbiota may act as a triggering factor linking inflammation to high-fat diet-induced metabolic syndrome. Interactions among microorganisms in the gut appear to have an important role in host energy homeostasis, with hydrogen-oxidizing methanogens enhancing the metabolism of fermentative bacteria. Existing evidence warrants further investigation of the microbial ecology of the human gut and points to modification of the gut microbiota as one means to treat people who are over-weight or obese.

Mayo Clin Proc. 2008 Apr;83(4):460-9

Interplay between obesity and associated metabolic disorders: new insights into the gut microbiota.

Obesity and associated metabolic disorders are worldwide epidemic. The literature provides new evidence that gut microbiota dysbiosis (at the phyla, genus, or species level) affects host metabolism and energy storage. Here we discuss new findings that may explain how gut microbiota can be involved in the development or in the control of obesity and associated low-grade inflammation. New powerful molecular biology methods and the use of gnotobiotic animal allowed to analyze the molecular link between gut bacteria and the host. Moreover, even if more studies are needed to unravel how changing gut microbiota impacts on the development of obesity and related metabolic alterations, probiotic and prebiotic approach appear as potential interesting treatments to reverse host metabolic alterations linked to gut microbiota dysbiosis.

Curr Opin Pharmacol. 2009 Dec;9(6):737-43

Intestinal microbiota and overweight.

The microbes in our gut can influence our weight by providing us with energy through the degradation of nondigestable carbohydrates and by affecting the cellular energy status of liver and muscle cells and the accumulation of lipids in adipose tissue. Thus, it is not surprising that in several studies the gastrointestinal microbiota of overweight and obese subjects has been found to differ from that of lean subjects. The initial findings linked obesity with proportionally decreased levels of the phylum Bacteroidetes and increased levels of the phylum Firmicutes. Later, several studies have assessed the association between overweight or obesity and the gastrointestinal microbiota, applying an array of molecular methods targeting the microbiota as a whole or specific bacterial groups or species within. However, at present it is difficult to draw conclusions on which of the observed microbiota alterations are relevant; essentially all of the bacterial groups that have been studied in more than one trial have given contradictory results in regard to their association with weight. Some of these discrepancies can result from methodological issues and some from the nature of the gastrointestinal microbiota, which is an extremely complex and dynamic microbial ecosystem with high subject specificity. In addition, selecting subjects purely based on weight may result in a largely heterogeneous group with several potentially confounding factors. While it may be premature to conclude which specific groups of bacteria are prominent in the intestinal tract of overweight and obese subjects, it appears clear that microbes contribute to weight gain and related health issues, such as the metabolic syndrome and type II diabetes. Therefore, it is important to continue to search for common microbial markers and predictors of obesity, and to study how these may be modulated with probiotics and prebiotics to promote health.

Benef Microbes. 2010 Nov;1(4):407-21

Immunosenescence and anti-immunosenescence therapies: the case of probiotics.

Aging is a complex process that negatively impacts the development of the immune system and its ability to function. Progressive changes in the T and B cell systems over the life span have a major impact on the capacity to respond to immune challenge. These cumulative age-associated changes in immune competence are termed immunosenescence. This process is mostly characterized by: (1) shrinkage of the T cell repertoire and accumulation of oligoclonal expansions of memory/effector cells directed toward ubiquitary infectious agents; (2) involution of the thymus and the exhaustion of naive T cells; and (3) chronic inflammatory status. Here we discuss possible strategies to counteract these main aspects of immunosenescence, in particular the role of the normalization of intestinal microflora by probiotics. A better understanding of immunosenescence and the development of new strategies to counteract it are essential for improving the quality of life of the elderly population.

Rejuvenation Res. 2008 Apr;11(2):425-32

The inflammatory status of old age can be nurtured from the intestinal environment.

PURPOSE OF REVIEW: Recent studies suggest an association between inflammation status and the presence of chronic disease in the elderly. The review examines publications that address the low level of chronic inflammation and emphasizes how an altered host-microbiota interaction at the gut level could contribute to maintaining a low systemic inflammatory status in the elderly. RECENT FINDINGS: The first population cross-sectional studies with relevant numbers of healthy elderlies show age-related global changes in gut microbiota with a consistent increase in nonpathogenic Gram-negative mainly Enterobacteria and country-specific changes in bifidobacteria. Noninvasive methods have permitted us to detect subclinical intestinal inflammation in the elderly population. Furthermore, few studies report on immune and/or inflammatory response; however, prebiotics, probiotics or synbiotics might improve the inflammatory condition of the elderly. SUMMARY: A better understanding of the mechanisms of host-gut microbiota cross-talk would significantly help in the design of novel nutritional strategies targeting immune reactivity at the mucosal level.

Curr Opin Clin Nutr Metab Care. 2008 Jan;11(1):13-20

Gut changes attributed to ageing: effects on intestinal microflora.

PURPOSE OF REVIEW: There is increased evidence of several impaired gastrointestinal functions with ageing. In the elderly, however, most gastrointestinal functions remain relatively intact because of the large reserve capacity of the intestine and the great secretion capacity of the pancreas. This review will focus on changes in gut microflora observed in the elderly and on the potential benefit of probiotics in this population. RECENT FINDINGS: Recent studies suggest that age affects the intestinal microflora with a decrease in anaerobes and bifidobacteria population and an increase in enterobacteria. These changes and the reduced intestinal immunity of the aged may favour gastrointestinal infections that are frequent in the elderly. Clostridium difficile-associated diarrhoea, one of the most common nosocomial infections in the elderly, has a profound effect on morbidity, mortality and health costs. Probiotics may have interesting positive effects on intestinal function, and the efficacy of treatment with Lactobacilli and Saccharomyces boulardii in Clostridium difficile-associated diarrhoea has been well established in a recent meta-analysis. Studies performed in healthy elderly patients suggest that diet supplementation with probiotics may reduce the impaired immunity associated with ageing. SUMMARY: Important changes in intestinal microflora of the elderly have recently been demonstrated and may have important clinical consequences. Further studies should be conducted to determine if the consumption of probiotics is associated with a lower infection rate and a higher effectiveness of vaccines.

Curr Opin Clin Nutr Metab Care. 2003 Jan;6(1):49-54

The inflammatory status of the elderly: the intestinal contribution.

A common finding in the elderly population is a chronic subclinical inflammatory status that coexists with immune dysfunction. These interconnected processes are of sufficient magnitude to impact health and survival time. In this review we discuss the different signals that may stimulate the inflammatory process in the aging population as well as the molecular and cellular components that can participate in the initiation, the modulation or termination of the said process. A special interest has been devoted to the intestine as a source of signals that can amplify local and systemic inflammation. Sentinel cells in the splanchnic area are normally exposed to more than one stimulus at a given time. In the intestine of the elderly, endogenous molecules produced by the cellular aging process and stress as well as exogenous evolutionarily conserved molecules from bacteria, are integrated into a network of receptors and molecular signalling pathways that result in chronic inflammatory activation. It is thus possible that nutritional interventions which modify the intestinal ecology can diminish the pro-inflammatory effects of the microbiota and thereby reinforce the mucosal barrier or modulate the cellular activation pathways.

Mutat Res. 2010 Aug 7;690(1-2):50-6

Human intestinal microbiota and healthy ageing.

Earlier studies have indicated a decrease in anaerobes and bifidobacteria and a concomitant increase in enterobacteria in the intestinal microbiota with ageing. However, new data obtained with molecular techniques suggests decreased stability and increased diversity of the gut microbiota with advancing age. Further, no simple marker change in microbiota composition can be identified. Except for the reduced immune function, ageing itself may have relatively little effect on overall gastrointestinal function. Concomitant changes in nutrition, increased incidence of disease and corresponding use of medication with advancing age modify the composition of the microbial community of the gastrointestinal tract. This mini-review will focus on the recent findings on the gut microbiota of the elderly and on the potential benefits of probiotics, prebiotics and synbiotics.

Ageing Res Rev. 2010 Apr;9(2):107-16

The interplay between the intestinal microbiota and the brain.

The intestinal microbiota consists of a vast bacterial community that resides primarily in the lower gut and lives in a symbiotic relationship with the host. A bidirectional neurohumoral communication system, known as the gut-brain axis, integrates the host gut and brain activities. Here, we describe the recent advances in our understanding of how the intestinal microbiota communicates with the brain via this axis to influence brain development and behaviour. We also review how this extended communication system might influence a broad spectrum of diseases, including irritable bowel syndrome, psychiatric disorders and demyelinating conditions such as multiple sclerosis.

Nat Rev Microbiol. 2012 Nov;10(11):735-42

Intestinal microbiota in functional bowel disorders: a Rome foundation report.

It is increasingly perceived that gut host-microbial interactions are important elements in the pathogenesis of functional gastrointestinal disorders (FGID). The most convincing evidence to date is the finding that functional dyspepsia and irritable bowel syndrome (IBS) may develop in predisposed individuals following a bout of infectious gastroenteritis. There has been a great deal of interest in the potential clinical and therapeutic implications of small intestinal bacterial overgrowth in IBS. However, this theory has generated much debate because the evidence is largely based on breath tests which have not been validated. The introduction of culture-independent molecular techniques provides a major advancement in our understanding of the microbial community in FGID. Results from 16S rRNA-based microbiota profiling approaches demonstrate both quantitative and qualitative changes of mucosal and faecal gut microbiota, particularly in IBS. Investigators are also starting to measure host-microbial interactions in IBS. The current working hypothesis is that abnormal microbiota activate mucosal innate immune responses which increase epithelial permeability, activate nociceptive sensory pathways and dysregulate the enteric nervous system. While we await important insights in this field, the microbiota is already a therapeutic target. Existing controlled trials of dietary manipulation, prebiotics, probiotics, synbiotics and non-absorbable antibiotics are promising, although most are limited by suboptimal design and small sample size. In this article, the authors provide a critical review of current hypotheses regarding the pathogenetic involvement of microbiota in FGID and evaluate the results of microbiota-directed interventions. The authors also provide clinical guidance on modulation of gut microbiota in IBS.

Gut . 2013 Jan;62(1):159-76

Spatial and temporal variability of the human microbiota.

The knowledge that our bodies are home to microbes is not new; van Leeuwenhoek first saw the microbes of the mouth and gut over three centuries ago. However, next generation sequencing technologies are enabling us to characterize our microbial consortia on an unprecedented scale, and are providing new insights into the range of variability of our microbiota and their contributions to our health. The microbiota far outnumber the human component of our selves, with 10 times more cells and at least 100 times more genes. Moreover, while individuals share over 99.9% of their human genome sequence, there are vast differences in the microbiome (the collection of genes of our associated microbes). This raises the question of the extent to which our microbial community determines our human physiological responses and susceptibility to disease. In order to develop technologies that allow us to manipulate the microbiome to improve health we must first understand the factors that influence spatial and temporal variation, stability in response to perturbation, and conditions that induce community-wide changes.

Clin Microbiol Infect. 2012 Jul;18 Suppl 4:8-11

Nutrient tasting and signaling mechanisms in the gut. II. The intestine as a sensory organ: neural, endocrine, and immune responses.

The lining of the gastrointestinal tract is the largest vulnerable surface that faces the external environment. Just as the other large external surface, the skin, is regarded as a sensory organ, so should the intestinal mucosa. In fact, the mucosa has three types of detectors: neurons, endocrine cells, and immune cells. The mucosa is in immediate contact with the intestinal contents so that nutrients can be efficiently absorbed, and, at the same time, it protects against the intrusion of harmful entities, such as toxins and bacteria, that may enter the digestive system with food. Signals are sent locally to control motility, secretion, tissue defense, and vascular perfusion; to other digestive organs, for example, to the stomach, gallbladder, and pancreas; and to the central nervous system, for example to influence feeding behavior. The three detecting systems in the intestine are more extensive than those of any other organ: the enteric nervous system contains on the order of 10(8) neurons, the gastroenteropancreatic endocrine system uses more than 20 identified hormones, and the gut immune system has 70-80% of the body’s immune cells. The gastrointestinal tract has an integrated response to changes in its luminal contents. When this response is maladjusted or is overwhelmed, the consequences can be severe, as in cholera intoxication, or debilitating, as in irritable bowel syndrome. Thus it is essential to obtain a full understanding of the sensory functions of the intestine, of how the body reacts to the information, and of how neural, hormonal, and immune signals interact.

Am J Physiol. 1999 Nov;277(5 Pt 1):G922-8

Fish oil

Docosahexaenoic acid-concentrated fish oil supplementation in subjects with mild cognitive impairment (MCI): a 12-month randomised, double-blind, placebo-controlled trial.

RATIONALE: Epidemiological studies have suggested a beneficial effect of fish oil supplementation in halting the initial progression of Alzheimer’s disease. However, it remains unclear whether fish oil affects cognitive function in older people with mild cognitive impairment (MCI). OBJECTIVES: This study investigated the effects of fish oil supplementation on cognitive function in elderly person with MCI. METHODS: This was a 12-month, randomised, double-blind, placebo-controlled study using fish oil supplementation with concentrated docosahexaenoic acid (DHA). Thirty six low-socioeconomic-status elderly subjects with MCI were randomly assigned to receive either concentrated DHA fish oil (n = 18) or placebo (n = 18) capsules. The changes of memory, psychomotor speed, executive function and attention, and visual-constructive skills were assessed using cognitive tests. Secondary outcomes were safety and tolerability of the DHA concentrate. RESULTS: The fish oil group showed significant improvement in short-term and working memory (F = 9.890; hp (2) = 0.254; p < 0.0001), immediate verbal memory (F = 3.715; hp (2) = 0.114; p < 0.05) and delayed recall capability (F = 3.986; hp (2) = 0.121; p < 0.05). The 12-month change in memory (p < 0.01) was significantly better in the fish oil group. Fish oil consumption was well tolerated, and the side effects were minimal and self-limiting. CONCLUSIONS: This study suggested the potential role of fish oil to improve memory function in MCI subjects. Studies with larger sample sizes, longer intervention periods, different fish oil dosages and genetic determinations should be investigated before definite recommendations can be made.

Psychopharmacology (Berl). 2013 Feb;225(3):605-12

Baseline omega-3 index correlates with aggressive and attention deficit disorder behaviours in adult prisoners.

BACKGROUND: There is emerging evidence that the supplementation of omega-3 contributes to a decrease in aggressive behaviour in prison populations. A challenge of such research is achieving statistical power against effect sizes which may be affected by the baseline omega-3 index. There are no published data on the blood omega-3 index with studies of this kind to assess the variability of the blood omega-3 index in conjunction with aggression and attention deficit assessments. OBJECTIVE: To determine if the variance of the omega-3 index is correlated with aggressive and attention deficit behaviour in a prison population. DESIGN: 136 adult male prisoners were recruited from South Coast Correctional Centre (SCCC), NSW Australia. A 7 point categorisation was used to quantify levels of aggressive behaviour (4 weeks) from individual SCCC case notes, whereby higher scores correspond to increasingly aggressive behaviour. Study participants completed the Aggression Questionnaire (AQ) and the Brown’s Attention Deficit Disorder Scales (BADDS), provided a blood sample for erythrocyte fatty acid analysis using gas chromatography and the omega-3 index was calculated. RESULTS: The baseline omega-3 index ranged from 2.3% to 10.3%, indicating that some participants already had substantial omega-3 intake, however a median of 4.7% indicated a lower overall omega-3 intake than the general Australian population. Assessment of aggressive and attention deficit behaviour shows that there were negative correlations between baseline omega-3 index and baseline aggression categorisation scores (r = -0.21, P = 0.016); total AQ score (r = -0.234, P = 0.011); Anger (r = -0.222 p = 0.016); Hostility AQ (r = -0.239, P = 0.009); indirect aggression (r = -0.188 p = 0.042); total BADDS (r = -0.263, p = 0.005); Activation (r = -0.224, p = 0.016); Attention (r = -0.192, p = 0.043); Effort (r = -0.253, p = 0.007); Affect (r = -0.330, p = 0.000) and Memory (r = -0.240, p = 0.010). CONCLUSIONS: There is a high variability in omega-3 status of a NSW prison population, and inmates with lower omega-3 index were more aggressive and had higher ADD scores.

PLoS One. 2015 Mar 20;10(3):e0120220

Improved working memory but no effect on striatal vesicular monoamine transporter type 2 after omega-3 polyunsaturated fatty acid supplementation.

Studies in rodents indicate that diets deficient in omega-3 polyunsaturated fatty acids (n-3 PUFA) lower dopamine neurotransmission as measured by striatal vesicular monoamine transporter type 2 (VMAT2) density and amphetamine-induced dopamine release. This suggests that dietary supplementation with fish oil might increase VMAT2 availability, enhance dopamine storage and release, and improve dopamine-dependent cognitive functions such as working memory. To investigate this mechanism in humans, positron emission tomography (PET) was used to measure VMAT2 availability pre- and post-supplementation of n-3 PUFA in healthy individuals. Healthy young adult subjects were scanned with PET using [(11)C]-(+)-a-dihydrotetrabenzine (DTBZ) before and after six months of n-3 PUFA supplementation (Lovaza, 2 g/day containing docosahexaenonic acid, DHA 750 mg/d and eicosapentaenoic acid, EPA 930 mg/d). In addition, subjects underwent a working memory task (n-back) and red blood cell membrane (RBC) fatty acid composition analysis pre- and post-supplementation. RBC analysis showed a significant increase in both DHA and EPA post-supplementation. In contrast, no significant change in [(11)C]DTBZ binding potential (BP(ND)) in striatum and its subdivisions were observed after supplementation with n-3 PUFA. No correlation was evident between n-3 PUFA induced change in RBC DHA or EPA levels and change in [(11)C]DTBZ BP(ND) in striatal subdivisions. However, pre-supplementation RBC DHA levels was predictive of baseline performance (i.e., adjusted hit rate, AHR on 3-back) on the n-back task (y = 0.19+0.07, r(2) = 0.55, p = 0.009). In addition, subjects AHR performance improved on 3-back post-supplementation (pre 0.65±0.27, post 0.80±0.15, p = 0.04). The correlation between n-back performance, and DHA levels are consistent with reports in which higher DHA levels is related to improved cognitive performance. However, the lack of change in [(11)C]DBTZ BP(ND) indicates that striatal VMAT2 regulation is not the mechanism of action by which n-3 PUFA improves cognitive performance.

PLoS One . 2012;7(10):e46832

Effects of supplementation with n-3 polyunsaturated fatty acids on cognitive performance and cardiometabolic risk markers in healthy 51 to 72 years old subjects: a randomized controlled cross-over study.

BACKGROUND: Higher plasma n-3 polyunsaturated fatty acids (PUFA) have been associated with a lower risk of age related cognitive decline, and to beneficially affect cardiometabolic risk factors. A relation exists between metabolic disorders such as diabetes type 2 and cognitive decline. Results regarding the potential effects of n-3 PUFA on risk factors in healthy subjects are divergent, and studies regarding the possible relation between cardiometabolic parameters and cognitive performance are scarce. The objective was to evaluate the effects of five weeks intake of long chain n-3 PUFA on cognitive performance in healthy individuals, and to exploit the possible relation between outcomes in cognitive tests to cardiometabolic risk parameters. METHODS: Fish oil n-3 PUFA (3g daily) were consumed during 5 weeks separated by a 5 week washout period in a cross-over placebo controlled study, including 40 healthy middle aged to elderly subjects. Cognitive performance was determined by tests measuring working memory (WM) and selective attention. RESULTS: Supplementation with n-3 PUFA resulted in better performance in the WM-test compared with placebo (p < 0.05). In contrast to placebo, n-3 PUFA lowered plasma triacylglycerides (P < 0.05) and systolic blood pressure (p < 0.0001). Systolic blood pressure (p < 0.05), f-glucose (p = 0.05), and s-TNF-a (p = 0.05), were inversely related to the performance in cognitive tests. CONCLUSIONS: Intake of n-3 PUFA improved cognitive performance in healthy subjects after five weeks compared with placebo. In addition, inverse relations were obtained between cardiometabolic risk factors and cognitive performance, indicating a potential of dietary prevention strategies to delay onset of metabolic disorders and associated cognitive decline.

Nutr J. 2012 Nov 22;11:99

Effects of fish oil supplementation on learning and behaviour of children from Australian Indigenous remote community schools: a randomised controlled trial.

Omega-3 fatty acids are essential for brain function. We recruited 409 children aged 3-13 years (M=8.27, SD=2.17) for a randomised controlled trial supplementing with placebo or fish oil capsules (providing 750mg docosahexaenoic plus eicosapentaenoic acids, and 60mg gamma linolenic acid/school day) for 20 school weeks (Phase 1) followed by one-way crossover to fish oil (Phase 2). Children undertook assessments of reading, spelling and non-verbal cognitive development (Draw-A-Person) at baseline, 20 and 40 weeks. Teachers completed Conners Behaviour Rating Scales (CBRS). The treatment group showed improvements in Draw-A-Person compared with the placebo during Phase 1 (p=0.029), with strongest effects in Indigenous 7-12 year olds (p=0.008). The placebo group showed significant within-group improvements after switching to treatment (p<0.001). There was no treatment effect for reading or spelling, and CBRS data were unable to be analysed. These findings may be understood in the context that sustained school attendance and nutrition interact to produce school-related achievement.

Prostaglandins Leukot Essent Fatty Acids. 2013 Aug;89(2-3):71-9

Alpha-linolenic acid-induced increase in neurogenesis is a key factor in the improvement in the passive avoidance task after soman exposure.

Exposure to organophosphorous (OP) nerve agents such as soman inhibits the critical enzyme acetylcholinesterase (AChE) leading to excessive acetylcholine accumulation in synapses, resulting in cholinergic crisis, status epilepticus and brain damage in survivors. The hippocampus is profoundly damaged after soman exposure leading to long-term memory deficits. We have previously shown that treatment with three sequential doses of alpha-linolenic acid, an essential omega-3 polyunsaturated fatty acid, increases brain plasticity in naïve animals. However, the effects of this dosing schedule administered after a brain insult and the underlying molecular mechanisms in the hippocampus are unknown. We now show that injection of three sequential doses of alpha-linolenic acid after soman exposure increases the endogenous expression of mature BDNF, activates Akt and the mammalian target of rapamycin complex 1 (mTORC1), increases neurogenesis in the subgranular zone of the dentate gyrus, increases retention latency in the passive avoidance task and increases animal survival. In sharp contrast, while soman exposure also increases mature BDNF, this increase did not activate downstream signaling pathways or neurogenesis. Administration of the inhibitor of mTORC1, rapamycin, blocked the alpha-linolenic acid-induced neurogenesis and the enhanced retention latency but did not affect animal survival. Our results suggest that alpha-linolenic acid induces a long-lasting neurorestorative effect that involves activation of mTORC1 possibly via a BDNF-TrkB-mediated mechanism.

Neuromolecular Med . 2015 Sep;17(3):251-69

n-3 PUFAs have beneficial effects on anxiety and cognition in female rats: Effects of early life stress.

Stressful life events, especially those in early life, can exert long-lasting changes in the brain, increasing vulnerability to mental illness especially in females. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) play a critical role in the development and function of the central nervous system (CNS). Thus, we investigated the influence of an eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) (80% EPA, 20% DHA) n-3 PUFAs mixture on stress-related behavioural and neurobiological responses. Sprague-Dawley female rats were subjected to an early-life stress, maternal separation (MS) procedure from postnatal days 2 to 12. Non-separated (NS) and MS rats were administered saline, EPA/DHA 0.4g/kg/day or EPA/DHA 1g/kg/day, respectively. In adulthood, EPA/DHA treated animals had a dose dependent reduction in anxiety in NS rats. Furthermore, cognitive performance in the novel object recognition task (NOR) was improved by EPA/DHA treatment in NS animals only. EPA/DHA 1g/kg/day decreased behavioural despair in the forced swim test. Notably, EPA/DHA high dose increased the translocation of GRs into the nucleus of NS rat hippocampus. However, the levels of mBDNF remained unchanged in all the experimental groups. The corticosterone response to an acute stress was blunted in MS rats and this was further attenuated by pre-treatment with EPA/DHA. Immune response and monoamine neurotransmission were significantly altered by early-life stress. In conclusion, our study supports the view that n-3 PUFAs are beneficial in neurodevelopmentally normal animals but have little positive benefit in animals exposed to early life stress.

Psychoneuroendocrinology. 2015 Aug;58:79-90

A randomized placebo-controlled pilot trial of omega-3 fatty acids and alpha lipoic acid in Alzheimer’s disease.

Oxidative stress, inflammation, and increased cholesterol levels are all mechanisms that have been associated with Alzheimer’s disease (AD) pathology. Several epidemiologic studies have reported a decreased risk of AD with fish consumption. This pilot study was designed to evaluate the effects of supplementation with omega-3 fatty acids alone (w-3) or omega-3 plus alpha lipoic acid (w-3 + LA) compared to placebo on oxidative stress biomarkers in AD. The primary outcome measure was peripheral F2-isoprostane levels (oxidative stress measure). Secondary outcome measures included performance on: Mini-Mental State Examination (MMSE), Activities of Daily Living/Instrumental Activities of Daily Living (ADL/IADL), and Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog). Thirty-nine AD subjects were randomized to one of three groups: 1) placebo, 2) w-3, or 3) w-3 + LA for a treatment duration of 12 months. Eighty seven percent (34/39) of the subjects completed the 12-month intervention. There was no difference between groups at 12 months in peripheral F2-isoprostane levels (p = 0.83). The w-3 + LA and w-3 were not significantly different than the placebo group in ADAS-cog (p = 0.98, p = 0.86) and in ADL (p = 0.15, p = 0.82). Compared to placebo, the w-3 + LA showed less decline in MMSE (p < 0.01) and IADL (p = 0.01) and the w-3 group showed less decline in IADL (p < 0.01). The combination of w-3 + LA slowed cognitive and functional decline in AD over 12 months. Because the results were generated from a small sample size, further evaluation of the combination of omega-3 fatty acids plus alpha-lipoic acid as a potential treatment in AD is warranted.

J Alzheimers Dis. 2014;38(1):111-20

Effects of n-3 fatty acids, EPA v. DHA, on depressive symptoms, quality of life, memory and executive function in older adults with mild cognitive impairment: a 6-month randomised controlled trial.

Depressive symptoms may increase the risk of progressing from mild cognitive impairment (MCI) to dementia. Consumption of n-3 PUFA may alleviate both cognitive decline and depression. The aim of the present study was to investigate the benefits of supplementing a diet with n-3 PUFA, DHA and EPA, for depressive symptoms, quality of life (QOL) and cognition in elderly people with MCI. We conducted a 6-month double-blind, randomised controlled trial. A total of fifty people aged >65 years with MCI were allocated to receive a supplement rich in EPA (1·67 g EPA + 0·16 g DHA/d; n 17), DHA (1·55 g DHA + 0·40 g EPA/d; n 18) or the n-6 PUFA linoleic acid (LA; 2·2 g/d; n 15). Treatment allocation was by minimisation based on age, sex and depressive symptoms (Geriatric Depression Scale, GDS). Physiological and cognitive assessments, questionnaires and fatty acid composition of erythrocytes were obtained at baseline and 6 months (completers: n 40; EPA n 13, DHA n 16, LA n 11). Compared with the LA group, GDS scores improved in the EPA (P=0·04) and DHA (P=0·01) groups and verbal fluency (Initial Letter Fluency) in the DHA group (P=0·04). Improved GDS scores were correlated with increased DHA plus EPA (r 0·39, P=0·02). Improved self-reported physical health was associated with increased DHA. There were no treatment effects on other cognitive or QOL parameters. Increased intakes of DHA and EPA benefited mental health in older people with MCI. Increasing n-3 PUFA intakes may reduce depressive symptoms and the risk of progressing to dementia. This needs to be investigated in larger, depressed samples with MCI.

Br J Nutr. 2012 Jun;107(11):1682-93

DHA supplementation improved both memory and reaction time in healthy young adults: a randomized controlled trial.

BACKGROUND: Docosahexaenoic acid (DHA) is important for brain function, and its status is dependent on dietary intakes. Therefore, individuals who consume diets low in omega-3 (n-3) polyunsaturated fatty acids may cognitively benefit from DHA supplementation. Sex and apolipoprotein E genotype (APOE) affect cognition and may modulate the response to DHA supplementation. OBJECTIVES: We investigated whether a DHA supplement improves cognitive performance in healthy young adults and whether sex and APOE modulate the response. DESIGN: Healthy adults (n = 176; age range: 18-45 y; nonsmoking and with a low intake of DHA) completed a 6-mo randomized, placebo-controlled, double-blind intervention in which they consumed 1.16 g DHA/d or a placebo. Cognitive performance was assessed by using a computerized cognitive test battery. For all tests, z scores were calculated and clustered into cognitive domains as follows: episodic and working memory, attention, reaction time (RT) of episodic and working memory, and attention and processing speed. ANCOVA was conducted with sex and APOE as independent variables. RESULTS: RTs of episodic and working memory improved with DHA compared with placebo [mean difference (95% CI): -0.18 SD (-0.33, -0.03 SD) (P = 0.02) and -0.36 SD (-0.58, -0.14 SD) (P = 0.002), respectively]. Sex × treatment interactions occurred for episodic memory (P = 0.006) and the RT of working memory (P = 0.03). Compared with the placebo, DHA improved episodic memory in women [0.28 SD (0.08, 0.48 SD); P = 0.006] and RTs of working memory in men [-0.60 SD (-0.95, -0.25 SD); P = 0.001]. APOE did not affect cognitive function, but there were some indications of APOE × sex × treatment interactions. CONCLUSIONS: DHA supplementation improved memory and the RT of memory in healthy, young adults whose habitual diets were low in DHA. The response was modulated by sex.

Am J Clin Nutr. 2013 May;97(5):1134-43

Oral nutritional supplements containing n-3 polyunsaturated fatty acids affect quality of life and functional status in lung cancer patients during multimodality treatment: an RCT.

BACKGROUND/OBJECTIVES: Our objective was to investigate effects of an oral nutritional supplement containing n-3 polyunsaturated fatty acids (FAs) on quality of life, performance status, handgrip strength and physical activity in patients with non-small cell lung cancer (NSCLC) undergoing multimodality treatment. SUBJECTS/METHODS: In a double-blind experiment, 40 patients with stage III NSCLC were randomised to receive 2 cans/day of a protein- and energy-dense oral nutritional supplement containing n-3 polyunsaturated FAs (2.02 g eicosapentaenoic acid+0.92 g docosahexaenoic acid/day) or an isocaloric control supplement, during multimodality treatment. Quality of life, Karnofsky Performance Status, handgrip strength and physical activity (by wearing an accelerometer) were assessed. Effects of intervention were analysed by generalised estimating equations. P-values <0.05 were regarded as statistically significant. RESULTS: The intervention group reported significantly higher on the quality of life parameters, physical and cognitive function (B=11.6 and B=20.7, P<0.01), global health status (B=12.2, P=0.04) and social function (B=22.1, P=0.04) than the control group after 5 weeks. The intervention group showed a higher Karnofsky Performance Status (B=5.3, P=0.04) than the control group after 3 weeks. Handgrip strength did not significantly differ between groups over time. The intervention group tended to have a higher physical activity than the control group after 3 and 5 weeks (B=6.6, P=0.04 and B=2.5, P=0.05). CONCLUSION: n-3 Polyunsaturated FAs may beneficially affect quality of life, performance status and physical activity in patients with NSCLC undergoing multimodality treatment.

Eur J Clin Nutr . 2012 Mar;66(3):399-404

Long-chain omega-3 fatty acids improve brain function and structure in older adults.

Higher intake of seafish or oil rich in long-chain omega-3 polyunsaturated fatty acids (LC-n3-FA) may be beneficial for the aging brain. We tested in a prospective interventional design whether high levels of supplementary LC-n3-FA would improve cognition, and addressed potential mechanisms underlying the effects. Sixty-five healthy subjects (50-75 years, 30 females) successfully completed 26 weeks of either fish oil (2.2 g/day LC-n3-FA) or placebo intake. Before and after the intervention period, cognitive performance, structural neuroimaging, vascular markers, and blood parameters were assayed. We found a significant increase in executive functions after LC-n3-FA compared with placebo (P = 0.023). In parallel, LC-n3-FA exerted beneficial effects on white matter microstructural integrity and gray matter volume in frontal, temporal, parietal, and limbic areas primarily of the left hemisphere, and on carotid intima media thickness and diastolic blood pressure. Improvements in executive functions correlated positively with changes in omega-3-index and peripheral brain-derived neurotrophic factor, and negatively with changes in peripheral fasting insulin. This double-blind randomized interventional study provides first-time evidence that LC-n3-FA exert positive effects on brain functions in healthy older adults, and elucidates underlying mechanisms. Our findings suggest novel strategies to maintain cognitive functions into old age.

Cereb Cortex. 2014 Nov;24(11):3059-68

Antidepressant-like effects of omega-3 fatty acids in postpartum model of depression in rats.

Postpartum depression (PPD) is a psychiatric disorder that occurs in 10-15% of childbearing women. It is hypothesized that omega-3 fatty acids, which are components of fish oil, may attenuate depression symptoms. In order to examine this hypothesis, the animal model of postpartum depression was established in the present study. Ovariectomized female rats underwent hormone-simulated pregnancy (HSP) regimen and received progesterone and estradiol benzoate or vehicle for 23 days, mimicking the actual rat’s pregnancy. The days after hormone termination were considered as the postpartum period. Forced feeding of menhaden fish oil, as a source of omega-3, with three doses of 1, 3, and 9g/kg/d, fluoxetine 15mg/kg/d, and distilled water 2ml/d per rat started in five postpartum-induced and one vehicle group on postpartum day 1 and continued for 15 consecutive days. On postpartum day 15, all groups were tested in the forced swimming test (FST) and open field test (OFT), followed by a biochemical assay. Results showed that the postpartum-induced rats not treated with menhaden fish oil, exhibited an increase in immobility time seen in FST, hippocampal concentration of corticosterone and plasmatic level of corticosterone, and pro-inflammatory cytokines. These depression-related effects were attenuated by supplementation of menhaden fish oil with doses of 3 and 9g/kg. Moreover, results of rats supplemented with menhaden fish oil were comparable to rats treated with the clinically effective antidepressant, fluoxetine. Taken together, these results suggest that menhaden fish oil, rich in omega-3, exerts beneficial effect on postpartum depression and decreases the biomarkers related to depression such as corticosterone and pro-inflammatory cytokines.

Behav Brain Res . 2014 Sep 1;271:65-71

Stomach health

Helicobacter pylori infection and gastric cancer.

Gastric cancer remains a major health burden on many societies claiming hundreds of thousands of lives every year. The discovery of Helicobacter pylori has no doubt revolutionised our understanding of this malignancy, which is now regarded as a paradigm for infection-induced chronic inflammation-mediated cancer. In this paper, we discuss the evidence for the association between H. pylori and gastric adenocarcinoma and MALT lymphoma. We also discuss the pathogenesis of these two forms of cancer and the factors that determine their outcome. There is no doubt that the knowledge accumulated over the past two decades will be translated into eventual victory over this killer cancer, largely because we now appreciate that the best way to prevent the cancer is by preventing acquisition of the infection in the first place, or by eradicating the infection in infected subjects. Defining the optimal timing of intervention is going to be the challenge facing us over the next two decades.

Best Pract Res Clin Gastroenterol. 2007; 21(2): 281-97

Immunology of Helicobacter pylori: insights into the failure of the immune response and perspectives on vaccine studies.

Helicobacter pylori infects the stomach of half of the human population worldwide and causes chronic active gastritis, which can lead to peptic ulcer disease, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. The host immune response to the infection is ineffective, because the bacterium persists and the inflammation continues for decades. Bacterial activation of epithelial cells, dendritic cells, monocytes, macrophages, and neutrophils leads to a T helper cell 1 type of adaptive response, but this remains inadequate. The host inflammatory response has a key functional role in disrupting acid homeostasis, which impacts directly on the colonization patterns of H. pylori and thus the extent of gastritis. Many potential mechanisms for the failure of the host response have been postulated, and these include apoptosis of epithelial cells and macrophages, inadequate effector functions of macrophages and dendritic cells, VacA inhibition of T-cell function, and suppressive effects of regulatory T cells. Because of the extent of the disease burden, many strategies for prophylactic or therapeutic vaccines have been investigated. The goal of enhancing the host’s ability to generate protective immunity has met with some success in animal models, but the efficacy of potential vaccines in humans remains to be demonstrated. Aspects of H. pylori immunopathogenesis are reviewed and perspectives on the failure of the host immune response are discussed. Understanding the mechanisms of immune evasion could lead to new opportunities for enhancing eradication and prevention of infection and associated disease.

Gastroenterology . 2007 Jul;133(1):288-308

Helicobacter pylori and probiotics.

Helicobacter pylori infection, a highly prevalent pathogen, is a major cause of chronic gastritis and peptic ulcer and a risk factor for gastric malignancies. Antibiotics-based H. pylori eradication treatment is 90% effective. However, it is expensive and causes side effects and antibiotic resistance. Probiotics could present a low-cost, large-scale alternative solution to prevent or decrease H. pylori colonization. A literature search of the MEDLINE database (1966-2006) has been performed selecting all in vitro, animal, and human fully published English-language studies dealing with H. pylori and probiotics. Probiotics had an in vitro inhibitory effect on H. pylori. Animal studies demonstrated that probiotic treatment is effective in reducing H. pylori-associated gastric inflammation. Seven of 9 human studies showed an improvement of H. pylori gastritis and decrease in H. pylori density after administration of probiotics. The addition of probiotics to standard antibiotic treatment improved H. pylori eradication rates (81% vs. 71%, with combination treatment vs. H. pylori-eradication treatment alone; chi(2)test: P=0.03). Probiotic treatment reduced H. pylori therapy-associated side effects (incidence of side effects: 23% vs. 46%, with combination therapy vs. H. pylori-eradication treatment alone; chi(2)test: P=0.04). No study could demonstrate the eradication of H. pylori infection by probiotic treatment. So long-term intake of products containing probiotic strains of probiotics may have a favorable effect on H. pylori infection in humans, particularly by reducing the risk of developing disorders associated with high degrees of gastric inflammation.

J Nutr. 2007 Mar;137(3 Suppl 2):812S-8S

Stressed mucosa.

Stress has been defined as an acute threat to the homeostasis of the organism. The mucosal lining of the gastrointestinal tract, a single layer of epithelial cells held together by tight junctions, provides a barrier between the external environment and the body’s internal milieu. Any mechanism that breaches the tight junction exposes the body to foreign material be it protein, microorganisms or toxins. Stresses include physiological (exercise), psychological, disease-related or drug-induced factors. Stress associated gastrointestinal disorders include functional dyspepsia irritable bowel syndrome (IBS), gastroesophageal reflux disease peptic ulcer disease, and inflammatory bowel disease (IBD). Some disease states disrupt gastrointestinal barrier function, e.g. infectious diarrhea, IBD, or celiac disease, whilst in others such as eczema it can be indirectly related to antigenic disruption of the barrier. Drugs, e.g. chemotherapy agents and nonsteroidal anti-inflammatory drugs, also disrupt barrier function. Malnutrition and nutritional deficiencies (zinc, folic acid, vitamin A) also predispose to mucosal damage. Assessment of gastrointestinal mucosal health has proved problematic as invasive techniques, whilst useful, provide limited data and no functional assessment. Noninvasive tests particularly breath tests do provide functional assessment and many can be used together as biomarkers to improve our ability to define a stressed mucosa. Therapeutic options include pharmacotherapies, immunomodulation or immunotherapy.

Nestle Nutr Workshop Ser Pediatr Program. 2007;59:133-42; discussion 143-6

Neuroimmune interaction in the gut: from bench to bedside.

The enteric nervous system plays a crucial role in the control of gastrointestinal motility and coordinates relaxation and contraction of the smooth muscle cells. Relaxation of the gut is mainly mediated by inhibitory non-adrenergic non-cholinergic (NANC) neurons, a subpopulation of enteric neurons which release a neurotransmitter different from acetylcholine and noradrenaline. Via in vitro work performed in Antwerp, we demonstrated in 1990 that these neurons release nitric oxide. Thereafter, my research has focused on the role of the inhibitory NANC neurons in the pathophysiology of postoperative ileus. This iatrogenic condition is characterized by general hypomotility of the entire gastrointestinal tract. In a rat model, we have confirmed that manipulation of the bowel indeed leads to activation of inhibitory NANC neurons during and immediately after abdominal surgery. However, this neuronal component is short lasting and does not explain the observation that ileus lasts several days. Based on this consideration, our research in recent years rather focused on this late phase of postoperative ileus. In Amsterdam, we developed a mouse model studying gastric emptying 24 hours after surgery as read out of postoperative ileus. This research provided new insights regarding the interaction between the immune system and the innervation of the gut. Manipulation of the bowel induced mast cell degranulation and activation of macrophages present in the gut wall leading to influx of inflammatory cells in the vicinity of the myenteric plexus. This local infiltrate subsequently activates inhibitory spinal pathways paralyzing the entire gastrointestinal tract. Conversely, we showed that stimulation of the vagus nerve before and during abdominal surgery prevents this infiltrate. Both in vitro and in vivo studies showed that acetylcholine release prevents activation of macrophages via nicotinic receptors. This finding illustrates the bidirectional communication between the immune system and the enteric nervous system. Next we showed that pharmacological interventions with mast cell stabilizers, antibodies against adhesion molecules and nicotinic agonists can prevent the influx of inflammatory cells and thereby shorten postoperative ileus. Especially as we also demonstrated mast cell activation and intestinal inflammation following surgery in man, these findings provide opportunities to develop new therapeutic strategies for the treatment of postoperative ileus. In summary, our work illustrates that the innervation of the intestine intensely communicates with the immune system. Inflammation activates inhibitory neural pathways whereas vagus nerve stimulation can suppress the immune system, in particular macrophages. These findings have led to the identification of new “targets” for the development of new treatments, not only for postoperative ileus, but possibly also for other gastrointestinal inflammatory diseases.

Verh K Acad Geneeskd Belg . 2006;68(5-6):329-55