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1.  Transforming Life: A Broad View of the Developmental Origins of Health and Disease Concept from an Ecological Justice Perspective 
The influential scientist Rene J. Dubos (1901–1982) conducted groundbreaking studies concerning early-life environmental exposures (e.g., diet, social interactions, commensal microbiota, housing conditions) and adult disease. However, Dubos looked beyond the scientific focus on disease, arguing that “mere survival is not enough”. He defined mental health as fulfilling human potential, and expressed concerns about urbanization occurring in tandem with disappearing access to natural environments (and elements found within them); thus modernity could interfere with health via “missing exposures”. With the advantage of emerging research involving green space, the microbiome, biodiversity and positive psychology, we discuss ecological justice in the dysbiosphere and the forces—financial inequity, voids in public policy, marketing and otherwise—that interfere with the fundamental rights of children to thrive in a healthy urban ecosystem and learn respect for the natural environment. We emphasize health within the developmental origins of health and disease (DOHaD) rubric and suggest that greater focus on positive exposures might uncover mechanisms of resiliency that contribute to maximizing human potential. We will entrain our perspective to socioeconomic disadvantage in developed nations and what we have described as “grey space”; this is a mental as much as a physical environment, a space that serves to insidiously reinforce unhealthy behavior, compromise positive psychological outlook and, ultimately, trans-generational health. It is a dwelling place that cannot be fixed with encephalobiotics or the drug-class known as psychobiotics.
doi:10.3390/ijerph13111075
PMCID: PMC5129285  PMID: 27827896
urbanization; socioeconomic; disadvantage; green space; environmental justice; depression; empathy; marketing; biodiversity; microbiota
2.  The Microbiome and Mental Health: Looking Back, Moving Forward with Lessons from Allergic Diseases 
Relationships between gastrointestinal viscera and human emotions have been documented by virtually all medical traditions known to date. The focus on this relationship has waxed and waned through the centuries, with noted surges in interest driven by cultural forces. Here we explore some of this history and the emerging trends in experimental and clinical research. In particular, we pay specific attention to how the hygiene hypothesis and emerging research on traditional dietary patterns has helped re-ignite interest in the use of microbes to support mental health. At present, the application of microbes and their structural parts as a means to positively influence mental health is an area filled with promise. However, there are many limitations within this new paradigm shift in neuropsychiatry. Impediments that could block translation of encouraging experimental studies include environmental forces that work toward dysbiosis, perhaps none more important than westernized dietary patterns. On the other hand, it is likely that specific dietary choices may amplify the value of future microbial-based therapeutics. Pre-clinical and clinical research involving microbiota and allergic disorders has predated recent work in psychiatry, an early start that provides valuable lessons. The microbiome is intimately connected to diet, nutrition, and other lifestyle variables; microbial-based psychopharmacology will need to consider this contextual application, otherwise the ceiling of clinical expectations will likely need to be lowered.
doi:10.9758/cpn.2016.14.2.131
PMCID: PMC4857870  PMID: 27121424
Depression; Anxiety; Diet; Human microbiome; Microbiota; Allergy and Immunology
3.  Natural environments, nature relatedness and the ecological theater: connecting satellites and sequencing to shinrin-yoku 
Recent advances in research concerning the public health value of natural environments have been remarkable. The growing interest in this topic (often housed under terms such as green and/or blue space) has been occurring in parallel with the microbiome revolution and an increased use of remote sensing technology in public health. In the context of biodiversity loss, rapid urbanization, and alarming rates of global non-communicable diseases (many associated with chronic, low-grade inflammation), discussions of natural vis-a-vis built environments are not merely fodder for intellectual curiosity. Here, we argue for increased interdisciplinary collaboration with the aim of better understanding the mechanisms—including aerobiological and epigenetic—that might help explain some of the noted positive health outcomes. It is our contention that some of these mechanisms are related to ecodiversity (i.e., the sum of biodiversity and geodiversity, including biotic and abiotic constituents). We also encourage researchers to more closely examine individual nature relatedness and how it might influence many outcomes that are at the interface of lifestyle habits and contact with ecodiversity.
doi:10.1186/s40101-016-0083-9
PMCID: PMC4712592  PMID: 26763049
4.  Dysbiotic drift: mental health, environmental grey space, and microbiota 
Advances in research concerning the mental health implications of dietary patterns and select nutrients have been remarkable. At the same time, there have been rapid increases in the understanding of the ways in which non-pathogenic microbes can potentially influence many aspects of human health, including those in the mental realm. Discussions of nutrition and microbiota are often overlapping. A separate, yet equally connected, avenue of research is that related to natural (for example, green space) and built environments, and in particular, how they are connected to human cognition and behaviors. It is argued here that in Western industrial nations a ‘disparity of microbiota’ might be expected among the socioeconomically disadvantaged, those whom face more profound environmental forces. Many of the environmental forces pushing against the vulnerable are at the neighborhood level. Matching the developing microbiome research with existing environmental justice research suggests that grey space may promote dysbiosis by default. In addition, the influence of Westernized lifestyle patterns, and the marketing forces that drive unhealthy behaviors in deprived communities, might allow dysbiosis to be the norm rather than the exception in those already at high risk of depression, subthreshold (subsyndromal) conditions, and subpar mental health. If microbiota are indeed at the intersection of nutrition, environmental health, and lifestyle medicine (as these avenues pertain to mental health), then perhaps the rapidly evolving gut-brain-microbiota conversation needs to operate through a wider lens. In contrast to the more narrowly defined psychobiotic, the term eco-psychotropic is introduced.
doi:10.1186/s40101-015-0061-7
PMCID: PMC4438628  PMID: 25947328
5.  Natural environments, ancestral diets, and microbial ecology: is there a modern “paleo-deficit disorder”? Part II 
Famed microbiologist René J. Dubos (1901–1982) was an early pioneer in the developmental origins of health and disease (DOHaD) construct. In the 1960s, he conducted groundbreaking research concerning the ways in which early-life experience with nutrition, microbiota, stress, and other environmental variables could influence later-life health outcomes. He recognized the co-evolutionary relationship between microbiota and the human host. Almost 2 decades before the hygiene hypothesis, he suggested that children in developed nations were becoming too sanitized (vs. our ancestral past) and that scientists should determine whether the childhood environment should be “dirtied up in a controlled manner.” He also argued that oft-celebrated growth chart increases via changes in the global food supply and dietary patterns should not be equated to quality of life and mental health. Here in the second part of our review, we reflect the words of Dubos off contemporary research findings in the areas of diet, the gut-brain-axis (microbiota and anxiety and depression) and microbial ecology. Finally, we argue, as Dubos did 40 years ago, that researchers should more closely examine the relevancy of silo-sequestered, reductionist findings in the larger picture of human quality of life. In the context of global climate change and the epidemiological transition, an allergy epidemic and psychosocial stress, our review suggests that discussions of natural environments, urbanization, biodiversity, microbiota, nutrition, and mental health, are often one in the same.
doi:10.1186/s40101-014-0040-4
PMCID: PMC4353476  PMID: 25889196
6.  Natural environments, ancestral diets, and microbial ecology: is there a modern “paleo-deficit disorder”? Part I 
Famed microbiologist René J. Dubos (1901–1982) was an early pioneer in the developmental origins of health and disease (DOHaD) construct. In the 1960s, he conducted groundbreaking experimental research concerning the ways in which early-life experience with nutrition, microbiota, stress, and other environmental variables could influence later-life health outcomes. He also wrote extensively on potential health consequences of a progressive loss of contact with natural environments (now referred to as green or blue space), arguing that Paleolithic experiences have created needs, particularly in the mental realm, that might not be met in the context of rapid global urbanization. He posited that humans would certainly adapt to modern urban landscapes and high technology, but there might be a toll to be paid in the form of higher psychological distress (symptoms of anxiety and depression) and diminished quality of life. In particular, there might be an erosion of humanness, exemplified by declines in altruism/empathy. Here in the first of a two-part review, we examine contemporary research related to natural environments and question to what extent Dubos might have been correct in some of his 50-year-old assertions.
doi:10.1186/s40101-015-0041-y
PMCID: PMC4318214  PMID: 25636731
7.  Analysis of β-N-methylamino-L-alanine (BMAA) in spirulina-containing supplements by liquid chromatography-tandem mass spectrometry 
Aquatic Biosystems  2014;10:5.
Over the last decade the amino acid beta-N-methylamino-L-alanine (BMAA) has come under intense scrutiny. International laboratory and epidemiological research continues to support the hypothesis that environmental exposure to BMAA (e.g., through dietary practices, water supply) can promote the risk of various neurodegenerative diseases. A wide variety of cyanobacteria spp. have previously been reported to produce BMAA, with production levels dependent upon species, strain and environmental conditions. Since spirulina (Arthrospira spp.) is a member of the cyanobacteria phylum frequently consumed via dietary supplements, the presence of BMAA in such products may have public health implications. In the current work, we have analyzed ten spirulina-containing samples for the presence of BMAA; six pure spirulina samples from two separate raw materials suppliers, and four commercially-available multi-ingredient products containing 1.45 g of spirulina per 8.5 g serving. Because of controversy surrounding the measurement of BMAA, we have used two complementary liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods: one based on reversed phase LC (RPLC) with derivatization and the other based on hydrophilic interaction LC (HILIC). Potential matrix effects were corrected for by internal standardization using a stable isotope labeled BMAA standard. BMAA was not detected at low limits of detection (80 ng/g dry weight) in any of these product samples. Although these results are reassuring, BMAA analyses should be conducted on a wider sample selection and, perhaps, as part of ongoing spirulina production quality control testing and specifications.
doi:10.1186/2046-9063-10-5
PMCID: PMC4130116  PMID: 25120905
Spirulina; Dietary supplements; BMAA; β-N-methylamino-L-alanine; Food chain
8.  Nutritional psychiatry research: an emerging discipline and its intersection with global urbanization, environmental challenges and the evolutionary mismatch 
In 21st-century public health, rapid urbanization and mental health disorders are a growing global concern. The relationship between diet, brain function and the risk of mental disorders has been the subject of intense research in recent years. In this review, we examine some of the potential socioeconomic and environmental challenges detracting from the traditional dietary patterns that might otherwise support positive mental health. In the context of urban expansion, climate change, cultural and technological changes and the global industrialization and ultraprocessing of food, findings related to nutrition and mental health are connected to some of the most pressing issues of our time. The research is also of relevance to matters of biophysiological anthropology. We explore some aspects of a potential evolutionary mismatch between our ancestral past (Paleolithic, Neolithic) and the contemporary nutritional environment. Changes related to dietary acid load, advanced glycation end products and microbiota (via dietary choices and cooking practices) may be of relevance to depression, anxiety and other mental disorders. In particular, the results of emerging studies demonstrate the importance of prenatal and early childhood dietary practices within the developmental origins of health and disease concept. There is still much work to be done before these population studies and their mirrored advances in bench research can provide translation to clinical medicine and public health policy. However, the clear message is that in the midst of a looming global epidemic, we ignore nutrition at our peril.
doi:10.1186/1880-6805-33-22
PMCID: PMC4131231  PMID: 25060574
9.  Weight gain and psychiatric treatment: is there as role for green tea and conjugated linoleic acid? 
Dietary supplement use is widespread in developed nations. In particular, patients who utilize mental health services also report frequent consumption of dietary supplements, often in relation to management of adverse events and specifically weight gain. Weight gain induced by psychotropic medications can further compound psychological distress and negatively influence compliance. Here we report on four cases of social anxiety disorder treated with the atypical antipsychotic quetiapine. Self-administration of conjugated linoleic acid and green tea extract may have influenced objective anthropomorphic measurements; each patient had an unexpected decrease in total body fat mass, a decrease in body fat percentage and an increase in lean body mass. Since weight gain is a common and undesirable side-effect with psychiatric medications, our observation strongly suggests the need for controlled clinical trials using these agents.
doi:10.1186/1476-511X-6-14
PMCID: PMC1876457  PMID: 17477874
10.  Fermented foods, microbiota, and mental health: ancient practice meets nutritional psychiatry 
The purposeful application of fermentation in food and beverage preparation, as a means to provide palatability, nutritional value, preservative, and medicinal properties, is an ancient practice. Fermented foods and beverages continue to make a significant contribution to the overall patterns of traditional dietary practices. As our knowledge of the human microbiome increases, including its connection to mental health (for example, anxiety and depression), it is becoming increasingly clear that there are untold connections between our resident microbes and many aspects of physiology. Of relevance to this research are new findings concerning the ways in which fermentation alters dietary items pre-consumption, and in turn, the ways in which fermentation-enriched chemicals (for example, lactoferrin, bioactive peptides) and newly formed phytochemicals (for example, unique flavonoids) may act upon our own intestinal microbiota profile. Here, we argue that the consumption of fermented foods may be particularly relevant to the emerging research linking traditional dietary practices and positive mental health. The extent to which traditional dietary items may mitigate inflammation and oxidative stress may be controlled, at least to some degree, by microbiota. It is our contention that properly controlled fermentation may often amplify the specific nutrient and phytochemical content of foods, the ultimate value of which may associated with mental health; furthermore, we also argue that the microbes (for example, Lactobacillus and Bifidobacteria species) associated with fermented foods may also influence brain health via direct and indirect pathways.
doi:10.1186/1880-6805-33-2
PMCID: PMC3904694  PMID: 24422720
11.  Intestinal microbiota, probiotics and mental health: from Metchnikoff to modern advances: Part I – autointoxication revisited 
Gut Pathogens  2013;5:5.
Mental health disorders, depression in particular, have been described as a global epidemic. Research suggests that a variety of lifestyle and environmental changes may be driving at least some portion of the increased prevalence. One area of flourishing research involves the relationship between the intestinal microbiota (as well as the related functional integrity of the gastrointestinal tract) and mental health. In order to appreciate the recent scientific gains in this area, and its potential future directions, it is critical to review the history of the topic. Probiotic administration (e.g. Lactobacillus) and fecal microbiota transfer for conditions associated with depression and anxiety is not a new concept. Here, in the first of a 3-part series, we begin by reviewing the origins of the contemporary research, providing a critical appraisal of what has become a revisionist history of the controversial term ‘autointoxication’. We argue that legitimate interests in the gut-brain-microbiota connection were obscured for decades by its association with a narrow historical legacy. Historical perspectives provide a very meaningful context to the current state of the contemporary research as outlined in parts II and III.
doi:10.1186/1757-4749-5-5
PMCID: PMC3607857  PMID: 23506618
Intestinal microbiota; Autointoxication; Depression; Anxiety; Probiotics; Microbial ecology; Lipopolysaccharide endotoxin; Diet; Intestinal permeability
12.  Intestinal microbiota, probiotics and mental health: from Metchnikoff to modern advances: part III – convergence toward clinical trials 
Gut Pathogens  2013;5:4.
Rapid scientific and technological advances have allowed for a more detailed understanding of the relevance of intestinal microbiota, and the entire body-wide microbiome, to human health and well-being. Rodent studies have provided suggestive evidence that probiotics (e.g. lactobacillus and bifidobacteria) can influence behavior. More importantly, emerging clinical studies indicate that the administration of beneficial microbes, via supplementation and/or fecal microbial transplant (FMT), can influence end-points related to mood state (glycemic control, oxidative status, uremic toxins), brain function (functional magnetic resonance imaging fMRI), and mental outlook (depression, anxiety). However, despite the advances in the area of gastro-biological psychiatry, it becomes clear that there remains an urgent need to explore the value of beneficial microbes in controlled clinical investigations. With the history explored in this series, it is fair to ask if we are now on the cusp of major clinical breakthroughs, or are we merely in the quicksand of Autointoxication II?
doi:10.1186/1757-4749-5-4
PMCID: PMC3605358  PMID: 23497650
Intestinal microbiota; Autointoxication; Depression; Anxiety; Probiotics; Microbial ecology; Lipopolysaccharide endotoxin; Diet; Intestinal permeability; MMP-9; Microbial ecosystems
13.  Intestinal microbiota, probiotics and mental health: from Metchnikoff to modern advances: Part II – contemporary contextual research 
Gut Pathogens  2013;5:3.
In recent years there has been a renewed interest concerning the ways in which the gastrointestinal tract – its functional integrity and microbial residents – might influence human mood (e.g. depression) and behavioral disorders. Once a hotbed of scientific interest in the early 20th century, this area lay dormant for decades, in part due to its association with the controversial term ‘autointoxication’. Here we review contemporary findings related to intestinal permeability, small intestinal bacterial overgrowth, lipopolysaccharide endotoxin (LPS) exposure, D-lactic acid, propionic acid, and discuss their relevance to microbiota and mental health. In addition, we include the context of modern dietary habits as they relate to depression, anxiety and their potential interaction with intestinal microbiota.
doi:10.1186/1757-4749-5-3
PMCID: PMC3601973  PMID: 23497633
Intestinal microbiota; Autointoxication; Depression; Anxiety; Probiotics; Microbial ecology; Lipopolysaccharide endotoxin; Diet; Intestinal permeability; Microbial ecosystems
14.  Vis Medicatrix naturae: does nature "minister to the mind"? 
The healing power of nature, vis medicatrix naturae, has traditionally been defined as an internal healing response designed to restore health. Almost a century ago, famed biologist Sir John Arthur Thomson provided an additional interpretation of the word nature within the context of vis medicatrix, defining it instead as the natural, non-built external environment. He maintained that the healing power of nature is also that associated with mindful contact with the animate and inanimate natural portions of the outdoor environment. A century on, excessive screen-based media consumption, so-called screen time, may be a driving force in masking awareness of the potential benefits of nature. With global environmental concerns, rapid urban expansion, and mental health disorders at crisis levels, diminished nature contact may not be without consequence to the health of the individual and the planet itself. In the context of emerging research, we will re-examine Sir J. Arthur Thomson's contention that the healing power of the nature-based environment - green space, forests and parks in particular - extends into the realm of mental health and vitality.
doi:10.1186/1751-0759-6-11
PMCID: PMC3353853  PMID: 22472137
15.  Acne vulgaris, probiotics and the gut-brain-skin axis - back to the future? 
Gut Pathogens  2011;3:1.
Over 70 years have passed since dermatologists John H. Stokes and Donald M. Pillsbury first proposed a gastrointestinal mechanism for the overlap between depression, anxiety and skin conditions such as acne. Stokes and Pillsbury hypothesized that emotional states might alter the normal intestinal microflora, increase intestinal permeability and contribute to systemic inflammation. Among the remedies advocated by Stokes and Pillsbury were Lactobacillus acidophilus cultures. Many aspects of this gut-brain-skin unifying theory have recently been validated. The ability of the gut microbiota and oral probiotics to influence systemic inflammation, oxidative stress, glycemic control, tissue lipid content and even mood itself, may have important implications in acne. The intestinal microflora may also provide a twist to the developing diet and acne research. Here we provide a historical perspective to the contemporary investigations and clinical implications of the gut-brain-skin connection in acne.
doi:10.1186/1757-4749-3-1
PMCID: PMC3038963  PMID: 21281494
16.  Clinical implications of lipid peroxidation in acne vulgaris: old wine in new bottles 
Acne vulgaris is a common dermatological disorder, one that is frequently associated with depression, anxiety and other psychological sequelae. In recent years there has been an increasing focus on the extent to which oxidative stress is involved in the pathophysiology of acne. Emerging studies have shown that patients with acne are under increased cutaneous and systemic oxidative stress. Indeed, there are indications that lipid peroxidation itself is a match that lights an inflammatory cascade in acne. The notion that lipid peroxidation is a 'starter gun' in acne is not a new one; here we review the nearly 50-year-old lipid peroxidation theory and provide a historical perspective to the contemporary investigations and clinical implications.
In addition, we present a novel hypothesis in which lipid peroxidation may be priming an increased susceptibility to co-morbid depression and anxiety in those with acne. The emerging research on the systemic burden of oxidative stress in acne sheds further light on the brain-skin axis. The recent findings also suggest potential avenues of approach for the treatment of acne via specific nutrients, dietary modifications, oral and topical interventions.
doi:10.1186/1476-511X-9-141
PMCID: PMC3012032  PMID: 21143923
17.  A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome 
Gut Pathogens  2009;1:6.
Chronic fatigue syndrome (CFS) is complex illness of unknown etiology. Among the broad range of symptoms, many patients report disturbances in the emotional realm, the most frequent of which is anxiety. Research shows that patients with CFS and other so-called functional somatic disorders have alterations in the intestinal microbial flora. Emerging studies have suggested that pathogenic and non-pathogenic gut bacteria might influence mood-related symptoms and even behavior in animals and humans. In this pilot study, 39 CFS patients were randomized to receive either 24 billion colony forming units of Lactobacillus casei strain Shirota (LcS) or a placebo daily for two months. Patients provided stool samples and completed the Beck Depression and Beck Anxiety Inventories before and after the intervention. We found a significant rise in both Lactobacillus and Bifidobacteria in those taking the LcS, and there was also a significant decrease in anxiety symptoms among those taking the probiotic vs controls (p = 0.01). These results lend further support to the presence of a gut-brain interface, one that may be mediated by microbes that reside or pass through the intestinal tract.
doi:10.1186/1757-4749-1-6
PMCID: PMC2664325  PMID: 19338686
18.  Plant based dietary supplement increases urinary pH 
Background
Research has demonstrated that the net acid load of the typical Western diet has the potential to influence many aspects of human health, including osteoporosis risk/progression; obesity; cardiovascular disease risk/progression; and overall well-being. As urinary pH provides a reliable surrogate measure for dietary acid load, this study examined whether a plant-based dietary supplement, one marketed to increase alkalinity, impacts urinary pH as advertised.
Methods
Using pH test strips, the urinary pH of 34 healthy men and women (33.9 +/- 1.57 y, 79.3 +/- 3.1 kg) was measured for seven days to establish a baseline urinary pH without supplementation. After this initial baseline period, urinary pH was measured for an additional 14 days while participants ingested the plant-based nutritional supplement. At the end of the investigation, pH values at baseline and during the treatment period were compared to determine the efficacy of the supplement.
Results
Mean urinary pH statistically increased (p = 0.03) with the plant-based dietary supplement. Mean urinary pH was 6.07 +/- 0.04 during the baseline period and increased to 6.21 +/- 0.03 during the first week of treatment and to 6.27 +/- 0.06 during the second week of treatment.
Conclusion
Supplementation with a plant-based dietary product for at least seven days increases urinary pH, potentially increasing the alkalinity of the body.
doi:10.1186/1550-2783-5-20
PMCID: PMC2585554  PMID: 18990209
19.  Acne vulgaris, mental health and omega-3 fatty acids: a report of cases 
Acne vulgaris is a common skin condition, one that is associated with significant psychological disability. The psychological impairments in acne include higher rates of depression, anxiety, anger and suicidal thoughts. Despite a paucity of clinical research, patients with skin conditions and/or mental health disorders are frequent consumers of dietary supplements. An overlap may exist between nutrients that potentially have both anti-acne and mood regulating properties; examples include omega-3 fatty acids from fish oil, chromium, zinc and selenium. Here we report on five cases of acne treated with eicosapentaenoic acid and antioxidant nutrients. Self-administration of these nutrients may have improved inflammatory acne lesions and global aspects of well-being; the observations suggest a need for controlled trials.
doi:10.1186/1476-511X-7-36
PMCID: PMC2577647  PMID: 18851733
20.  Omega-3 fatty acids and major depression: A primer for the mental health professional 
Omega-3 fatty acids play a critical role in the development and function of the central nervous system. Emerging research is establishing an association between omega-3 fatty acids (alpha-linolenic, eicosapentaenoic, docosahexaenoic) and major depressive disorder. Evidence from epidemiological, laboratory and clinical studies suggest that dietary lipids and other associated nutritional factors may influence vulnerability and outcome in depressive disorders. Research in this area is growing at a rapid pace. The goal of this report is to integrate various branches of research in order to update mental health professionals.
doi:10.1186/1476-511X-3-25
PMCID: PMC533861  PMID: 15535884

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