Life Extension Magazine®

Issue: Mar 2016

Theanine, Uric acid, Mood, and Sinus health

Theanine, Uric acid, Mood, and Sinus health

By Life Extension.

L-Theanine

Effects of L-theanine or caffeine intake on changes in blood pressure under physical and psychological stresses.

BACKGROUND: L-theanine, an amino acid contained in green tea leaves, is known to block the binding of L-glutamic acid to glutamate receptors in the brain, and has been considered to cause anti-stress effects by inhibiting cortical neuron excitation. Both L-theanine and caffeine, which green tea contains, have been highlighted for their beneficial effects on cognition and mood. METHODS: In this study, we investigated the effects of orally administered L-theanine or caffeine on mental task performance and physiological activities under conditions of physical or psychological stress in humans. Fourteen participants each underwent three separate trials, in which they orally took either L-theanine + placebo, caffeine + placebo, or placebo only. RESULTS: The results after the mental tasks showed that L-theanine significantly inhibited the blood-pressure increases in a high-response group, which consisted of participants whose blood pressure increased more than average by a performance of a mental task after placebo intake. Caffeine tended to have a similar but smaller inhibition of the blood-pressure increases caused by the mental tasks. The result of the Profile of Mood States after the mental tasks also showed that L-theanine reduced the Tension-Anxiety scores as compared with placebo intake. CONCLUSIONS: The findings above denote that L-theanine not only reduces anxiety but also attenuates the blood-pressure increase in high-stress-response adults.

J Physiol Anthropol . 2012 Oct 29;31:28

The neuropharmacology of L-theanine(N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent.

L-theanine (N-ethyl-L-glutamine) or theanine is a major amino acid uniquely found in green tea. L-theanine has been historically reported as a relaxing agent, prompting scientific research on its pharmacology. Animal neurochemistry studies suggest that L-theanine increases brain serotonin, dopamine, GABA levels and has micromolar affinities for AMPA, Kainate and NMDA receptors. In addition has been shown to exert neuroprotective effects in animal models possibly through its antagonistic effects on group 1 metabotrophic glutamate receptors. Behavioural studies in animals suggest improvement in learning and memory. Overall, L-theanine displays a neuropharmacology suggestive of a possible neuroprotective and cognitive enhancing agent and warrants further investigation in animals and humans.

J Herb Pharmacother. 2006;6(2):21-30

L-theanine attenuates abstinence signs in morphine-dependent rhesus monkeys and elicits anxiolytic-like activity in mice.

L-theanine, 2-amino-4-(ethylcar-bamoyl) butyric acid, an amino acid found in green tea (Camellia sinensis), is sold in the United States as a dietary supplement to reduce stress and improve cognition and mood. The observations that L-theanine has been shown to inhibit caffeine’s stimulatory effects and that caffeine produces precipitated withdrawal signs in opioid-addicted monkeys and some opioid withdrawal signs in some normal monkeys, suggest that L-theanine may suppress opioid withdrawal signs. Additionally, L-theanine produces anxiolytic effects in humans indicating that it has anti-anxiety properties. Thus, in these studies we determined whether L-theanine attenuates opioid-withdrawal signs in morphine-dependent rhesus monkeys, a model for spontaneous opioid withdrawal in human opioid addicts. We also evaluated whether L-theanine decreases anxiety-like behavior in mice, using the elevated plus maze and marble burying assays. L-theanine significantly attenuated designated opioid withdrawal signs, including fighting, rigid abdominal muscles, vocalizing on palpation of abdomen, pacing, retching, wet-dog shakes, and masturbation. It had a relatively quick onset of action that persisted for at least 2.5h. L-theanine also produced anxiolytic-like effects in the elevated plus maze and the marble burying assay in naïve mice at doses that did not significantly affect motor behavior. The results of these studies suggest that L-theanine may be useful in the pharmacotherapy of treating opioid withdrawal as well as anxiety-associated behaviors.

Pharmacol Biochem Behav. 2012 Dec;103(2):245-52

Acute effects of tea constituents L-theanine, caffeine, and epigallocatechin gallate on cognitive function and mood: a systematic review and meta-analysis.

A systematic review and meta-analysis was conducted on 11 randomized placebo-controlled human studies of acute effects of tea constituents L-theanine and epigallocatechin gallate, administered alone or in combination with caffeine, on cognitive function and mood. The outcome measures of mood were alertness, calmness, and contentedness, derived from the Bond-Lader scales, and state anxiety, from the State-Trait Anxiety Inventory. Cognitive measures assessed were attentional switch, intersensory attention, and rapid visual information processing. Standardized mean differences between placebo and treatment groups are presented for each study and outcome measure. Meta-analysis using a random-effects model was conducted when data were available for three or more studies. Evidence of moderate effect sizes in favor of combined caffeine and L-theanine in the first 2 hours postdose were found for outcome measures Bond-Lader alertness, attentional switching accuracy, and, to a lesser extent, some unisensory and multisensory attentional outcomes. Moderator analysis of caffeine and L-theanine doses revealed trends toward greater change in effect size for caffeine dose than for L-theanine dose, particularly during the first hour postdose.

Nutr Rev. 2014 Aug;72(8):507-22

Retour aux sources: defining the structural basis of glutamate receptor activation.

Ionotropic glutamate receptors (iGluRs) are the major excitatory neurotransmitter receptor in the vertebrate CNS and, as a result, their activation properties lie at the heart of much of the neuronal network activity observed in the developing and adult brain. iGluRs have also been implicated in many nervous system disorders associated with postnatal development (e.g. autism, schizophrenia), cerebral insult (e.g. stroke, epilepsy), and disorders of the ageing brain (e.g. Alzheimer's disease, Parkinsonism). In view of this, an emphasis has been placed on understanding how iGluRs activate and desensitize in functional and structural terms. Early structural models of iGluRs suggested that the strength of the agonist response was primarily governed by the degree of closure induced in the ligand-binding domain (LBD). However, recent studies have suggested a more nuanced role for the LBD with current evidence identifying the iGluR LBD interface as a “hotspot” regulating agonist behaviour. Such ideas remain to be consolidated with recently solved structures of full-length iGluRs to account for the global changes that underlie channel activation and desensitization

J Physiol. 2015 Jan 1;593(1):97-110

Metabotropic glutamate receptors as targets for new antipsychotic drugs: Historical perspective and critical comparative assessment.

In this review, we aim to present, discuss and clarify our current understanding regarding the prediction of possible antipsychotic effects of metabotropic glutamate (mGlu) receptor ligands. The number of preclinical trials clearly indicates, that this group of compounds constitutes an excellent alternative to presently used antipsychotic therapy, being effective not only to positive, but also negative and cognitive symptoms of schizophrenia. Although the results of clinical trials that were performed for the group of mGlu2/3 agonists were not so enthusiastic as in animal studies, they still showed that mGlu ligands do not induced variety of side effects typical for presently used antipsychotics, and were generally well tolerated. The lack of satisfactory effectiveness towards schizophrenia symptoms of mGlu2/3 activators in humans could be a result of variety of uncontrolled factors and unidentified biomarkers different for each schizophrenia patient, that should be taken into consideration in the future set of clinical trials. The subject is still open for further research, and the novel classes of mGlu5 or mGlu2/3 agonists/PAMs were recently introduced, including the large group of compounds from the third group of mGlu receptors, especially of mGlu4 subtype. Finally, more precise treatment based on simultaneous administration of minimal doses of the ligands for two or more receptors, seems to be promising in the context of symptoms-specific schizophrenia treatment.

Pharmacol Ther . 2016 Jan;157:10-27

Effects of L-theanine on posttraumatic stress disorder induced changes in rat brain gene expression.

Posttraumatic stress disorder (PTSD) is characterized by the occurrence of a traumatic event that is beyond the normal range of human experience. The future of PTSD treatment may specifically target the molecular mechanisms of PTSD. In the US, approximately 20% of adults report taking herbal products to treat medical illnesses. L-theanine is the amino acid in green tea primarily responsible for relaxation effects. No studies have evaluated the potential therapeutic properties of herbal medications on gene expression in PTSD. We evaluated gene expression in PTSD-induced changes in the amygdala and hippocampus of Sprague-Dawley rats. The rats were assigned to PTSD-stressed and nonstressed groups that received either saline, midazolam, L-theanine, or L-theanine + midazolam. Amygdala and hippocampus tissue samples were analyzed for changes in gene expression. One-way ANOVA was used to detect significant difference between groups in the amygdala and hippocampus. Of 88 genes examined, 17 had a large effect size greater than 0.138. Of these, 3 genes in the hippocampus and 5 genes in the amygdala were considered significant (P < 0.05) between the groups. RT-PCR analysis revealed significant changes between groups in several genes implicated in a variety of disorders ranging from PTSD, anxiety, mood disorders, and substance dependence.

ScientificWorldJournal . 2014;2014:419032

Uric acid

Epidemiology of hyperuricemia and gout.

Gout is an increasingly common medical problem. The traditional risk factors of male sex and high red meat or alcohol consumption have been joined by a wave of newer risk factors, such as increased longevity, the metabolic syndrome (hypertension, diabetes, dyslipidemia, truncal obesity, increased cardiovascular disease risk), use of diuretics, low-dose aspirin, or cyclosporine, and end-stage renal disease. Atypical presentations of gout in the elderly can mimic osteoarthritis and rheumatoid arthritis. There is a resurgence of interest in hyperuricemia as an independent and potentially modifiable cardiovascular risk factor. The pharmacologic management of gout in general practice suffers from a number of quality-control issues. This article reviews these and other new epidemiologic data on this ancient disease.

Am J Manag Care. 2005 Nov;11(15 Suppl):S435-42; quiz S465-8

Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007-2008.

OBJECTIVE: To estimate the prevalence of gout and hyperuricemia based on the latest nationally representative sample of US men and women (National Health and Nutrition Examination Survey [NHANES] 2007-2008). METHODS: Using data from 5,707 participants in NHANES 2007-2008, we estimated the prevalence of gout and hyperuricemia. During home interviews for NHANES 2007-2008, all participants were asked about a history of health professional- or physician-diagnosed gout. Our primary definition of hyperuricemia was a serum urate level of >7.0 mg/dl for men and >5.7 mg/dl for women. We explored potential secular trends in these estimates and their possible explanations by comparing them with estimates based on 18,825 participants in NHANES-III (1988-1994). RESULTS: The prevalence of gout among US adults in 2007-2008 was 3.9% (8.3 million individuals). The prevalence among men was 5.9% (6.1 million), and the prevalence among women was 2.0% (2.2 million). The mean serum urate levels were 6.14 mg/dl among men and 4.87 mg/dl among women, corresponding to hyperuricemia prevalences of 21.2% and 21.6%, respectively. These estimates were higher than those in NHANES-III, with differences of 1.2% in the prevalence of gout (95% confidence interval [95% CI] 0.6, 1.9), 0.15 mg/dl in the serum urate level (95% CI 0.07, 0.24), and 3.2% in the prevalence of hyperuricemia (95% CI 1.2, 5.2). These differences were substantially attenuated after adjusting for body mass index and/or hypertension. CONCLUSION: These findings from nationally representative samples of US adults suggest that the prevalence of both gout and hyperuricemia remains substantial and may have increased over the past 2 decades, which is likely related to increasing frequencies of adiposity and hypertension.

Arthritis Rheum . 2011 Oct;63(10):3136-41

Increasing prevalence of gout and hyperuricemia over 10 years among older adults in a managed care population.

OBJECTIVE: To determine whether the prevalence of gout and/or clinically significant hyperuricemia increased in a managed care population over 10 years. METHODS: The study was a descriptive analysis utilizing an administrative claims database to ascertain 10-year trends in prevalence of gout and/or hyperuricemia. Prevalence rates were calculated cross-sectionally for each year (1990-99) and expressed/compared as rates per 1,000 enrollees. RESULTS: The prevalence of gout and/or hyperuricemia in the overall population increased by about 2 cases per 1000 enrollees over 10 years. In the > 75 year age group, rates increased from 21 per 1,000 persons in 1990 to 41 per 1,000 in 1999. In the 65-74 year age group, prevalence increased from between 21 and 24 per 1,000 persons in the years 1990-92 to over 31 per 1000 during the years 1997-99. Prevalence rates in younger age groups (< 65 years) stayed consistently low during the years under study. There were sex differences in most age groups, with men having the greater burden of disease at every time point. CONCLUSION: Prevalence of gout and/or hyperuricemia in the overall study population increased during the 10-year period. When stratified by age, there were increases in prevalence among groups over age 65 in both sexes. Although gout prevalence increased in both sexes over the 10-year period, men still had most of the burden of disease. In ages younger than 65, men had 4 times higher prevalence than women (4:1 ratio), but in the older age groups (> 65), the gender gap narrowed to 1 woman to every 3 men with gout and/or hyperuricemia (3:1 ratio).

J Rheumatol . 2004 Aug;31(8):1582-7

Uric acid, hyperuricemia,and vascular diseases.

Uric acid is the product of purine metabolism. It is known that hyperuricemia, defined as high levels of blood uric acid, is the major etiological factor of gout. A number of epidemiological reports have increasingly linked hyperuricemia with cardiovascular and neurological diseases. Studies highlighting the pathogenic mechanisms of uric acid point to an inflammatory response as the primary mechanism for inducing gout and possibly contributing to uric acid's vascular effects. Monosodium urate (MSU) crystals induce an inflammatory reaction, which are recognized by toll-like receptors (TLRs). These TLRs then activate NALP3 inflammasome. MSU also triggers neutrophil activation and further produces immune mediators, which lead to a proinflammatory response. In addition, soluble uric acid can also mediate the generation of free radicals and function as a pro-oxidant. This review summarizes the epidemiological studies of hyperuricemia and cardiovascular disease, takes a brief look at hyperuricemia and its role in neurological diseases, and highlights the studies of the advanced pathological mechanisms of uric acid and inflammation.

Front Biosci (Landmark Ed) . 2012 Jan 1;17:656-69

Gout and hyperuricemia.

Gout is a condition characterized by the deposition of monosodium urate crystals in the joints or soft tissue. The four phases of gout include asymptomatic hyperuricemia, acute gouty arthritis, intercritical gout and chronic tophaceous gout. The peak incidence occurs in patients 30 to 50 years old, and the condition is much more common in men than in women. Patients with asymptomatic hyperuricemia do not require treatment, but efforts should be made to lower their urate levels by encouraging them to make changes in diet or lifestyle. Acute gout most commonly affects the first metatarsal joint of the foot, but other joints are also commonly involved. Definitive diagnosis requires joint aspiration with demonstration of birefringent crystals in the synovial fluid under a polarized light microscope. Treatment includes nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, corticosteroids and analgesics. In patients without complications, NSAID therapy is preferred.

Am Fam Physician . 1999 Feb 15;59(4):925-34

An open-label, 6-month study of allopurinol safety in gout: the LASSO study.

OBJECTIVES: Allopurinol is the most widely prescribed serum uric acid-lowering therapy (ULT) in gout. To achieve serum uric acid (sUA) concentrations associated with clinical benefit, allopurinol is serially uptitrated with sUA monitoring. Suboptimal dosing is a key contributor to poor clinical outcomes, but few data are available on the safety and efficacy of dose-titrated allopurinol, particularly at doses > 300 mg/d. The objective of this open-label study was to investigate the safety and efficacy of allopurinol under conditions where investigators were encouraged to titrate to optimal, medically appropriate doses. METHODS: Long-term Allopurinol Safety Study Evaluating Outcomes in Gout Patients (LASSO) was a large, 6-month, multicenter study of allopurinol (NCT01391325). Adults meeting American Rheumatism Association Criteria for Classification of Acute Arthritis of Primary Gout and ≥ 2 gout flares in the previous year were eligible. Investigators were encouraged (but not required) to titrate allopurinol doses to achieve target sUA < 6.0mg/dL. The primary objective was evaluation of the safety of dose-titrated allopurinol by clinical and laboratory examinations at monthly visits. Secondary objectives included sUA-lowering efficacy and gout flare frequency. RESULTS: Of 1735 patients enrolled, 1732 received ≥ 1 allopurinol doses. The maximal daily allopurinol dose during study was < 300 mg in 14.4%, 300 mg in 65.4%, and > 300 mg in 20.2% of patients; dosing duration was 115.5, 152.0, and 159.7 days, respectively. Overall, baseline demographic characteristics and comorbidity rates were similar across these three categories, but patients receiving > 300-mg maximal dose had more severe gout. Treatment-emergent adverse events possibly related to allopurinol occurred in 15.2%, 9.5%, and 11.4% of patients in the < 300-, 300-, and > 300-mg categories, respectively. Rash incidence was low (1.5%) and allopurinol hypersensitivity syndrome was not reported. No clinically meaningful changes occurred in laboratory values. sUA < 6.0mg/dL at month 6 was achieved by 35.9% of patients overall: 22.4%, 35.0%, and 48.3% in dosing categories < 300, 300, and > 300 mg, respectively. CONCLUSIONS: This large multicenter study found that the allopurinol dose-titration strategy was well tolerated, without new safety signals emerging over 6 months. However, despite encouragement to treat to target, significant proportions of patients did not achieve target sUA.

Semin Arthritis Rheum. 2015 Oct;45(2):174-83

Serum urate during acute gout.

OBJECTIVE: To study the frequency of normal serum urate (SU) levels during acute gout in the largest studies of acute gout treatment to date. METHODS: Data collected from 2 randomized controlled clinical trials assessing the efficacy of etoricoxib or indomethacin for 7 days in acute gout were used to assess SU levels during acute gouty attacks. Efficacy was similar with both agents, so both groups were combined for analysis. RESULTS: A total of 339 patients were enrolled in the 2 studies; 94% were male; mean age was 50.5 years. At baseline, 14% of patients had a "true" normal SU (<or=6 mg/dl) and 32% had SU<or=8 mg/dl during acute gout. Baseline mean SU was 7.1 versus 8.5 mg/dl (p<0.001) in those taking allopurinol versus nonusers. Patients taking chronic allopurinol were more likely to have lower SU at baseline compared to those not taking chronic allopurinol (p<0.001) during the acute attack. CONCLUSION: A normal SU level at presentation does not exclude an acute gouty attack. In the largest studies of acute gout to date, attacks still occurred despite SU levels being below 6.8 mg/dl, the saturation level for urate. This may be attributed to persistence of tophi and an increased body uric acid pool. Additional studies are needed to determine the correlation between SU and the body uric acid pool as well as the relationship to timing of changes during acute gout.

J Rheumatol. 2009 Jun;36(6):1287-9

Mood

The association between depression and leukocyte telomere length: a meta-analysis.

BACKGROUND: Telomeres protect the ends of chromosomes, and shorter leukocyte telomeres are associated with poor health. Depression may be associated with the shortening of leukocyte telomeres. The present study set out to consolidate the varying effect sizes found so far in studies of depression and telomere length and to identify moderators of the relationship between depression and telomere length. METHODS: A meta-analytic investigation of the relationship between depression and leukocyte telomere length used information from 21,040 participants. RESULTS: A significant effect size, r = -.12, P < .001, indicated that depression was associated with shorter telomere length. Several variables significantly moderated effect size. Concurrent associations (k = 25) between depression and telomere length were significantly stronger than longitudinal associations (k = 5). Studies that used the Southern blot (k = 3) and fluorescent in situ hybridization (FISH; k = 2) assays to measure telomere length showed larger effect sizes than studies that used quantitative polymerase chain reaction (qPCR; k = 25). Finally, study reports that indicated that the telomere assays were conducted blind to depression level of participants (k = 11) had significantly lower effect sizes than those of other studies (k = 19). CONCLUSIONS: The significant relationship between depression and shorter telomere length is consistent with a theoretical model positing that distress, such as experienced in depression, results in physiological changes leading to shortened telomeres.

Depress Anxiety . 2015 Apr;32(4):229-38

Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects.

In a previous clinical study, a probiotic formulation (PF) consisting of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 (PF) decreased stress-induced gastrointestinal discomfort. Emerging evidence of a role for gut microbiota on central nervous system functions therefore suggests that oral intake of probiotics may have beneficial consequences on mood and psychological distress. The aim of the present study was to investigate the anxiolytic-like activity of PF in rats, and its possible effects on anxiety, depression, stress and coping strategies in healthy human volunteers. In the preclinical study, rats were daily administered PF for 2 weeks and subsequently tested in the conditioned defensive burying test, a screening model for anti-anxiety agents. In the clinical trial, volunteers participated in a double-blind, placebo-controlled, randomised parallel group study with PF administered for 30 d and assessed with the Hopkins Symptom Checklist (HSCL-90), the Hospital Anxiety and Depression Scale (HADS), the Perceived Stress Scale, the Coping Checklist (CCL) and 24 h urinary free cortisol (UFC). Daily subchronic administration of PF significantly reduced anxiety-like behaviour in rats (P < 0·05) and alleviated psychological distress in volunteers, as measured particularly by the HSCL-90 scale (global severity index, P < 0·05; somatisation, P < 0·05; depression, P < 0·05; and anger-hostility, P < 0·05), the HADS (HADS global score, P < 0·05; and HADS-anxiety, P < 0·06), and by the CCL (problem solving, P < 0·05) and the UFC level (P < 0·05). L. helveticus R0052 and B. longum R0175 taken in combination display anxiolytic-like activity in rats and beneficial psychological effects in healthy human volunteers.

Br J Nutr. 2011 Mar;105(5):755-64

Mood and gut feelings.

Evidence is accumulating to suggest that gut microbes (microbiota) may be involved in neural development and function, both peripherally in the enteric nervous system and centrally in the brain. There is an increasing and intense current interest in the role that gut bacteria play in maintaining the health of the host. Altogether the mass of intestinal bacteria represents a virtual inner organ with 100 times the total genetic material contained in all the cells in the human body. Surprisingly, the characterization of this extraordinarily diverse population is only just beginning, since some 60% of these microbes have never been cultured. Commensal organisms live in a state of harmonious symbiosis with each other and their host, however, a disordered balance amongst gut microbes is now thought to be an associated or even causal factor for chronic medical conditions as varied as obesity and inflammatory bowel diseases. While evidence is still limited in psychiatric illnesses, there are rapidly coalescing clusters of evidence which point to the possibility that variations in the composition of gut microbes may be associated with changes in the normal functioning of the nervous system. This review focuses on these data and suggests that the concept should be explored further to increase our understanding of mood disorders, and possibly even uncover missing links to a number of co-morbid medical diseases.

Brain Behav Immun. 2010 Jan;24(1):9-16.

Intestinal barrier function and the brain-gut axis.

The luminal-mucosal interface of the intestinal tract is the first relevant location where microorganism-derived antigens and all other potentially immunogenic particles face the scrutiny of the powerful mammalian immune system. Upon regular functioning conditions, the intestinal barrier is able to effectively prevent most environmental and external antigens to interact openly with the numerous and versatile elements that compose the mucosal-associated immune system. This evolutionary super system is capable of processing an astonishing amount of antigens and non-immunogenic particles, approximately 100 tons in one individual lifetime, only considering food-derived components. Most important, to develop oral tolerance and proper active immune responses needed to prevent disease and inflammation, this giant immunogenic load has to be managed in a way that physiological inflammatory balance is constantly preserved. Adequate functioning of the intestinal barrier involves local and distant regulatory networks integrating the so-called brain-gut axis. Along this complex axis both brain and gut structures participate in the processing and execution of response signals to external and internal changes coming from the digestive tract, using multidirectional pathways to communicate. Dysfunction of brain-gut axis facilitates malfunctioning of the intestinal barrier, and vice versa, increasing the risk of uncontrolled immunological reactions that may trigger mucosal and brain low-grade inflammation, a putative first step to the initiation of more permanent gut disorders. In this chapter, we describe the structure, function and interactions of intestinal barrier, microbiota and brain-gut axis in both healthy and pathological conditions.

Adv Exp Med Biol. 2014;817:73-113

Gut-microbiota-brain axis and its effect on neuropsychiatric disorders with suspected immune dysregulation.

PURPOSE: Gut microbiota regulate intestinal function and health. However, mounting evidence indicates that they can also influence the immune and nervous systems and vice versa. This article reviews the bidirectional relationship between the gut microbiota and the brain, termed the microbiota-gut-brain (MGB) axis, and discusses how it contributes to the pathogenesis of certain disorders that may involve brain inflammation. METHODS: Articles were identified with a search of Medline (starting in 1980) by using the key words anxiety, attention-deficit hypersensitivity disorder (ADHD), autism, cytokines, depression, gut, hypothalamic-pituitary-adrenal (HPA) axis, inflammation, immune system, microbiota, nervous system, neurologic, neurotransmitters, neuroimmune conditions, psychiatric, and stress. FINDINGS: Various afferent or efferent pathways are involved in the MGB axis. Antibiotics, environmental and infectious agents, intestinal neurotransmitters/neuromodulators, sensory vagal fibers, cytokines, and essential metabolites all convey information to the central nervous system about the intestinal state. Conversely, the hypothalamic-pituitary-adrenal axis, the central nervous system regulatory areas of satiety, and neuropeptides released from sensory nerve fibers affect the gut microbiota composition directly or through nutrient availability. Such interactions seem to influence the pathogenesis of a number of disorders in which inflammation is implicated, such as mood disorder, autism-spectrum disorders, attention-deficit hypersensitivity disorder, multiple sclerosis, and obesity. IMPLICATIONS: Recognition of the relationship between the MGB axis and the neuroimmune systems provides a novel approach for better understanding and management of these disorders. Appropriate preventive measures early in life or corrective measures such as use of psychobiotics, fecal microbiota transplantation, and flavonoids are discussed.

Clin Ther. 2015 May 1;37(5):984-95

Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice.

Indigenous microbiota have several beneficial effects on host physiological functions; however, little is known about whether or not postnatal microbial colonization can affect the development of brain plasticity and a subsequent physiological system response. To test the idea that such microbes may affect the development of neural systems that govern the endocrine response to stress, we investigated hypothalamic-pituitary-adrenal (HPA) reaction to stress by comparing germfree (GF), specific pathogen free (SPF) and gnotobiotic mice. Plasma ACTH and corticosterone elevation in response to restraint stress was substantially higher in GF mice than in SPF mice, but not in response to stimulation with ether. Moreover, GF mice also exhibited reduced brain-derived neurotrophic factor expression levels in the cortex and hippocampus relative to SPF mice. The exaggerated HPA stress response by GF mice was reversed by reconstitution with Bifidobacterium infantis. In contrast, monoassociation with enteropathogenic Escherichia coli, but not with its mutant strain devoid of the translocated intimin receptor gene, enhanced the response to stress. Importantly, the enhanced HPA response of GF mice was partly corrected by reconstitution with SPF faeces at an early stage, but not by any reconstitution exerted at a later stage, which therefore indicates that exposure to microbes at an early developmental stage is required for the HPA system to become fully susceptible to inhibitory neural regulation. These results suggest that commensal microbiota can affect the postnatal development of the HPA stress response in mice.

J Physiol. 2004 Jul 1;558(Pt 1):263-75

Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses.

BACKGROUND: Adverse early life events are associated with a maladaptive stress response system and might increase the vulnerability to disease in later life. Several disorders have been associated with early life stress, ranging from depression to irritable bowel syndrome. This makes the identification of the neurobiological substrates that are affected by adverse experiences in early life invaluable. METHODS: The purpose of this study was to assess the effect of early life stress on the brain-gut axis. Male rat pups were stressed by separating them from their mothers for 3 hours daily between postnatal days 2-12. The control group was left undisturbed with their mothers. Behavior, immune response, stress sensitivity, visceral sensation, and fecal microbiota were analyzed. RESULTS: The early life stress increased the number of fecal boli in response to a novel stress. Plasma corticosterone was increased in the maternally separated animals. An increase in the systemic immune response was noted in the stressed animals after an in vitro lipopolysaccharide challenge. Increased visceral sensation was seen in the stressed group. There was an alteration of the fecal microbiota when compared with the control group. CONCLUSIONS: These results show that this form of early life stress results in an altered brain-gut axis and is therefore an important model for investigating potential mechanistic insights into stress-related disorders including depression and IBS.

Biol Psychiatry. 2009 Feb 1;65(3):263-7

Sinus health

Antibiotic use in relation to the risk of breast cancer.

CONTEXT: Use of antibiotics may be associated with risk of breast cancer through effects on immune function, inflammation, and metabolism of estrogen and phytochemicals; however, clinical data on the association between antibiotic use and risk of breast cancer are sparse. OBJECTIVE: To examine the association between use of antibiotics and risk of breast cancer. DESIGN, SETTING, AND PARTICIPANTS: Case-control study among 2,266 women older than 19 years with primary, invasive breast cancer (cases) enrolled in a large, nonprofit health plan for at least 1 year between January 1, 1993, and June 30, 2001, and 7953 randomly selected female health plan members (controls), frequency-matched to cases on age and length of enrollment. Cases were ascertained from the Surveillance, Epidemiology, and End Results cancer registry. Antibiotic use was ascertained from computerized pharmacy records. MAIN OUTCOME MEASURE: Association between extent of antibiotic use and risk of breast cancer. RESULTS: Increasing cumulative days of antibiotic use were associated with increased risk of incident breast cancer, adjusted for age and length of enrollment. For categories of increasing use (0, 1-50, 51-100, 101-500, 501-1,000, and > or =1,001 days), odds ratios (95% confidence intervals) for breast cancer were 1.00 (reference), 1.45 (1.24-1.69), 1.53 (1.28-1.83), 1.68 (1.42-2.00), 2.14 (1.60-2.88), and 2.07 (1.48-2.89) (P<.001 for trend). Increased risk was observed in all antibiotic classes studied and in a subanalysis having breast cancer fatality as the outcome. Among women with the highest levels of tetracycline or macrolide use, risk of breast cancer was not elevated in those using these antibiotics exclusively for acne or rosacea (indications that could be risk factors for breast cancer due to altered hormone levels), compared with those using them exclusively for respiratory tract infections, adjusted for age and length of enrollment (odds ratio, 0.91; 95% confidence interval, 0.44-1.87). CONCLUSIONS: Use of antibiotics is associated with increased risk of incident and fatal breast cancer. It cannot be determined from this study whether antibiotic use is causally related to breast cancer, or whether indication for use, overall weakened immune function, or other factors are pertinent underlying exposures. Although further studies are needed, these findings reinforce the need for prudent long-term use of antibiotics.

JAMA. 2004 Feb 18;291(7):827-35

Global warming will bring new fungal diseases for mammals.

Fungi are major pathogens of plants, other fungi, rotifers, insects, and amphibians, but relatively few cause disease in mammals. Fungi became important human pathogens only in the late 20th century, primarily in hosts with impaired immunity as a consequence of medical interventions or HIV infection. The relatively high resistance of mammals has been attributed to a combination of a complex immune system and endothermy. Mammals maintain high body temperatures relative to environmental temperatures, creating a thermally restrictive ambient for the majority of fungi. According to this view, protection given by endothermy requires a temperature gradient between those of mammals and the environment. We hypothesize that global warming will increase the prevalence of fungal diseases in mammals by two mechanisms: (i) increasing the geographic range of currently pathogenic species and (ii) selecting for adaptive thermotolerance for species with significant pathogenic potential but currently not pathogenic by virtue of being restricted by mammalian temperatures.

MBio. 2010 May 18;1(1)

Candida biofilms and their role in infection.

Pathogenic fungi in the genus Candida can cause both superficial and serious systemic disease, and are now recognized as major agents of hospital-acquired infection. Many Candida infections involve the formation of biofilms on implanted devices such as indwelling catheters or prosthetic heart valves. Biofilms of Candida albicans formed in vitro on catheter material consist of matrix-enclosed microcolonies of yeasts and hyphae, arranged in a bilayer structure. The biofilms are resistant to a range of antifungal agents currently in clinical use, including amphotericin B and fluconazole, and there appear to be multiple resistance mechanisms. Recent studies with mixed biofilms containing Candida and bacterial species suggest that extensive and striking interactions occur between the prokaryotic and eukaryotic cells in these adherent populations.

Trends Microbiol. 2003 Jan;11(1):30-6

The diagnosis and incidence of allergic fungal sinusitis.

OBJECTIVE: To reevaluate the current criteria for diagnosing allergic fungal sinusitis (AFS) and determine the incidence of AFS in patients with chronic rhinosinusitis (CRS). METHODS: This prospective study evaluated the incidence of AFS in 210 consecutive patients with CRS with or without polyposis, of whom 101 were treated surgically. Collecting and culturing fungi from nasal mucus require special handling, and novel methods are described. Surgical specimen handling emphasizes histologic examination to visualize fungi and eosinophils in the mucin. The value of allergy testing in the diagnosis of AFS is examined. RESULTS: Fungal cultures of nasal secretions were positive in 202 (96%) of 210 consecutive CRS patients. Allergic mucin was found in 97 (96%) of 101 consecutive surgical cases of CRS. Allergic fungal sinusitis was diagnosed in 94 (93%) of 101 consecutive surgical cases with CRS, based on histopathologic findings and culture results. Immunoglobulin E-mediated hypersensitivity to fungal allergens was not evident in the majority of AFS patients. CONCLUSION: The data presented indicate that the diagnostic criteria for AFS are present in the majority of patients with CRS with or without polyposis. Since the presence of eosinophils in the allergic mucin, and not a type I hypersensitivity, is likely the common denominator in the pathophysiology of AFS, we propose a change in terminology from AFS to eosinophilic fungal rhinosinusitis.

Mayo Clin Proc. 1999 Sep;74(9):877-84

Assessing risk factors for systemic fungal infections.

The incidence of invasive fungal infection has increased in recent years. Most infections are caused by Candida albicans and Aspergillus spp. but the emergence of other fungal infections is changing the spectrum of disease. Immunosuppression and breakdown of anatomical barriers such as the skin are the major risk factors for fungal infections. Health care workers encounter at-risk patients in various settings, including AIDS clinics and intensive care, transplantation and oncology units. Patients with prolonged and deep neutropenia (haematological malignancy patients) are most at risk and are therefore most likely to receive prophylactic therapy. Practical measures can be taken to avoid exposing the patient to fungi (air filtration, regular hand washing, avoiding plants and flowers) and antifungal agents can be administered to prevent systemic fungal infection. Most fungal infections have non-specific symptoms; this makes recognition of the signs and symptoms of the disease important but also makes diagnosis difficult and empirical treatment necessary. Some antifungal agents have limitations but new formulations will improve therapy and play a key role in future antifungal strategies.

Eur J Cancer Care (Engl). 2001 Mar;10(1):56-62

Dietary mycotoxins, co-exposure, and carcinogenesis in humans: short review.

Mycotoxins, toxic secondary metabolites of fungi, affect global agriculture so prolifically that they are virtually ubiquitous at some concentration in the average human diet. Studies of in vitro and in vivo toxicity are discussed, leading to investigations of co-exposed mycotoxins, as well as carcinogenic effects. Some of the most common and toxicologically significant mycotoxins, such as the aflatoxins, ochratoxins, fumonisins, deoxynivalenol, T-2 toxin, HT-2 toxin, patulin, zearalenone, and some ergot alkaloids are outlined. The wide variety of pathogenic mechanisms these compounds employ are shown capable of inducing a complex set of interactions. Of particular note are potential synergisms between mycotoxins with regard to carcinogenic attributable risk, indicating an important field for future study.

Mutat Res Rev Mutat Res . 2015 Oct-Dec; 766:32-41

The fungi: 1, 2, 3 ... 5.1 million species?

PREMISE OF THE STUDY: Fungi are major decomposers in certain ecosystems and essential associates of many organisms. They provide enzymes and drugs and serve as experimental organisms. In 1991, a landmark paper estimated that there are 1.5 million fungi on the Earth. Because only 70000 fungi had been described at that time, the estimate has been the impetus to search for previously unknown fungi. Fungal habitats include soil, water, and organisms that may harbor large numbers of understudied fungi, estimated to outnumber plants by at least 6 to 1. More recent estimates based on high-throughput sequencing methods suggest that as many as 5.1 million fungal species exist. METHODS: Technological advances make it possible to apply molecular methods to develop a stable classification and to discover and identify fungal taxa. KEY RESULTS: Molecular methods have dramatically increased our knowledge of Fungi in less than 20 years, revealing a monophyletic kingdom and increased diversity among early-diverging lineages. Mycologists are making significant advances in species discovery, but many fungi remain to be discovered. CONCLUSIONS: Fungi are essential to the survival of many groups of organisms with which they form associations. They also attract attention as predators of invertebrate animals, pathogens of potatoes and rice and humans and bats, killers of frogs and crayfish, producers of secondary metabolites to lower cholesterol, and subjects of prize-winning research. Molecular tools in use and under development can be used to discover the world's unknown fungi in less than 1000 years predicted at current new species acquisition rates.

Am J Bot . 2011 Mar;98(3):426-38

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