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Acceptability, Tolerability, and Estimates of Putative Treatment Effects of Probiotics as Adjunctive Treatment in Patients With Depression: A Randomized Clinical Trial.
Nikolova, VL, Cleare, AJ, Young, AH, Stone, JM
JAMA psychiatry. 2023;80(8):842-847
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About 60% of patients with major depressive disorder (MDD) do not fully respond to anti-depressant treatments. The microbiota-gut-brain axis is thought to be involved in the development of MDD, making the microbiome a promising target for new treatments. The aim of this double-blind, randomised, placebo-controlled trial, including 50 adult patients with major depressive disorder, was to evaluate the tolerability, acceptability and efficacy of a multi-strain probiotic supplement for 8 weeks as an adjunctive to antidepressant drugs. There were no serious adverse events; all reported non-serious events were of gastrointestinal nature and more common in the probiotic group (it was not reported whether the difference was statistically significant). A high adherence rate of 97.2% suggests a high level of acceptability. Depressive mood symptoms improved significantly more in the probiotic group. Greater improvements in anxiety in the probiotic were also seen in some, but not all anxiety scales. The authors concluded that a multi-strain probiotic supplement is a promising adjunct to anti-depressant treatment in patients with MDD, with high tolerability and acceptability.
Abstract
IMPORTANCE The microbiota-gut-brain axis is a promising target for novel treatments for mood disorders, such as probiotics. However, few clinical trials have been conducted, and further safety and efficacy data are needed to support this treatment approach. OBJECTIVE To provide acceptability and tolerability data and estimates of intervention effect size for probiotics as adjunctive treatment for patients with major depressive disorder (MDD). DESIGN, SETTING, AND PARTICIPANTS In this single-center, double-blind, placebo-controlled pilot randomized clinical trial, adults aged 18 to 55 years with MDD taking antidepressant medication but having an incomplete response were studied. A random sample was recruited from primary and secondary care services and general advertising in London, United Kingdom. Data were collected between September 2019 and May 2022 and analyzed between July and September 2022. INTERVENTION Multistrain probiotic (8 billion colony-forming units per day) or placebo daily for 8 weeks added to ongoing antidepressant medication. MAIN OUTCOMES AND MEASURES The pilot outcomes of the trial were retention, acceptability, tolerability, and estimates of putative treatment effect on clinical symptoms (depression: Hamilton Depression Rating Scale [HAMD-17] and Inventory of Depressive Symptomatology [IDS] scores; anxiety: Hamilton Anxiety Rating Scale [HAMA] and General Anxiety Disorder [GAD-7] scores) to be used as indicators for a definitive trial. RESULTS Of 50 included participants, 49 received the intervention and were included in intent-to-treat analyses; of these, 39 (80%) were female, and the mean (SD) age was 31.7 (9.8) years. A total of 24 were randomized to probiotic and 25 to placebo. Attrition was 8% (1 in the probiotic group and 3 in the placebo group), adherence was 97.2%, and there were no serious adverse reactions. For the probiotic group, mean (SD) HAMD-17 scores at weeks 4 and 8 were 11.00 (5.13) and 8.83 (4.28), respectively; IDS, 30.17 (11.98) and 25.04 (11.68); HAMA, 11.71 (5.86) and 8.17 (4.68); and GAD-7, 7.78 (4.12) and 7.63 (4.77). For the placebo group, mean (SD) HAMD-17 scores at weeks 4 and 8 were 14.04 (3.70) and 11.09 (3.22), respectively; IDS, 33.82 (9.26) and 29.64 (9.31); HAMA, 14.70 (5.47) and 10.95 (4.48); and GAD-7, 10.91 (5.32) and 9.48 (5.18). Standardized effect sizes (SES) from linear mixed models demonstrated that the probiotic group attained greater improvements in depressive symptoms according to HAMD-17 scores (week 4: SES, 0.70; 95% CI, 0.01-0.98) and IDS Self Report scores (week 8: SES, 0.64; 95% CI, 0.03-0.87) as well as greater improvements in anxiety symptoms according to HAMA scores (week 4: SES, 0.67; 95% CI, 0-0.95; week 8: SES, 0.79; 95% CI, 0.06-1.05), but not GAD-7 scores (week 4: SES, 0.57; 95% CI, -0.01 to 0.82; week 8: SES, 0.32; 95% CI, -0.19 to 0.65), compared with the placebo group. CONCLUSIONS AND RELEVANCE The acceptability, tolerability, and estimated effect sizes on key clinical outcomes are promising and encourage further investigation of probiotics as add-on treatment for people with MDD in a definitive efficacy trial. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03893162.
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COVID-19 and chronic fatigue syndrome: Is the worst yet to come?
Wostyn, P
Medical hypotheses. 2021;146:110469
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A proportion of COVID-19 patients develop post-COVID-19 syndrome, with long-term symptoms such as persistent fatigue, muscle pains, depressive symptoms, and non-restorative sleep, similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In this article the author presents his medical hypothesis that, in a subset of patients at least, post-COVID-19 fatigue syndrome may result from damage to olfactory (smell) sensory neurons, which in turn may lead to toxic build-up within the central nervous system (CNS) through congestion of the glymphatic system (the waste clearance system of the CNS). Loss of smell and altered sensation of taste have been reported in 33–80% of COVID-19 patients but the underlying mechanisms are not yet known. Most of these patients regain their sense of smell within 1-3 weeks, suggesting that the virus does not affect the olfactory neurons but their surrounding supporting cells. Some patients, however, do not regain their sense of smell for months which may point to the destruction of neurons. A decrease in olfactory neurons may affect the flow of the cerebrospinal fluid (CSF) in an area important for CSF drainage. This may cause an increase in intracranial pressure (idiopathic intracranial hypertension, IIH) and congestion of the glymphatic system, which have been associated with chronic fatigue syndrome, as well as with headaches and tinnitus, symptoms also commonly seen in COVID-19 patients. The author states that if this hypothesis is confirmed, glymphatic-lymphatic drainage therapies, such as osteopathy, should be recommended as early treatment for patients with post-COVID-19 fatigue syndrome.
Abstract
There has been concern about possible long-term sequelae resembling myalgic encephalomyelitis/chronic fatigue syndrome in COVID-19 patients. Clarifying the mechanisms underlying such a "post-COVID-19 fatigue syndrome" is essential for the development of preventive and early treatment methods for this syndrome. In the present paper, by integrating insights pertaining to the glymphatic system and the nasal cerebrospinal fluid outflow pathway with findings in patients with chronic fatigue syndrome, idiopathic intracranial hypertension, and COVID-19, I provide a coherent conceptual framework for understanding the pathophysiology of post-COVID-19 fatigue syndrome. According to this hypothesis, this syndrome may result from damage to olfactory sensory neurons, causing reduced outflow of cerebrospinal fluid through the cribriform plate, and further leading to congestion of the glymphatic system with subsequent toxic build-up within the central nervous system. I further postulate that patients with post-COVID-19 fatigue syndrome may benefit from cerebrospinal fluid drainage by restoring glymphatic transport and waste removal from the brain. Obviously, further research is required to provide further evidence for the presence of this post-viral syndrome, and to provide additional insight regarding the relative contribution of the glymphatic-lymphatic system to it. Other mechanisms may also be involved. If confirmed, the glymphatic-lymphatic system could represent a target in combating post-COVID-19 fatigue syndrome. Moreover, further research in this area could also provide new insights into the understanding of chronic fatigue syndrome.
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Systemic Perturbations in Amine and Kynurenine Metabolism Associated with Acute SARS-CoV-2 Infection and Inflammatory Cytokine Responses.
Lawler, NG, Gray, N, Kimhofer, T, Boughton, B, Gay, M, Yang, R, Morillon, AC, Chin, ST, Ryan, M, Begum, S, et al
Journal of proteome research. 2021;20(5):2796-2811
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Understanding the action of Covid-19 and the host response is paramount to developing personalised treatments and improving recovery rates. This cohort study of 64 individuals aimed to determine underlying biological signatures of individuals with severe and mild Covid-19, to potentially risk stratify patients and provide targeted treatments. The results showed that several biological signatures were disrupted with infection, some increased and some decreased and indicated possible liver, brain, and inflammatory disruptions. There was also evidence of a time-based pattern of biological disruptions, which may be of significance when looking at “long Covid” syndrome. It was concluded that identifying the hosts biological response to the virus offers insights into the viral action on the body. The action of Covid-19 on processes in the brain may indicate a secondary effect of the virus. Using biological markers to predict recovery of individuals suffering from “long Covid” may also be a possibility. This study could be used by healthcare professionals to understand which biological processes may be disrupted during Covid-19 infection, with the view to testing to understand who may be at risk of long-term complications post recovery.
Abstract
We performed quantitative metabolic phenotyping of blood plasma in parallel with cytokine/chemokine analysis from participants who were either SARS-CoV-2 (+) (n = 10) or SARS-CoV-2 (-) (n = 49). SARS-CoV-2 positivity was associated with a unique metabolic phenotype and demonstrated a complex systemic response to infection, including severe perturbations in amino acid and kynurenine metabolic pathways. Nine metabolites were elevated in plasma and strongly associated with infection (quinolinic acid, glutamic acid, nicotinic acid, aspartic acid, neopterin, kynurenine, phenylalanine, 3-hydroxykynurenine, and taurine; p < 0.05), while four metabolites were lower in infection (tryptophan, histidine, indole-3-acetic acid, and citrulline; p < 0.05). This signature supports a systemic metabolic phenoconversion following infection, indicating possible neurotoxicity and neurological disruption (elevations of 3-hydroxykynurenine and quinolinic acid) and liver dysfunction (reduction in Fischer's ratio and elevation of taurine). Finally, we report correlations between the key metabolite changes observed in the disease with concentrations of proinflammatory cytokines and chemokines showing strong immunometabolic disorder in response to SARS-CoV-2 infection.
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Immediate and long-term consequences of COVID-19 infections for the development of neurological disease.
Heneka, MT, Golenbock, D, Latz, E, Morgan, D, Brown, R
Alzheimer's research & therapy. 2020;12(1):69
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Covid-19 may cause brain dysfunction evidenced by symptoms individuals experience once they have contracted the disease. Loss of smell, taste and confusion have all been reported by patients and a number of severe cases have reported incidences of stroke. These are all of concern, as Covid-19 can severely affect the elderly who ordinarily are the most likely to suffer from brain disorders. This small review paper of 27 studies stated that there are four possible ways in which Covid-19 may affect the brain, which put Covid-19 sufferers at an increased risk of long-term brain disorders. This was supported by findings, which showed one third of Covid-19 patients leave hospital with evidence of brain dysfunction. Inflammation was heavily reviewed by the authors as a possible causal factor. It was concluded that patients who survive Covid-19 infection are at an increased risk for developing brain disorders such as Alzheimer's disease, however it was acknowledged that further studies are required. Clinicians could use this study to understand the possible need for both short-term and long-term monitoring of brain function in individuals who have survived Covid-19, especially if they are elderly.
Abstract
Increasing evidence suggests that infection with Sars-CoV-2 causes neurological deficits in a substantial proportion of affected patients. While these symptoms arise acutely during the course of infection, less is known about the possible long-term consequences for the brain. Severely affected COVID-19 cases experience high levels of proinflammatory cytokines and acute respiratory dysfunction and often require assisted ventilation. All these factors have been suggested to cause cognitive decline. Pathogenetically, this may result from direct negative effects of the immune reaction, acceleration or aggravation of pre-existing cognitive deficits, or de novo induction of a neurodegenerative disease. This article summarizes the current understanding of neurological symptoms of COVID-19 and hypothesizes that affected patients may be at higher risk of developing cognitive decline after overcoming the primary COVID-19 infection. A structured prospective evaluation should analyze the likelihood, time course, and severity of cognitive impairment following the COVID-19 pandemic.
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Potential causal factors of CFS/ME: a concise and systematic scoping review of factors researched.
Muller, AE, Tveito, K, Bakken, IJ, Flottorp, SA, Mjaaland, S, Larun, L
Journal of translational medicine. 2020;18(1):484
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Chronic fatigue syndrome /myalgic encephalomyelitis (CFS/ME) is complex and probably triggered by several interconnected factors and the identification of these is essential to develop better treatments and preventative measures. This systematic scoping review of 1161 studies aimed to discuss potential causal factors of CFS/ME. The results showed that there were several main causal factors that were investigated in the literature and no single factor dominated the research; immunological, psychological/psychosocial/socioeconomic, infectious, and neuroendocrinal/hormonal/metabolic. Studies varied in their design and methods. Interestingly research in this area was at its highest before 1995 and from 2015-2019, studies have markedly decreased. It was concluded that large variations in methods and design of studies of causal factor studies, is problematic. More large, well designed studies are required especially as research has declined recently and considering post covid-19 fatigue. This study could be used by healthcare professionals to understand where there are gaps in the research to design more robust studies in the future.
Abstract
BACKGROUND Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is understood as a complex condition, likely triggered and sustained by an interplay of biological, psychological, and social factors. Little oversight exists of the field of causal research. This systematic scoping review explores potential causal factors of CFS/ME as researched by primary studies. METHODS We searched eight databases for primary studies that examined potential causal factors of CFS/ME. Based on title/abstract review, two researchers independently sorted each study's factors into nine main categories and 71 subordinate categories, using a system developed with input given during a 2018 ME conference, specialists and representatives from a ME patient advocacy group, and using BMJ Best Practice's description of CFS/ME etiology. We also extracted data related to study design, size, diagnostic criteria and comparison groups. RESULTS We included 1161 primary studies published between January 1979 and June 2019. Based on title/abstract analysis, no single causal factor dominated in these studies, and studies reported a mean of 2.73 factors. The four most common factors were: immunological (297 studies), psychological (243), infections (198), and neuroendocrinal (198). The most frequent study designs were case-control studies (894 studies) comparing CFS/ME patients with healthy participants. More than half of the studies (that reported study size in the title/abstract) included 100 or fewer participants. CONCLUSION The field of causal hypotheses of CFS/ME is diverse, and we found that the studies examined all the main categories of possible factors that we had defined a priori. Most studies were not designed to adequately explore causality, rather to establish hypotheses. We need larger studies with stronger study designs to gain better knowledge of causal factors of CFS/ME.
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Maternal anxiety and diet quality among mothers and toddlers from low-income households.
Trude, ACB, Black, MM, Surkan, PJ, Hurley, KM, Wang, Y
Maternal & child nutrition. 2020;16(4):e12992
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Childhood obesity is increasing and is an indicator that obesity may develop in adulthood. Mothers have a large influence on children’s weight-related behaviours and diet quality, but mental well-being of the mother in relation to this is understudied. Mothers from low-income households may be susceptible to lower mental well-being and low diet quality potentially influencing their children. This observational study of 277 low-income mother-toddler relationships aimed to examine the association of maternal anxiety and toddler diet quality over six months. The results showed that higher maternal anxiety was associated with lower maternal diet quality and lower toddler diet quality. It was concluded that high anxiety in mothers with toddlers from low-income households is associated with poorer diet quality in both the mother and toddler. However, it should be noted that whether anxiety is causing poor diet or poor diet is causing anxiety cannot be determined. This study could be used by healthcare professionals to include nutritional recommendations with anxiety management to improve parental and toddler diet.
Abstract
We evaluated the association between maternal anxiety score and diet quality over time among mothers and toddlers in low-income families. Longitudinal data were collected from 267 mother-toddler dyads in an obesity prevention trial. Participants were recruited from the Special Supplemental Nutrition Program for Women, Infants and Children and paediatric clinics between 2007 and 2010. Dyads were assessed at study enrolment (Time 1), 6-month (Time 2), and 12-month follow-up (Time 3). On the basis of a 1-day 24-hr dietary recall, we estimated maternal and toddler diet quality using the Healthy Eating Index 2015. Anxiety, a time-varying variable, was assessed via the State-Trait Anxiety Inventory. Associations between maternal anxiety score and maternal and toddler diet quality over time were assessed in adjusted mixed models. Maternal and toddler diet quality were positively correlated (r = .48, p < .001). Higher maternal anxiety scores were related to lower toddler Healthy Eating Index scores (b = -0.51, 95% confidence interval, CI [-0.87, -0.15]) with no significant variation over time. The relation between maternal diet quality and anxiety score varied over time (b = 0.28, p = .03, for time-anxiety interaction). Higher maternal anxiety scores were associated with lower maternal diet quality at Time 1 (b = -0.71, 95% CI [-1.09, 0.34]) and at Time 2 (b = -0.51, 95% CI [-0.97, -0.05]), but not at Time 3 (b = -0.14, 95% CI [-0.54, 0.26]). Findings suggest that mothers and toddlers exhibited similar low-quality dietary patterns and that lower diet quality was associated with higher maternal anxiety scores. Approaches to enhance diet quality may consider incorporating anxiety-reducing strategies into maternal and toddler care and feeding behaviour guidelines.
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The effect of exercise on anxiety in the elderly worldwide: a systematic review and meta-analysis.
Kazeminia, M, Salari, N, Vaisi-Raygani, A, Jalali, R, Abdi, A, Mohammadi, M, Daneshkhah, A, Hosseinian-Far, M, Shohaimi, S
Health and quality of life outcomes. 2020;18(1):363
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Anxiety occurs in all age groups. In the US 15-52% of the elderly have anxiety related symptoms and these tend to manifest as physical problems such as insomnia, behavioural, sensory, urinary, cardiovascular, and gastrointestinal disorders. The elderly are more prone to anxiety due to loss or reduction of self-esteem, reduction of activity and stimulation, loss of friends and relatives, loss of physical independence, chronic diseases, changes in daily life or living environment, fear of death and lack of social support. Physical activity is a simple, cheap therapeutic approach. There are several preliminary studies on the effect of exercise training on reducing anxiety in the elderly, but there are inconsistencies between their results. The purpose of this meta-analysis is to resolve such inconsistencies. This meta-analysis included 19 studies published from 1999 until December 2019. Results of this study showed that sport significantly reduces anxiety in the elderly. Therefore, a regular exercise plan can be considered as a part of the elderly care program.
Abstract
BACKGROUND Physical activity and exercise are among the most important, simplest, and cheapest approaches to anxiety treatment, especially for the elderly. Their positive effects on improvement of mental disorders in the elderly have attracted a considerable level of attention. Therefore, the present study was conducted to determine the effect of sport on reducing anxiety in the elderly using meta-analysis. METHODS In this study, national and international databases of SID, MagIran, IranMedex, IranDoc, Cochrane, Embase, ScienceDirect, Scopus, PubMed, and Web of Science were searched to find studies published electronically from 1999 to 2019. Heterogeneity between the collected studies was determined using the Cochran's test (Q) and I2. Due to presence of heterogeneity, the random effects model was used to estimate the standardized mean difference of sport test scores obtained from the measurement of anxiety reduction among the elderly, between the intervention group before and after the test. RESULTS In this meta-analysis and systematic review, 19 papers finally met the inclusion criteria. The overall sample size of all collected studies for the meta-analysis was 841 s. Mean anxiety score before and after intervention were 38.7 ± 5.6 33.7 ± 3.4 respectively, denoting a decrease in anxiety score after intervention. CONCLUSION Results of this study indicates that Sport significantly reduces Anxiety in the Elderly. Therefore, a regular exercise program can be considered as a part of the elderly care program.
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Cannabidiol in Anxiety and Sleep: A Large Case Series.
Shannon, S, Lewis, N, Lee, H, Hughes, S
The Permanente journal. 2019;23:18-041
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After the psychoactive tetrahydrocannabinol (THC), cannabidiol (CBD) is the second most abundant, and non-psychoactive, cannabinoid of the cannabis plant. CBD appears to have a calming effect on the central nervous system, however, clinical evidence for its use is limited. The purpose of the present study is to describe the effects of CBD on anxiety and sleep. A retrospective chart review of 72 adult patients with primary concerns of anxiety (47 patients) or poor sleep (25 patients) and treated with CBD for at least 1 month as an adjunct to usual treatment, was conducted at a large integrative psychiatric outpatient clinic. Nearly all patients were given CBD 25 mg/d in capsule form. If anxiety complaints predominated, the dosing was every morning, after breakfast. If sleep complaints predominated, the dosing was every evening, after dinner. Monthly visits included clinical evaluation and documentation of patients’ anxiety and sleep status. Whilst anxiety scores showed a rapid and sustained decrease over the three months study period, no sustained improvements in sleep was seen. The treatment with CBD was generally well accepted and tolerated. The authors conclude that these results support the existing scientific evidence, and that more clinical research is needed to provide better clinical guidance on the use of CBD.
Abstract
CONTEXT Cannabidiol (CBD) is one of many cannabinoid compounds found in cannabis. It does not appear to alter consciousness or trigger a "high." A recent surge in scientific publications has found preclinical and clinical evidence documenting value for CBD in some neuropsychiatric disorders, including epilepsy, anxiety, and schizophrenia. Evidence points toward a calming effect for CBD in the central nervous system. Interest in CBD as a treatment of a wide range of disorders has exploded, yet few clinical studies of CBD exist in the psychiatric literature. OBJECTIVE To determine whether CBD helps improve sleep and/or anxiety in a clinical population. DESIGN A large retrospective case series at a psychiatric clinic involving clinical application of CBD for anxiety and sleep complaints as an adjunct to usual treatment. The retrospective chart review included monthly documentation of anxiety and sleep quality in 103 adult patients. MAIN OUTCOME MEASURES Sleep and anxiety scores, using validated instruments, at baseline and after CBD treatment. RESULTS The final sample consisted of 72 adults presenting with primary concerns of anxiety (n = 47) or poor sleep (n = 25). Anxiety scores decreased within the first month in 57 patients (79.2%) and remained decreased during the study duration. Sleep scores improved within the first month in 48 patients (66.7%) but fluctuated over time. In this chart review, CBD was well tolerated in all but 3 patients. CONCLUSION Cannabidiol may hold benefit for anxiety-related disorders. Controlled clinical studies are needed.
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Effects of Probiotics on Cognitive Reactivity, Mood, and Sleep Quality.
Marotta, A, Sarno, E, Del Casale, A, Pane, M, Mogna, L, Amoruso, A, Felis, GE, Fiorio, M
Frontiers in psychiatry. 2019;10:164
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Gut and brain communicate with each other via the so-called gut-brain axis, which involves the neural, endocrine, and immune systems. The intestinal microbiota are thought to play a crucial role in this bidirectional communication. The aim of this double-blind, placebo-controlled pilot study was to investigate whether a multi-strain probiotic supplement can improve psychological wellbeing in healthy volunteers. 33 participants completed the trial and received either the probiotic powder or placebo for 6 weeks. Psychological assessments through a number of questionnaires relating to mood, sleep and personality aspects were carried out at baseline, weeks 3 and 6 and after a 3 week washout period. Significant improvements were seen in sleep and several aspects of mood in the probiotic but not the control group, although there were no statistically significant differences between the two groups. The authors conclude that probiotics might help to promote psychological well-being and speculate that probiotics, by interacting with intestinal microbiota, can facilitate the production of precursors of neuroactive substances involved in modulating emotional processing, sleep, and other brain functions.
Abstract
Recent demonstration that probiotics administration has positive effects on mood state in healthy populations suggests its possible role as an adjunctive therapy for depression in clinical populations and as a non-invasive strategy to prevent depressive mood state in healthy individuals. The present study extends current knowledge on the beneficial effects of probiotics on psychological well-being, as measured by changes in mood (e.g., cognitive reactivity to sad mood, depression, and anxiety), personality dimensions, and quality of sleep, which have been considered as related to mood. For this double-blind, placebo-controlled study 38 healthy volunteers assigned to an experimental or control group assumed a daily dose of a probiotic mixture (containing Lactobacillus fermentum LF16, L. rhamnosus LR06, L. plantarum LP01, and Bifidobacterium longum BL04) or placebo, respectively, for 6 weeks. Mood, personality dimensions, and sleep quality were assessed four times (before the beginning of the study, at 3 and 6 weeks, and at 3 weeks of washout). A significant improvement in mood was observed in the experimental group, with a reduction in depressive mood state, anger, and fatigue, and an improvement in sleep quality. No between-groups differences were found. These findings corroborate the positive effect of probiotics on mood state and suggest that probiotics administration may improve psychological well-being by ameliorating aspects of mood and sleep quality.
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Tryptophan Metabolism in Inflammaging: From Biomarker to Therapeutic Target.
Sorgdrager, FJH, Naudé, PJW, Kema, IP, Nollen, EA, Deyn, PP
Frontiers in immunology. 2019;10:2565
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Inflammation is a normal physiological process activated by the immune system in response to injury or infection. As we age, the immune system changes and the balance between pro- and anti-inflammatory agents can shift. This causes a chronic inflammatory state referred to as inflammaging. The rate of inflammaging is strongly associated with age-related disability, disease and mortality. The way in which the essential amino acid tryptophan (Trp) is broken down affects inflammation. If it is converted to kynurenine (Kyn) and its metabolites, inflammation is modulated. Studies have shown that the Kyn/Trp ratio, measured in blood, is strongly associated with ageing in humans. It could therefore be a useful marker to predict the onset of age-related diseases. This review discusses the metabolism of Trp and the links to inflammation. The authors hypothesize how intervening in these pathways could impact health- and lifespan. Future studies are needed to confirm the value of Trp metabolism as a biomarker for (un)healthy ageing and as drug target for inflammaging-related disease.
Abstract
Inflammation aims to restore tissue homeostasis after injury or infection. Age-related decline of tissue homeostasis causes a physiological low-grade chronic inflammatory phenotype known as inflammaging that is involved in many age-related diseases. Activation of tryptophan (Trp) metabolism along the kynurenine (Kyn) pathway prevents hyperinflammation and induces long-term immune tolerance. Systemic Trp and Kyn levels change upon aging and in age-related diseases. Moreover, modulation of Trp metabolism can either aggravate or prevent inflammaging-related diseases. In this review, we discuss how age-related Kyn/Trp activation is necessary to control inflammaging and alters the functioning of other metabolic faiths of Trp including Kyn metabolites, microbiota-derived indoles and nicotinamide adenine dinucleotide (NAD+). We explore the potential of the Kyn/Trp ratio as a biomarker of inflammaging and discuss how intervening in Trp metabolism might extend health- and lifespan.