Melatonin: Roles in influenza, Covid-19, and other viral infections.
Reviews in medical virology. 2020;30(3):e2109
Plain language summary
Viruses like influenza and coronaviruses change quickly, making it challenging to develop effective treatments and vaccines in a short time frame. Consequently, the use of generic substances that limit viral effects are of high interest. In this paper, the authors summarize a range of mechanisms in which melatonin can alter the impact of virus infections and infection-associated inflammatory overdrive aka cytokine storm. Melatonin, the sleep hormone, is well known for its potent antioxidant and anti-inflammatory action. It seems highly likely that melatonin can modulate the cellular function of all cells, mostly via mitochondrial function. This is particularly relevant in immune cells. For example, the daytime variance in immune function seems to be closely linked with mitochondrial activity and energy production. Other relevant mechanisms described are the antiviral role of melatonin-induced sirtuins - proteins that regulate cellular health-, the impact of viruses on cell coordinating microRNA, the role of the gut microbiome and gut permeability, as well as sympathetic nervous system activation and the protective effects of parasympathetic activation. Also considered are pre-existing health conditions and conditions that are linked with a decline in melatonin along with ageing, all being groups in which severity of viral infections is felt. This paper may be of interest to those who like to explore in more depth the mechanisms behind melatonin and its ability to influence viral disease progression.
There is a growing appreciation that the regulation of the melatonergic pathways, both pineal and systemic, may be an important aspect in how viruses drive the cellular changes that underpin their control of cellular function. We review the melatonergic pathway role in viral infections, emphasizing influenza and covid-19 infections. Viral, or preexistent, suppression of pineal melatonin disinhibits neutrophil attraction, thereby contributing to an initial "cytokine storm", as well as the regulation of other immune cells. Melatonin induces the circadian gene, Bmal1, which disinhibits the pyruvate dehydrogenase complex (PDC), countering viral inhibition of Bmal1/PDC. PDC drives mitochondrial conversion of pyruvate to acetyl-coenzyme A (acetyl-CoA), thereby increasing the tricarboxylic acid cycle, oxidative phosphorylation, and ATP production. Pineal melatonin suppression attenuates this, preventing the circadian "resetting" of mitochondrial metabolism. This is especially relevant in immune cells, where shifting metabolism from glycolytic to oxidative phosphorylation, switches cells from reactive to quiescent phenotypes. Acetyl-CoA is a necessary cosubstrate for arylalkylamine N-acetyltransferase, providing an acetyl group to serotonin, and thereby initiating the melatonergic pathway. Consequently, pineal melatonin regulates mitochondrial melatonin and immune cell phenotype. Virus- and cytokine-storm-driven control of the pineal and mitochondrial melatonergic pathway therefore regulates immune responses. Virus-and cytokine storm-driven changes also increase gut permeability and dysbiosis, thereby suppressing levels of the short-chain fatty acid, butyrate, and increasing circulating lipopolysaccharide (LPS). The alterations in butyrate and LPS can promote viral replication and host symptom severity via impacts on the melatonergic pathway. Focussing on immune regulators has treatment implications for covid-19 and other viral infections.
Using psychoneuroimmunity against COVID-19.
Brain, behavior, and immunity. 2020;87:4-5
Plain language summary
This viewpoint article raises awareness of the threat of COVID-19 poses to psychiatric patients who are in mental health hospitals. Those patients appear to have a much elevated mortality rate and are potentially more vulnerable to the effects of panic/anxiety due to the pandemic. Their lifestyle choices, influenced by fears about the virus, may also have a negative effect on their immunity. The article also raises the issue of the effects the pandemic and associated changes to day-to-day life can have on the mental and general health of the rest of the population, and in particular to mental health professionals, whose ability to care for their psychiatric patients may be impaired. The authors also briefly discuss the psychological and immunological mechanisms that connect our mental state to the ability of our immune system to fight infections, and the impact of our lifestyles and environments. To summarise they state that infected patients, uninfected quarantined individuals and medical professionals all require mental health supporting strategies, and that epidemiological studies of potential long-term psychiatric consequences are essential.
The worldwide outbreak of coronavirus disease 2019 (COVID-19) raises concerns of widespread panic and anxiety in individuals subjected to the real or perceived threat of the virus. Compared to general populations, patients who are institutionalized in a closed unit are also very vulnerable to COVID-19 infection and complications. This crisis touched on difficult issues of not only psychiatric care and ethics, but also psychological impacts to psychiatric care givers. In this Viewpoint, we address both physical and biopsychosocial aspects of this infection, as well as the psychoneuroimmunity of preventive strategies of healthy lifestyle, regular exercise, balanced nutrition, quality sleep and a strong connection with people. Social distancing and wearing masks might help us from pathogen exposure, yet such these measures also prevent us from expressing compassion and friendliness. Therefore, all forms of psychological support should be routinely implemented not only to consider psychological resilience but also to enhance psychoneuroimmunity against COVID-19.
Predictors of chronic fatigue in adolescents six months after acute Epstein-Barr virus infection: A prospective cohort study.
Brain, behavior, and immunity. 2019;75:94-100
Plain language summary
Chronic fatigue is defined as substantial fatigue lasting for more than six months. The main aim of this study is to investigate predictors of chronic fatigue six months after an acute Epstein-Barr virus (EBV) infection. This study includes the prospective results from the first six months of the CEBA project (chronic fatigue following acute Epstein-Barr virus infection in adolescents), which encompasses a prospective, a cross-sectional and a randomized controlled design with a total follow-up time of 21 months. A total of 200 adolescents with EBV and 70 healthy controls were included. Results indicate that fatigue six months after acute EBV infection is significantly and independently predicted by baseline clinical symptoms, functional impairments, negative emotions, verbal memory, plasma c-reactive protein (CRP) and plasma vitamin B12. On average, baseline CRP levels were significantly lower in the acute EBV infection group as compared to healthy controls. Authors conclude that development of fatigue is to a larger extent predicted by baseline variables related to symptoms and functions than to baseline variables reflecting infectious and immune processes.
INTRODUCTION Acute Epstein-Barr virus (EBV) infection is a trigger of chronic fatigue and Chronic Fatigue Syndrome (CFS). This study investigated baseline predictors of chronic fatigue six months after an acute EBV infection. MATERIALS AND METHODS A total of 200 adolescents (12-20 years old) with acute EBV infection were assessed for 149 possible baseline predictors and followed prospectively. We performed linear regression to assess possible associations between baseline predictors and fatigue (Chalder Fatigue Questionnaire total score) six months after the acute EBV infection. A total of 70 healthy controls were included for cross-sectional reference. This study is part of the CEBA-project (Chronic fatigue following acute Epstein-Barr virus infection in adolescents). RESULTS In the final multiple linear regression model, fatigue six months after acute EBV infection was significantly and independently predicted by the following baseline variables (regression coefficient B[95% CI]): Sensory sensitivity (0.8[0.09-1.6]), pain severity (0.2[0.02-0.3]), functional impairment (1000 steps/day) (-0.3[-0.5 to -0.08]), negative emotions (anxiety) (0.4[0.2-0.6]), verbal memory (correct word recognition) (1.7[0.1-3.3]), plasma C-reactive protein (2.8[1.1-4.4] for CRP values >0.86) and plasma Vitamin B12 (-0.005[-0.01 to -0.001]). CONCLUSIONS Development of fatigue after acute EBV infection is to a larger extent predicted by baseline variables related to symptoms and functions than to baseline variables reflecting infectious and immune processes. TRIAL REGISTRATION ClinicalTrials, ID: NCT02335437, https://clinicaltrials.gov/ct2/show/NCT02335437.
A Large Randomized Trial: Effects of Mindfulness-Based Stress Reduction (MBSR) for Breast Cancer (BC) Survivors on Salivary Cortisol and IL-6.
Biological research for nursing. 2019;21(1):39-49
Plain language summary
Breast cancer survivors (BCS) often experience physiological and psychological stressors related to their diagnosis and treatment, and a disruption of cortisol function can affect cancer risk and progression. Increased levels of the stress hormone cortisol and interleukin-6 (IL-6), a pro-inflammatory immune mediator, have been associated with acute and chronic stress levels. Mindfulness-Based Stress Reduction (MBSR) is a clinical stress-reducing program, which has been found to decrease psychological and physical symptoms associated with stress. The purpose of this randomised study, involving 299 BCS, was to evaluate the efficacy of MBSR in reducing cortisol and IL-6 levels, compared to a usual-care control treatment. Statistically significant reductions in cortisol levels were seen after the delivery of the MBSR program at both time points (week 1 and 6), and at week 6 only for IL-6. There was no significant difference in change in cortisol or IL6 levels over time between the MBSR and the usual-care groups. An association was observed between levels of IL-6 and psychological and physical symptoms and quality of life, but not for cortisol. The authors conclude that MBSR can alleviate the stress response in the short term for breast cancer survivors.
Breast cancer survivors (BCS) often experience psychological and physiological symptoms after cancer treatment. Mindfulness-based stress reduction (MBSR), a complementary and alternative therapy, has reduced subjective measures of stress, anxiety, and fatigue among BCS. Little is known, however, about how MBSR affects objective markers of stress, specifically the stress hormone cortisol and the pro-inflammatory cytokine interleukin-6 (IL-6). In the present study, BCS ( N = 322) were randomly assigned to a 6-week MBSR program for BC or usual-care control. Measurements of cortisol, IL-6, symptoms, and quality of life were obtained at orientation and 6 weeks. Cortisol and IL-6 were also measured prior to and after the MBSR(BC) class Weeks 1 and 6. The mean age of participants was 56.6 years and 69.4% were White non-Hispanic. Most had Stage I (33.8%) or II (35.7%) BC, and 35.7% had received chemotherapy and radiation. Cortisol levels were reduced immediately following MBSR(BC) class compared to before the class Weeks 1 and 6 (Wilcoxon-signed rank test; p < .01, d = .52-.56). IL-6 was significantly reduced from pre- to postclass at Week 6 (Wilcoxon-signed rank test; p < .01, d = .21). No differences were observed between the MBSR(BC) and control groups from baseline to Week 6 using linear mixed models. Significant relationships with small effect sizes were observed between IL-6 and both symptoms and quality of life in both groups. Results support the use of MBSR(BC) to reduce salivary cortisol and IL-6 levels in the short term in BCS.
Gut dysbiosis: a potential link between increased cancer risk in ageing and inflammaging.
The Lancet. Oncology. 2018;19(6):e295-e304
Plain language summary
This study looks at the important role our gut bacterial and commensal microbes play in supporting immunity and potentially reducing the risk of cancer from aging. Cancer risk increases as we age and is one of the main causes of reduced life expectancy. Our gut microbiome changes continually in response to diet, lifestyle, infection, and activation of immune responses. Gut dysbiosis is characterised by a shift towards proinflammatory commensals and a reduction of beneficial microbes, which can cause impairment and leakiness of the intestinal barrier. This is thought to trigger inflammaging or rather aging in a state of continual inflammation, where the immune system is in a heightened state of activation, and the body essentially creates an environment conducive to cancer. The gut is populated by trillions of species of bacteria which work together with our immune cells. As we age the diversity and density of these beneficial bacteria reduce. Therapies which support the balance of our commensal bacteria may prove effective at reducing rates of cancer in the elderly.
Cancer incidence substantially increases with ageing in both men and women, although the reason for this increase is unknown. In this Series paper, we propose that age-associated changes in gut commensal microbes, otherwise known as the microbiota, facilitate cancer development and growth by compromising immune fitness. Ageing is associated with a reduction in the beneficial commensal microbes, which control the expansion of pathogenic commensals and maintain the integrity of the intestinal barrier through the production of mucus and lipid metabolites, such as short-chain fatty acids. Expansion of gut dysbiosis and leakage of microbial products contributes to the chronic proinflammatory state (inflammaging), which negatively affects the immune system and impairs the removal of mutant and senescent cells, thereby enabling tumour outgrowth. Studies in animal models and the importance of commensals in cancer immunotherapy suggest that this status can be reversible. Thus, interventions that alter the composition of the gut microbiota might reduce inflammaging and rejuvenate immune functions to provide anticancer benefits in frail elderly people.
Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome.
Plain language summary
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained persistent fatigue, cognitive dysfunction, sleep disturbances, orthostatic intolerance, fever, swollen lymph glands and irritable bowel syndrome (IBS). It is associated with gut bacterial dysbiosis, systemic inflammation and both gastro intestinal (GI) and neurological disturbances. The extent to which the gastrointestinal microbiome and peripheral inflammation are associated with ME/CFS remains unclear. This experiment looked at fecal bacterial samples and metabolic pathway markers in 50 ME/CFS patients and 50 healthy controls. In ME/CFS subgroups, measures of symptom severity including pain, fatigue, and reduced motivation were correlated with the amounts and types of gut bacteria and certain metabolic pathways. Future prospective studies should consider more detailed exploration of IBS subtypes, associated GI symptoms, and their relationship to ME/CFS dysbiosis. This may enable more accurate diagnosis and the development of specific therapeutic strategies.
BACKGROUND Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained persistent fatigue, commonly accompanied by cognitive dysfunction, sleeping disturbances, orthostatic intolerance, fever, lymphadenopathy, and irritable bowel syndrome (IBS). The extent to which the gastrointestinal microbiome and peripheral inflammation are associated with ME/CFS remains unclear. We pursued rigorous clinical characterization, fecal bacterial metagenomics, and plasma immune molecule analyses in 50 ME/CFS patients and 50 healthy controls frequency-matched for age, sex, race/ethnicity, geographic site, and season of sampling. RESULTS Topological analysis revealed associations between IBS co-morbidity, body mass index, fecal bacterial composition, and bacterial metabolic pathways but not plasma immune molecules. IBS co-morbidity was the strongest driving factor in the separation of topological networks based on bacterial profiles and metabolic pathways. Predictive selection models based on bacterial profiles supported findings from topological analyses indicating that ME/CFS subgroups, defined by IBS status, could be distinguished from control subjects with high predictive accuracy. Bacterial taxa predictive of ME/CFS patients with IBS were distinct from taxa associated with ME/CFS patients without IBS. Increased abundance of unclassified Alistipes and decreased Faecalibacterium emerged as the top biomarkers of ME/CFS with IBS; while increased unclassified Bacteroides abundance and decreased Bacteroides vulgatus were the top biomarkers of ME/CFS without IBS. Despite findings of differences in bacterial taxa and metabolic pathways defining ME/CFS subgroups, decreased metabolic pathways associated with unsaturated fatty acid biosynthesis and increased atrazine degradation pathways were independent of IBS co-morbidity. Increased vitamin B6 biosynthesis/salvage and pyrimidine ribonucleoside degradation were the top metabolic pathways in ME/CFS without IBS as well as in the total ME/CFS cohort. In ME/CFS subgroups, symptom severity measures including pain, fatigue, and reduced motivation were correlated with the abundance of distinct bacterial taxa and metabolic pathways. CONCLUSIONS Independent of IBS, ME/CFS is associated with dysbiosis and distinct bacterial metabolic disturbances that may influence disease severity. However, our findings indicate that dysbiotic features that are uniquely ME/CFS-associated may be masked by disturbances arising from the high prevalence of IBS co-morbidity in ME/CFS. These insights may enable more accurate diagnosis and lead to insights that inform the development of specific therapeutic strategies in ME/CFS subgroups.