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The Role of Lung and Gut Microbiota in the Pathology of Asthma.
Barcik, W, Boutin, RCT, Sokolowska, M, Finlay, BB
Immunity. 2020;52(2):241-255
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Over 300 million people suffer with asthma worldwide and it has emerged that microbiome analysis of the lung and gut bacteria, fungi, viruses, and archaea may help with disease management. This microbiome plays an important role in immune response. Disturbances to these microbes, known as dysbiosis, may influence onset of disease and the body’s ability to respond naturally, and/or to pharmaceutical treatments. Asthma is not a singular disease and there are great variations in symptom severity and underlying immune mechanisms. Patients are typically classified as type 2 or non-type 2. Type 2 patients tend to be allergic to common air-born allergens which can trigger an attack. Treatment usually consists of glucocorticosteroids or novel biologicals. Non type-2 asthma is associated with obesity-related asthma and typically responds poorly to steroid treatment. For a long time, researchers believed the human lungs to be sterile, so they were initially not included in the 2007 Human Microbiome Project. It has since been shown that, like the gut, the lungs and respiratory tract also host various microbes, and this healthy-airway microbiota influence innate and adaptive immune processes. The Gut-Lung axis also confers additional microbial benefits from the intestines. In asthma patients, there is often an over-dominance of pathogenic bacteria. Fungal dysbiosis is associated with high-risk asthma phenotypes in childhood. Viral infections have been shown as a primary cause of asthmatic episodes. Future diagnosis and treatment of patients with asthma should be assisted by analysis of the composition and metabolic activity of an individual’s microbiome.
Abstract
Asthma is a common chronic respiratory disease affecting more than 300 million people worldwide. Clinical features of asthma and its immunological and molecular etiology vary significantly among patients. An understanding of the complexities of asthma has evolved to the point where precision medicine approaches, including microbiome analysis, are being increasingly recognized as an important part of disease management. Lung and gut microbiota play several important roles in the development, regulation, and maintenance of healthy immune responses. Dysbiosis and subsequent dysregulation of microbiota-related immunological processes affect the onset of the disease, its clinical characteristics, and responses to treatment. Bacteria and viruses are the most extensively studied microorganisms relating to asthma pathogenesis, but other microbes, including fungi and even archaea, can potently influence airway inflammation. This review focuses on recently discovered connections between lung and gut microbiota, including bacteria, fungi, viruses, and archaea, and their influence on asthma.
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COVID-19 infection: the perspectives on immune responses.
Shi, Y, Wang, Y, Shao, C, Huang, J, Gan, J, Huang, X, Bucci, E, Piacentini, M, Ippolito, G, Melino, G
Cell death and differentiation. 2020;27(5):1451-1454
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The SARS-CoV-2 infection triggers an immune response which varies greatly from one person to another. It can be roughly divided into three stages: stage I, an asymptomatic incubation period with or without detectable virus; stage II, non-severe symptomatic period with the presence of virus; stage III, severe respiratory symptomatic stage with high viral load. Currently around 15% of people infected end up in severe stage III. There appears to be a two-phase immune response; an early protective phase and a second inflammation-driven damaging phase. In phase one the adaptive immune system responds to the virus. Being in good general health is important in this phase to limiting the progression of the disease to a more severe stage. In phase two the innate immune system response to tissue damage caused by the virus could lead to widespread inflammation of the lungs and acute respiratory distress syndrome or respiratory failure. Therapeutically this raises the question of whether the immune response should be boosted in phase one and suppressed in phase two. There also appears to be an element of viral relapse in some patients discharged from hospital indicating that a virus-eliminating immune response may be difficult to achieve naturally. These same patients may also not respond to vaccines. Overall, it is still unclear why some people develop severe disease, whilst others do not. Overall immunity alone does not explain the differences in disease presentation.
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3.
Using psychoneuroimmunity against COVID-19.
Kim, SW, Su, KP
Brain, behavior, and immunity. 2020;87:4-5
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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.
Abstract
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.
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The COVID-19 Pandemic: a Call to Action to Identify and Address Racial and Ethnic Disparities.
Laurencin, CT, McClinton, A
Journal of racial and ethnic health disparities. 2020;7(3):398-402
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The severe acute respiratory syndrome coronavirus 2 virus was first identified in late 2019 in Wuhan, China. Various unsubstantiated reports emerged declaring that the genetic constitution of Blacks or even the presence of melanin rendered Blacks immune to the virus. This study is a call of action which reviews preliminary data on race and ethnicity in the peer-reviewed literature for citizens in America affected by COVID-19. Findings demonstrate that communities of colour (Blacks) have a higher rate of infection and death in comparison to their population percentage in the state of Connecticut. However, authors are unable to draw conclusions since race and ethnicity data is missing and the data in this paper is the earliest data available. Therefore, the authors call for action to identify and address racial and ethnic health disparities in the COVID-19 crisis.
Abstract
The Coronavirus disease 2019 (COVID-19) pandemic has significantly impacted and devastated the world. As the infection spreads, the projected mortality and economic devastation are unprecedented. In particular, racial and ethnic minorities may be at a particular disadvantage as many already assume the status of a marginalized group. Black Americans have a long-standing history of disadvantage and are in a vulnerable position to experience the impact of this crisis and the myth of Black immunity to COVID-19 is detrimental to promoting and maintaining preventative measures. We are the first to present the earliest available data in the peer-reviewed literature on the racial and ethnic distribution of COVID-19-confirmed cases and fatalities in the state of Connecticut. We also seek to explode the myth of Black immunity to the virus. Finally, we call for a National Commission on COVID-19 Racial and Ethnic Health Disparities to further explore and respond to the unique challenges that the crisis presents for Black and Brown communities.
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Harnessing the immune system to overcome cytokine storm and reduce viral load in COVID-19: a review of the phases of illness and therapeutic agents.
Khadke, S, Ahmed, N, Ahmed, N, Ratts, R, Raju, S, Gallogly, M, de Lima, M, Sohail, MR
Virology journal. 2020;17(1):154
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Severe manifestations of COVID-19 infection and mortality are associated with a cytokine storm. This is an excessive inflammatory response to the infection leading to an overproduction of pro-inflammatory signalling molecules, which consequently contributes to tissue and organ damage. This literature review summarised current knowledge, as of June 2020, about virus-associated cytokine storm, virus-host interactions and immunological mechanism, to gain a better understanding of the phenomena observed in COVID-19 infections and devise better treatment strategies. The review briefly outlines the epidemiology of COVID-19, predictors of severity of disease, mode of transmission, testing, viral structure, mechanism of invasion of the host cell, replication and immune invasion and the progression of the four stages of the cytokine storm. The second part of the review discusses antiviral therapeutics of interest with a table summarising drugs, mechanism and available data. This article may be of interest to those who like to delve further into the mechanisms and immune components involved in a cytokine storm and gain an oversight of the pathways targeted by allopathic agents that have been put forward as treatment options.
Abstract
BACKGROUND Coronavirus disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2, previously named 2019-nCov), a novel coronavirus that emerged in China in December 2019 and was declared a global pandemic by World Health Organization by March 11th, 2020. Severe manifestations of COVID-19 are caused by a combination of direct tissue injury by viral replication and associated cytokine storm resulting in progressive organ damage. DISCUSSION We reviewed published literature between January 1st, 2000 and June 30th, 2020, excluding articles focusing on pediatric or obstetric population, with a focus on virus-host interactions and immunological mechanisms responsible for virus associated cytokine release syndrome (CRS). COVID-19 illness encompasses three main phases. In phase 1, SARS-CoV-2 binds with angiotensin converting enzyme (ACE)2 receptor on alveolar macrophages and epithelial cells, triggering toll like receptor (TLR) mediated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ƙB) signaling. It effectively blunts an early (IFN) response allowing unchecked viral replication. Phase 2 is characterized by hypoxia and innate immunity mediated pneumocyte damage as well as capillary leak. Some patients further progress to phase 3 characterized by cytokine storm with worsening respiratory symptoms, persistent fever, and hemodynamic instability. Important cytokines involved in this phase are interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α. This is typically followed by a recovery phase with production of antibodies against the virus. We summarize published data regarding virus-host interactions, key immunological mechanisms responsible for virus-associated CRS, and potential opportunities for therapeutic interventions. CONCLUSION Evidence regarding SARS-CoV-2 epidemiology and pathogenesis is rapidly evolving. A better understanding of the pathophysiology and immune system dysregulation associated with CRS and acute respiratory distress syndrome in severe COVID-19 is imperative to identify novel drug targets and other therapeutic interventions.
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The Role of Bacteria and Its Derived Metabolites in Chronic Pain and Depression: Recent Findings and Research Progress.
Li, S, Hua, D, Wang, Q, Yang, L, Wang, X, Luo, A, Yang, C
The international journal of neuropsychopharmacology. 2020;23(1):26-41
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Depression is closely associated with chronic pain yet the connection between these comorbidities is ambiguous. Recent studies have shown alterations in the gut microbiome may contribute to cognitive dysfunction via the microbiota-gut-brain axis. The aim of this systematic review is to summarize the existing evidence of the role of the gut microbiome in chronic pain and depression and explore potential mechanisms of gut dysbiosis in the development of these conditions. This review found metabolic products from the gut microbiota can mediate neuro-inflammation and neuro-immunity pathways in pain and depression, and that dysbiosis in the gut may contribute to the cause of chronic pain and depression. The authors conclude the metabolic products from the gut bacteria offer new insights to the connection between the gut microbiota and mechanisms of pain and depression, while showing potential as a therapeutic target.
Abstract
BACKGROUND Chronic pain is frequently comorbid with depression in clinical practice. Recently, alterations in gut microbiota and metabolites derived therefrom have been found to potentially contribute to abnormal behaviors and cognitive dysfunction via the "microbiota-gut-brain" axis. METHODS PubMed was searched and we selected relevant studies before October 1, 2019. The search keyword string included "pain OR chronic pain" AND "gut microbiota OR metabolites"; "depression OR depressive disorder" AND "gut microbiota OR metabolites". We also searched the reference lists of key articles manually. RESULTS This review systematically summarized the recent evidence of gut microbiota and metabolites in chronic pain and depression in animal and human studies. The results showed the pathogenesis and therapeutics of chronic pain and depression might be partially due to gut microbiota dysbiosis. Importantly, bacteria-derived metabolites, including short-chain fatty acids, tryptophan-derived metabolites, and secondary bile acids, offer new insights into the potential linkage between key triggers in gut microbiota and potential mechanisms of depression. CONCLUSION Studying gut microbiota and its metabolites has contributed to the understanding of comorbidity of chronic pain and depression. Consequently, modulating dietary structures or supplementation of specific bacteria may be an available strategy for treating chronic pain and depression.
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Coronavirus disease 2019 (COVID-19) and obesity. Impact of obesity and its main comorbidities in the evolution of the disease.
Cornejo-Pareja, IM, Gómez-Pérez, AM, Fernández-García, JC, Barahona San Millan, R, Aguilera Luque, A, de Hollanda, A, Jiménez, A, Jimenez-Murcia, S, Munguia, L, Ortega, E, et al
European eating disorders review : the journal of the Eating Disorders Association. 2020;28(6):799-815
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The Covid-19 pandemic has caused thousands of deaths worldwide. Being obese is associated with worse outcomes following infection with Covid-19. This review aimed to summarise the data available on the relationship between Covid-19 and obesity, and explored some of the possible reasons for this relationship. The researchers found that obesity is an independent and strong risk factor for severe infection, Intensive Care Unit (ICU) admission and death. The impact of obesity might be of particular relevance in males and in younger individuals. Long‐term complications of Covid‐19 could also be more frequent and severe in obese subjects. There are many potential mechanisms that could explain this relationship. These include the effects of obesity and related diseases such as diabetes, high blood pressure and heart disease on the immune system, lung function, vitamin D deficiency and male hormones. The researchers also discussed the possibility of fat cells acting as a possible reservoir for Covid-19 infection. Research into Covid-19 is still at a very early stage and more studies are needed.
Abstract
The COVID-19 pandemic is posing a great challenge worldwide. Its rapid progression has caused thousands of deaths worldwide. Although multiple aspects remain to be clarified, some risk factors associated with a worse prognosis have been identified. These include obesity and some of its main complications, such as diabetes and high blood pressure. Furthermore, although the possible long-term complications and psychological effects that may appear in survivors of COVID-19 are not well known yet, there is a concern that those complications may be greater in obese patients. In this manuscript, we review some of the data published so far and the main points that remain to be elucidated are emphasized.
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Borrelia burgdorferi peptidoglycan is a persistent antigen in patients with Lyme arthritis.
Jutras, BL, Lochhead, RB, Kloos, ZA, Biboy, J, Strle, K, Booth, CJ, Govers, SK, Gray, J, Schumann, P, Vollmer, W, et al
Proceedings of the National Academy of Sciences of the United States of America. 2019;116(27):13498-13507
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Lyme disease is a varied, multisystem disorder caused by the spiral-shaped bacteria Borrelia burgdorferi (Bb). Advanced stages of the disease can present with oligoarthritis, most commonly involving the knee joints. Peptidoglycan (PG) is a compound that makes up the cell envelope of Bb and other bacteria. It acts as a microbe-associated molecular pattern, which can trigger the immune system and induces pro-inflammatory responses. This article summarises a series of cell, human, and animal studies supporting the theory that PG is a contributor to persistent Lyme’s arthritis (LA) far beyond the eradication of the pathogen. Significantly elevated inflammatory markers as well as antibodies to PG and Bb itself have been found in patients with LA before and after antibiotic therapy. The inflammatory response to Bb PG seems to be particularly high when compared to other bacteria. In summary, the authors suggest that PG accumulation in the joints and subsequent persistent inflammation contribute to LA and that targeting the specific inflammatory pathways involved may yield potential therapeutic interventions. This article could be of interest to those looking to understand more about the mechanisms and specific inflammatory responses involved in LA.
Abstract
Lyme disease is a multisystem disorder caused by the spirochete Borrelia burgdorferi A common late-stage complication of this disease is oligoarticular arthritis, often involving the knee. In ∼10% of cases, arthritis persists after appropriate antibiotic treatment, leading to a proliferative synovitis typical of chronic inflammatory arthritides. Here, we provide evidence that peptidoglycan (PG), a major component of the B. burgdorferi cell envelope, may contribute to the development and persistence of Lyme arthritis (LA). We show that B. burgdorferi has a chemically atypical PG (PGBb) that is not recycled during cell-wall turnover. Instead, this pathogen sheds PGBb fragments into its environment during growth. Patients with LA mount a specific immunoglobulin G response against PGBb, which is significantly higher in the synovial fluid than in the serum of the same patient. We also detect PGBb in 94% of synovial fluid samples (32 of 34) from patients with LA, many of whom had undergone oral and intravenous antibiotic treatment. These same synovial fluid samples contain proinflammatory cytokines, similar to those produced by human peripheral blood mononuclear cells stimulated with PGBb In addition, systemic administration of PGBb in BALB/c mice elicits acute arthritis. Altogether, our study identifies PGBb as a likely contributor to inflammatory responses in LA. Persistence of this antigen in the joint may contribute to synovitis after antibiotics eradicate the pathogen. Furthermore, our finding that B. burgdorferi sheds immunogenic PGBb fragments during growth suggests a potential role for PGBb in the immunopathogenesis of other Lyme disease manifestations.
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Pain regulation by gut microbiota: molecular mechanisms and therapeutic potential.
Guo, R, Chen, LH, Xing, C, Liu, T
British journal of anaesthesia. 2019;123(5):637-654
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Acute pain serves to protect us from further tissue damage. Chronic pain is debilitating and significantly reduces the quality of life for affected individuals and their loved ones. The relationship between gut bacteria and various diseases, including chronic pain, is receiving increasing attention. This review article discusses the current understanding of the role of the gut microbiota in pain regulation and what the science says in relation to gut bacteria manipulation and chronic pain. The authors of the review discuss the role of various compounds and metabolites of gut bacteria in relation to inflammation, neuropathic pain, visceral pain and headache. Whilst a lot of the current findings are based on results of rodent studies, the emerging evidence suggests that gut dysbiosis participates in various chronic pain conditions in a number of ways. Therefore, modulation of the gut microbiome through diet and pro- and pre-biotics is warranted for use by Nutrition Practitioners.
Abstract
The relationship between gut microbiota and neurological diseases, including chronic pain, has received increasing attention. The gut microbiome is a crucial modulator of visceral pain, whereas recent evidence suggests that gut microbiota may also play a critical role in many other types of chronic pain, including inflammatory pain, headache, neuropathic pain, and opioid tolerance. We present a narrative review of the current understanding on the role of gut microbiota in pain regulation and discuss the possibility of targeting gut microbiota for the management of chronic pain. Numerous signalling molecules derived from gut microbiota, such as by-products of microbiota, metabolites, neurotransmitters, and neuromodulators, act on their receptors and remarkably regulate the peripheral and central sensitisation, which in turn mediate the development of chronic pain. Gut microbiota-derived mediators serve as critical modulators for the induction of peripheral sensitisation, directly or indirectly regulating the excitability of primary nociceptive neurones. In the central nervous system, gut microbiota-derived mediators may regulate neuroinflammation, which involves the activation of cells in the blood-brain barrier, microglia, and infiltrating immune cells, to modulate induction and maintenance of central sensitisation. Thus, we propose that gut microbiota regulates pain in the peripheral and central nervous system, and targeting gut microbiota by diet and pharmabiotic intervention may represent a new therapeutic strategy for the management of chronic pain.
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Impact of red meat, processed meat and fibre intake on risk of late-onset chronic inflammatory diseases: prospective cohort study on lifestyle factors using the Danish 'Diet, Cancer and Health' cohort (PROCID-DCH): protocol.
Rasmussen, NF, Rubin, KH, Stougaard, M, Tjønneland, A, Stenager, E, Lund Hetland, M, Glintborg, B, Bygum, A, Andersen, V
BMJ open. 2019;9(3):e024555
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Chronic inflammatory diseases (CIDs) can be considered as systemic diseases which primarily affect one organ such as the intestine, skin, joints or the brain. The primary aim of this study was to investigate the impact of fibre, red meat and processed meat on disease risk outcomes of late-onset CID in the ‘Diet, Cancer and Health’ (DCH) cohort. The study is an observational prospective cohort study. The study will use data from 57,053 persons from the prospective Danish cohort study ‘Diet, Cancer and Health’ together with National Health Registry data. The study does not only target one CID but it looks at several CIDs. Furthermore, the linkage to Danish health registries will ensure almost complete follow-up of the study population since the Danish health registries are considered the internationally most comprehensive with high validity.
Abstract
INTRODUCTION Chronic inflammatory diseases (CIDs) (Crohn's disease, ulcerative colitis, psoriasis, psoriatic arthritis, rheumatoid arthritis and multiple sclerosis) are diseases of the immune system that have some shared genetic and environmental predisposing factors, but still few studies have investigated the effects of lifestyle on disease risk of several CIDs. The primary aim of this prospective cohort study is to investigate the impact of fibre, red meat and processed meat on risk of late-onset CID, with the perspective that results of this study can contribute in supporting future diet recommendations for effective personalised prevention. METHODS AND ANALYSIS The study will use data from 57 053 persons from the prospective Danish cohort study 'Diet, Cancer and Health' together with National Health Registry data. The follow-up period is from December 1993 to December 2018. Questionnaire data on diet and lifestyle were collected at entry to the Diet, Cancer and Health study. The outcome CID is defined as having a diagnosis of one of the CIDs registered in the National Patient Registry or, for multiple sclerosis, in the Danish Multiple Sclerosis Registry during follow-up and being treated with a drug used for the specific disease. The major outcome of the analyses will be to detect variability in risk of late onset of any CID and, if power allows, disease risk of late onset of each CID diagnosis between persons with different fibre and red meat, and processed meat intake. The outcome will be adjusted for age, sex, body mass index, physical activity, energy, alcohol, fermented dairy products, education, smoking status, hormone replacement therapy and comorbidity. ETHICS AND DISSEMINATION The study is approved by the Danish Data Protection Agency (2012-58-0018). The core study is an open register-based cohort study. The study does not need approval from the Ethics committee or Institutional Review Board by Danish law. Study findings will be disseminated through peer-reviewed journals, patient associations and presentations at international conferences. TRIAL REGISTRATION NUMBER NCT03456206; Post-results.