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Cigarette Smoke Extract Disturbs Mitochondria-Regulated Airway Epithelial Cell Responses to Pneumococci.
Aghapour, M, Tulen, CBM, Abdi Sarabi, M, Weinert, S, Müsken, M, Relja, B, van Schooten, FJ, Jeron, A, Braun-Dullaeus, R, Remels, AH, et al
Cells. 2022;11(11)
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Cigarette smoking can affect airway epithelial cells, causing overproduction of mucus, damage, and inflammation, which may result in the progression of airway diseases. Airway epithelial cells (AEC) rely on mitochondria for energy, and mitochondrial dysfunction may affect innate immunity and the integrity of the airway epithelium. Cigarette smoking is found to accelerate mitochondrial damage within AEC. Maintaining a normal microbial composition within the respiratory tract is essential for maintaining immunity. There is evidence that smoking cigarettes disrupts the microbial composition and increases the spread of pathogenic bacteria such as Streptococcus pneumoniae (Sp) which causes inflammation. By exposing 16HBE cells to Sp and cigarette smoke extract (CSE), this study investigated the effect of cigarette smoking on mitochondrial dysfunction in ACE in an in vitro model. Additionally, the study examined the direct and indirect pathways involved in cigarette smoking-induced mitochondrial dysfunction and altered innate immune response to Sp infection. CSE exposure decreases mitochondrial complex protein levels and mitochondrial membrane potential, which affects energy production. It also increases mitochondrial oxidative stress and mitochondrial degradation. All these factors lead to mitochondrial dysfunction in ACE. CSE exposure to ACE was associated with altered gene expression in the tight and adherence junctions that serve as a protective barrier against pathogens and pollutants and reduced type I interferon immune responses to Sp. Using the results of this study, healthcare professionals can gain a better understanding of the impact of cigarette smoking on mitochondrial dysfunction and how it increases susceptibility to Sp-related immune responses. It is necessary to conduct further studies to evaluate the effects of cigarette smoking on mitochondrial dysfunction, microbial composition disruption, and the interaction between AECs and elevated immune responses.
Abstract
Mitochondrial functionality is crucial for the execution of physiologic functions of metabolically active cells in the respiratory tract including airway epithelial cells (AECs). Cigarette smoke is known to impair mitochondrial function in AECs. However, the potential contribution of mitochondrial dysfunction in AECs to airway infection and airway epithelial barrier dysfunction is unknown. In this study, we used an in vitro model based on AECs exposed to cigarette smoke extract (CSE) followed by an infection with Streptococcus pneumoniae (Sp). The levels of oxidative stress as an indicator of mitochondrial stress were quantified upon CSE and Sp treatment. In addition, expression of proteins associated with mitophagy, mitochondrial content, and biogenesis as well as mitochondrial fission and fusion was quantified. Transcriptional AEC profiling was performed to identify the potential changes in innate immune pathways and correlate them with indices of mitochondrial function. We observed that CSE exposure substantially altered mitochondrial function in AECs by suppressing mitochondrial complex protein levels, reducing mitochondrial membrane potential and increasing mitochondrial stress and mitophagy. Moreover, CSE-induced mitochondrial dysfunction correlated with reduced enrichment of genes involved in apical junctions and innate immune responses to Sp, particularly type I interferon responses. Together, our results demonstrated that CSE-induced mitochondrial dysfunction may contribute to impaired innate immune responses to Sp.
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Oral birch pollen immunotherapy with apples: Results of a phase II clinical pilot study.
Nothegger, B, Reider, N, Covaciu, CE, Cova, V, Ahammer, L, Eidelpes, R, Unterhauser, J, Platzgummer, S, Raffeiner, E, Tollinger, M, et al
Immunity, inflammation and disease. 2021;9(2):503-511
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The prevalence of birch pollen allergy (BPA) has increased in recent years and has led to a rise in birch pollen-related food allergy (prFA). The current immunotherapy approach for BPA is to use birch pollen extract to attenuate the allergic response. While it has been successful for BPA, it has shown little to no effect on prFA, illuminating a current gap in the research. The aim of this pilot study was to assess the clinical efficacy of immunotherapy by daily apple consumption in developing permanent oral tolerance to apples and simultaneously to birch‐pollen. Sixteen participants consumed apples daily over an eight month period. Various allergy responses were measured during the peak birch pollen season. The results demonstrated continuous consumption of apples by BPA patients with prFA to apples could both improve prFA and birch-pollen induced allergic reactions. Based on these results, the authors conclude that oral immunotherapy with fresh apples is feasible and safe for the treatment of both BPA and birch prFA. As this was a small pilot study, a larger controlled trial is needed to confirm the potential of this treatment option in the clinical setting.
Abstract
BACKGROUND Seventy percent of patients suffering from birch pollen allergy (BPA) develop a pollen-related food allergy (prFA), especially to apples, due to a clinically relevant cross-reactivity between the major allergen in birch Bet v 1 and Mal d 1 in apples. Therefore allergen-specific immunotherapy with fresh apples (AITA) could be a promising natural treatment of both BPA and prFA. OBJECTIVE To assess the clinical efficacy of immunotherapy by daily apple consumption for patients with BPA and prFA. METHODS A daily defined increasing amount of selected cultivars (Red Moon®, Pink Lady®, Topaz, Golden Delicious) was continuously consumed by 16 patients (12 female; median age; 50; range, 23-68 years), leading to increased intake of allergen over a period of at least 8 months. Specific IgE and IgG4 to Bet v 1 and Mal d 1, conjunctival and oral provocation tests, skin reactivity, and the average daily rhinoconjunctivitis combined symptom and medication score (CSMS) were measured during the peak birch pollen season. RESULTS After 8 months of therapy, patients showed increased tolerance to apples (p < .001) and a decreased skin reactivity to apples. Oral allergy syndrome to other birch prFA than apple also decreased (p < .05). Moreover, daily rhinoconjunctivitis CSMS declined by 34% (p < .001), as did conjunctival reactivity to birch pollen extract by 27% (p < .01), while specific IgG4 to Mal d 1 and Bet v 1 increased (p < .01).
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Serum vitamin E levels and chronic inflammatory skin diseases: A systematic review and meta-analysis.
Liu, X, Yang, G, Luo, M, Lan, Q, Shi, X, Deng, H, Wang, N, Xu, X, Zhang, C
PloS one. 2021;16(12):e0261259
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Vitiligo, Psoriasis, Acne and Atopic Dermatitis are chronic immune-mediated inflammatory skin conditions characterised by itchy skin. In previous studies, decreased serum vitamin E levels have been associated with an increased risk of skin diseases. Nuts, oils from plants, and vegetables contain vitamin E, which is a dietary bioactive compound that has anti-inflammatory and antioxidant properties. In this systematic review and meta-analysis, twenty case-controlled studies were included, of which thirteen specifically examined alpha-tocopherol levels. Psoriasis, Vitiligo, atopic dermatitis, and acne patient groups had significantly lower levels of serum Vitamin E than the control groups. There is no clear understanding of the pathogenesis of chronic inflammatory skin conditions. One of the underlying mechanisms is the interaction between oxidative stress and the immune system, as well as the accumulation of free radicals in the epidermal layers of the skin. As there is limited evidence regarding the benefits of Vitamin E in improving chronic inflammatory skin conditions, further robust studies are necessary. Healthcare professionals can use this research to gain a better understanding of the potential clinical applications of vitamin E in the treatment of skin disorders.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Low serum vitamin E levels are reported to be associated with several chronic inflammatory skin diseases, such as vitiligo, psoriasis, atopic dermatitis, and acne.
- Practitioners could consider vitamin E therapy in those with low serum concentrations
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
This systematic review and meta-analysis report on the association between serum vitamin E levels and chronic inflammatory skin diseases.
The review which followed PRISMA reporting guidelines, screened 892 studies. After the selection and exclusions, 20 case-control studies were included involving a total of 1172 patients.
The studies that were included focused mainly on chronic inflammatory diseases, including vitiligo, psoriasis, atopic dermatitis, and acne. Eight studies included only adults, five included only children or teenagers and six studies included adults and children. One study had no age description.
Thirteen studies stated that alpha-tocopherol was used in their investigations. However, seven studies did not describe the subunit of vitamin E.
Primary clinical outcomes were:
- Seven studies, with 351 cases and 350 controls reported that compared with the control group, vitiligo patients had lower serum vitamin E concentrations (Standard Mean Difference (SMD):0.70, 95% Cl:121-0.19.
- Six studies investigated the change of serum vitamin E levels in patients with psoriasis, with 278 cases and 257 controls. Compared with the control group, psoriasis patients had lower serum vitamin E concentrations (SMD: -2.37, 95% CI: -3.57 to -1.18).
- The serum vitamin E Levels in patients with atopic dermatitis were observed in 4 studies, with 259 cases and 307 controls. Compared with the control group atopic dermatitis patients had lower serum vitamin E concentrations (SMD: -1.08, 95% CI: -1.80 to -0.36).
Levels of serum vitamin E in acne patients were reported in 3 studies, with 284 cases and 186 controls. Compared with the control group, acne patients had lower serum concentration levels of vitamin E (SMD: -0.67, 95% CI: -1.05 to -0.30).
No publication bias was found in any association (Egger’s test >0.05), though heterogeneity was considerable in every case (I2 > 80%), though this interaction was not significant for acne (p=0.879). Associations were not split by age, or any other cofactor, however sensitivity analyses did not indicate modification of the results.
The authors also assessed the association between skin disease severity and serum vitamin E concentrations. Overall, more severe disease was associated with a lower serum vitamin E concentration (SMD -1.56, 95% CI:-2.53 to -059).
Clinical practice applications:
- Vitamin E has gained the attention of researchers as a potential adjuvant therapy for various skin disorders due to its excellent antioxidant and anti-inflammatory properties.
- This review reports on the low levels of serum vitamin E found in patients with vitiligo, psoriasis, atopic dermatitis, and acne, and also suggests that serum concentrations of vitamin E are lower in those with more severe disease. Based on these findings, practitioners could therefore consider investigating the serum vitamin E levels of patients with inflammatory skin diseases and consider including vitamin E in their treatment protocols if their serum vitamin E levels are low.
Considerations for future research:
- The small number of studies in this review indicates the need for further research to be done on vitamin E and inflammatory skin diseases.
- Although there are reports on the antioxidant and anti-inflammatory properties of vitamin E, further investigations are needed to determine the exact mechanism of action in inflammatory skin diseases.
- Additionally, further investigation is needed to evaluate which chemical forms of vitamin E and their dosage amounts have beneficial effects on inflammatory skin diseases.
Abstract
BACKGROUND Vitamin E has long been linked to skin health, including all of its possible functions in cosmetic products, to its roles in membrane integrity and even the aging process. However, reports on the relationship between serum vitamin E levels and the risk of chronic inflammatory skin diseases have been inconsistent. We performed a systematic review and meta-analysis to evaluate the association between serum vitamin E levels and chronic inflammatory skin diseases. METHODS We searched the PubMed, Web of Science and Scopus databases, with no time limit up to 30.06.2021. Studies examining serum vitamin E levels in patients with chronic inflammatory skin diseases were selected. RESULTS Twenty articles met the inclusion criteria. Compared with controls, a lower vitamin E level was found in patients with vitiligo (SMD: -0.70, 95% CI: -1.21 to -0.19), psoriasis (SMD: -2.73, 95% CI: -3.57 to -1.18), atopic dermatitis (SMD: -1.08, 95% CI: -1.80 to -0.36) and acne (SMD: -0.67, 95% CI: -1.05 to -0.30). CONCLUSIONS Our meta-analysis showed that serum vitamin E levels were lower in patients suffering from vitiligo, psoriasis, atopic dermatitis and acne. This study highlights the need to evaluate vitamin E status to improve its level in patients with skin diseases.
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Naturalization of the microbiota developmental trajectory of Cesarean-born neonates after vaginal seeding.
Song, SJ, Wang, J, Martino, C, Jiang, L, Thompson, WK, Shenhav, L, McDonald, D, Marotz, C, Harris, PR, Hernandez, CD, et al
Med (New York, N.Y.). 2021;2(8):951-964.e5
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Studies on model organisms show that foetal development can be modulated by microbial products from the pregnant mother’s microbiota, and early colonisation is critical for immune system development. However, natural transmission and colonisation of maternal microbes is impaired by caesarean section (CS) delivery. The aim of this study was to determine the effect of restoring exposure to maternal vaginal fluids after CS birth. This study is a large observational study of 177 infants born to 174 mothers. Physicians assessed healthy mothers who were set to deliver vaginally or by scheduled CS. Results demonstrate that microbial differences associated with delivery mode can be reduced by exposure to a vaginal microbial source at birth. In fact, birth mode significantly differentiated infant gut and skin microbiome development, and that seeding worked to adjust the trajectory of CS-delivered infants through partial restoration of microbiome features associated with a vaginal delivery. Authors conclude that restoring natural exposures at birth may be one way to reduce the risk of CS-associated diseases such as obesity, asthma, allergies, and immune disfunctions. However, randomised clinical trials on large cohorts are needed to gain conclusive evidence for microbial restoration at birth improving health outcomes.
Abstract
BACKGROUND Early microbiota perturbations are associated with disorders that involve immunological underpinnings. Cesarean section (CS)-born babies show altered microbiota development in relation to babies born vaginally. Here we present the first statistically powered longitudinal study to determine the effect of restoring exposure to maternal vaginal fluids after CS birth. METHODS Using 16S rRNA gene sequencing, we followed the microbial trajectories of multiple body sites in 177 babies over the first year of life; 98 were born vaginally, and 79 were born by CS, of whom 30 were swabbed with a maternal vaginal gauze right after birth. FINDINGS Compositional tensor factorization analysis confirmed that microbiota trajectories of exposed CS-born babies aligned more closely with that of vaginally born babies. Interestingly, the majority of amplicon sequence variants from maternal vaginal microbiomes on the day of birth were shared with other maternal sites, in contrast to non-pregnant women from the Human Microbiome Project (HMP) study. CONCLUSIONS The results of this observational study prompt urgent randomized clinical trials to test whether microbial restoration reduces the increased disease risk associated with CS birth and the underlying mechanisms. It also provides evidence of the pluripotential nature of maternal vaginal fluids to provide pioneer bacterial colonizers for the newborn body sites. This is the first study showing long-term naturalization of the microbiota of CS-born infants by restoring microbial exposure at birth. FUNDING C&D, Emch Fund, CIFAR, Chilean CONICYT and SOCHIPE, Norwegian Institute of Public Health, Emerald Foundation, NIH, National Institute of Justice, Janssen.
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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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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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A clinically meaningful metric of immune age derived from high-dimensional longitudinal monitoring.
Alpert, A, Pickman, Y, Leipold, M, Rosenberg-Hasson, Y, Ji, X, Gaujoux, R, Rabani, H, Starosvetsky, E, Kveler, K, Schaffert, S, et al
Nature medicine. 2019;25(3):487-495
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The human immune system changes with age, ultimately leading to a clinically evident, profound deterioration resulting in high morbidity and mortality rates attributed to infectious and chronic diseases. The aim of this study was to assess at high resolution the dynamics of older adults’ immune systems. The study uses multiple ‘omics’ technologies in a cohort of 135 adults (63 young adults and 72 older adults) of different ages who were sampled longitudinally over the course of 9 years to comprehensively capture population- and individual-level changes in the immune system over time. Results indicate that immune-cell frequencies changed at substantially different rates; some cell subsets show no directionality of change yet differ between young and old individuals, whereas other cell subsets continued changing (either increasing or decreasing) throughout the course of the study. Authors postulate that an individual’s immune age is a function of life history, namely environmental exposure coupled with genetic background. Thus, immune modulators may one day be identified that affect the position of an individual’s immune system along the immunological landscape.
Abstract
Immune responses generally decline with age. However, the dynamics of this process at the individual level have not been characterized, hindering quantification of an individual's immune age. Here, we use multiple 'omics' technologies to capture population- and individual-level changes in the human immune system of 135 healthy adult individuals of different ages sampled longitudinally over a nine-year period. We observed high inter-individual variability in the rates of change of cellular frequencies that was dictated by their baseline values, allowing identification of steady-state levels toward which a cell subset converged and the ordered convergence of multiple cell subsets toward an older adult homeostasis. These data form a high-dimensional trajectory of immune aging (IMM-AGE) that describes a person's immune status better than chronological age. We show that the IMM-AGE score predicted all-cause mortality beyond well-established risk factors in the Framingham Heart Study, establishing its potential use in clinics for identification of patients at risk.
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8.
Does the microbiome and virome contribute to myalgic encephalomyelitis/chronic fatigue syndrome?
Newberry, F, Hsieh, SY, Wileman, T, Carding, SR
Clinical science (London, England : 1979). 2018;132(5):523-542
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Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) (ME/CFS) is a disabling and debilitating disease. Several studies have shown alterations in the gut microbiome (dysbiosis) in patients with ME/CFS. However, in focusing on the bacterial components of the microbiome, the viral component of the microbiome (known as the virome) has been neglected. Viruses can change the microbiome which can influence the health. This area is therefore important for research into ME/CFS. This article provides a comprehensive review of the current evidence supporting microbiome alterations in ME/CFS patients. Additionally, the challenges associated with microbiome studies are discussed. A literature search was done and 11 papers were found that had examined the microbiome ME/CFS patients, dating from 1998 to 2017. It was not possible to compare the studies statistically but from looking at each one individually there is sufficient evidence to support the claim of an altered intestinal microbiome in ME/CFS patients. ME/CFS is multifactorial and potential dysbiosis should be considered to be only part of the picture. Future studies are needed to adopt standardized techniques and analyses. As research increases, it is becoming clear that the virome can directly and indirectly affect host health, and may play a role in the pathogenesis of ME/CFS.
Abstract
Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) (ME/CFS) is a disabling and debilitating disease of unknown aetiology. It is a heterogeneous disease characterized by various inflammatory, immune, viral, neurological and endocrine symptoms. Several microbiome studies have described alterations in the bacterial component of the microbiome (dysbiosis) consistent with a possible role in disease development. However, in focusing on the bacterial components of the microbiome, these studies have neglected the viral constituent known as the virome. Viruses, particularly those infecting bacteria (bacteriophages), have the potential to alter the function and structure of the microbiome via gene transfer and host lysis. Viral-induced microbiome changes can directly and indirectly influence host health and disease. The contribution of viruses towards disease pathogenesis is therefore an important area for research in ME/CFS. Recent advancements in sequencing technology and bioinformatics now allow more comprehensive and inclusive investigations of human microbiomes. However, as the number of microbiome studies increases, the need for greater consistency in study design and analysis also increases. Comparisons between different ME/CFS microbiome studies are difficult because of differences in patient selection and diagnosis criteria, sample processing, genome sequencing and downstream bioinformatics analysis. It is therefore important that microbiome studies adopt robust, reproducible and consistent study design to enable more reliable and valid comparisons and conclusions to be made between studies. This article provides a comprehensive review of the current evidence supporting microbiome alterations in ME/CFS patients. Additionally, the pitfalls and challenges associated with microbiome studies are discussed.
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Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome.
Nagy-Szakal, D, Williams, BL, Mishra, N, Che, X, Lee, B, Bateman, L, Klimas, NG, Komaroff, AL, Levine, S, Montoya, JG, et al
Microbiome. 2017;5(1):44
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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.
Abstract
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.