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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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Swimming pool exposure is associated with autonomic changes and increased airway reactivity to a beta-2 agonist in school aged children: A cross-sectional survey.
Cavaleiro Rufo, J, Paciência, I, Silva, D, Martins, C, Madureira, J, Oliveira Fernandes, E, Padrão, P, Moreira, P, Delgado, L, Moreira, A
PloS one. 2018;13(3):e0193848
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Studies have shown an association between swimming in chemically-treated pools and a higher risk of asthma in children, although the mechanism is not fully understood. This study aimed to investigate how swimming pool attendance influences lung and nervous system function in school-aged children. Around 800 children were classified as current swimmers (CS), past swimmers (PS) or non-swimmers (NS). The children underwent several tests to determine their lung function and allergic response to common allergens. Parasympathetic nervous system function was tested by measuring the speed at which their pupils constricted in response to light. The current swimmers group had significantly lower pupil constriction speeds compared to PS and NS, suggesting a poorer functioning of the autonomic nervous system, possibly due to inflammation resulting from swimming pool chemical exposure. CS experienced greater constriction of the airways compared to NS. A non-significant trend for a higher risk of asthma, atopic eczema and rhinitis, was observed in swimmers. The authors concluded that swimming pool attendance appears to be associated with autonomic nervous system changes and increased baseline airway smooth muscle constriction even in children without asthma.
Abstract
BACKGROUND Endurance swimming exercises coupled to disinfection by-products exposure has been associated with increased airways dysfunction and neurogenic inflammation in elite swimmers. However, the impact of swimming pool exposure at a recreational level on autonomic activity has never been explored. Therefore, this study aimed to investigate how swimming pool attendance is influencing lung and autonomic function in school-aged children. METHODS A total of 858 children enrolled a cross sectional survey. Spirometry and airway reversibility to beta-2 agonist, skin-prick-tests and exhaled nitric oxide measurements were performed. Pupillometry was used to evaluate autonomic nervous function. Children were classified as current swimmers (CS), past swimmers (PS) and non-swimmers (NS), according to the amount of swimming practice. RESULTS Current swimmers group had significantly lower maximum and average pupil constriction velocities when compared to both PS and NS groups (3.8 and 5.1 vs 3.9 and 5.3 vs 4.0 and 5.4 mm/s, p = 0.03 and p = 0.01, respectively). Moreover, affinity to the beta-2 agonist and levels of exhaled nitric oxide were significantly higher in CS when compared to NS (70 vs 60 mL and 12 vs 10 ppb, p<0.01 and p = 0.03, respectively). A non-significant trend for a higher risk of asthma, atopic eczema and allergic rhinitis was found with more years of swimming practice, particularly in atopic individuals (β = 1.12, 1.40 and 1.31, respectively). After case-case analysis, it was possible to observe that results were not influenced by the inclusion of individuals with asthma. CONCLUSIONS Concluding, swimming pool attendance appears to be associated with autonomic changes and increased baseline airway smooth muscle constriction even in children without asthma.
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The Role of Bacteria, Probiotics and Diet in Irritable Bowel Syndrome.
Harper, A, Naghibi, MM, Garcha, D
Foods (Basel, Switzerland). 2018;7(2)
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Irritable bowel syndrome (IBS) affects 10-25% of the population worldwide but to date, no definitive effective treatment protocol has been established. This review explores the role of probiotics, bacteria and diet as potential causes of IBS and what role they may play in its treatment and management. The authors concluded that though there is clear evidence of alteration in the overall diversity and specific abundance of intestinal bacteria in IBS sufferers there, is no clear picture in relation to how this affects symptoms of IBS. Future randomised control trials are required to establish effectiveness of diet and probiotic supplementation as interventions in the management of IBS.
Abstract
Irritable bowel syndrome is a highly prevalent gastrointestinal disorder that threatens the quality of life of millions and poses a substantial financial burden on healthcare systems around the world. Intense research into the human microbiome has led to fascinating discoveries which directly and indirectly implicate the diversity and function of this occult organ in irritable bowel syndrome (IBS) pathophysiology. The benefit of manipulating the gastrointestinal microbiota with diet and probiotics to improve symptoms has been demonstrated in a wealth of both animal and human studies. The positive and negative mechanistic roles bacteria play in IBS will be explored and practical probiotic and dietary choices offered.
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Fecal Microbiome and Food Allergy in Pediatric Atopic Dermatitis: A Cross-Sectional Pilot Study.
Fieten, KB, Totté, JEE, Levin, E, Reyman, M, Meijer, Y, Knulst, A, Schuren, F, Pasmans, SGMA
International archives of allergy and immunology. 2018;175(1-2):77-84
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Atopic diseases, such as atopic dermatitis (AD), asthma and rhinitis, are on the increase worldwide. Exposure to microbes may be important in the development of an atopic disease. Specifically, reduced early-life exposure is thought to be a contributing factor because microbial colonisation of the intestines during infancy plays a crucial role in the maturation of the immune system. AD, also called eczema, is an inflammatory skin disease often seen in small children. Food allergies are common in children with AD, the most common allergens being eggs, cow’s milk, peanuts, soy and wheat. This cross-sectional observational pilot study with 82 young children with a diagnosis of AD set out to identify distinct microbial patterns in the children’s faecal microbiomes associated with a clinical diagnosis of food allergy. Stool and blood samples were collected for a microbiome analysis and IgE antibody measurement, respectively. 20 children had a confirmed food allergy (most commonly to cow’s milk and peanuts), while almost half of the children without a diagnosed food allergy were sensitised to common food allergens after a food challenge. The study identified a faecal microbial signature in children with AD that differentiates between the presence and absence of food allergy. Children with AD and food allergy had more Escherichia coli and Bifidobacterium pseudocatenulatum species and less Bifidobacterium breve, Faecalibacterium prausnitzii and Akkermansia muciniphila species than children without food allergy. The authors concluded that the study supports a hypothesis that the intestinal microbiome differs in children with AD, depending on whether they have a food allergy or not. They call for future studies to confirm these findings.
Abstract
BACKGROUND Exposure to microbes may be important in the development of atopic disease. Atopic diseases have been associated with specific characteristics of the intestinal microbiome. The link between intestinal microbiota and food allergy has rarely been studied, and the gold standard for diagnosing food allergy (double-blind placebo-controlled food challenge [DBPCFC]) has seldom been used. We aimed to distinguish fecal microbial signatures for food allergy in children with atopic dermatitis (AD). METHODS Pediatric patients with AD, with and without food allergy, were included in this cross-sectional observational pilot study. AD was diagnosed according to the UK Working Party criteria. Food allergy was defined as a positive DBPCFC or a convincing clinical history, in combination with sensitization to the relevant food allergen. Fecal samples were analyzed using 16S rRNA microbial analysis. Microbial signature species, discriminating between the presence and absence food allergy, were selected by elastic net regression. RESULTS Eighty-two children with AD (39 girls) with a median age of 2.5 years, and 20 of whom were diagnosed with food allergy, provided fecal samples. Food allergy to peanut and cow's milk was the most common. Six bacterial species from the fecal microbiome were identified, that, when combined, distinguished between children with and without food allergy: Bifidobacterium breve, Bifidobacterium pseudocatenulatum, Bifidobacterium adolescentis, Escherichia coli, Faecalibacterium prausnitzii, and Akkermansia muciniphila (AUC 0.83, sensitivity 0.77, specificity 0.80). CONCLUSIONS In this pilot study, we identified a microbial signature in children with AD that discriminates between the absence and presence of food allergy. Future studies are needed to confirm our findings.
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The microbiome and autoimmunity: a paradigm from the gut-liver axis.
Li, B, Selmi, C, Tang, R, Gershwin, ME, Ma, X
Cellular & molecular immunology. 2018;15(6):595-609
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The incidence of autoimmune and inflammatory diseases has been increasing worldwide. Changes in environmental factors, such as modern lifestyle, diet, antibiotics and hygiene are thought to play a critical role in the development of various autoimmune diseases. It is the mucosal microbial flora that is shaped by our environment and communicates with the innate and adaptive immune systems, and when disrupted, can lead to the loss of immune tolerance and dysregulated immune cells. This review paper provides an overview of the interactions between the intestinal microbiome and the immune system. It explains how these interactions affect host autoimmunity locally and systemically and sheds light on the molecular mechanisms, utilised by microbes that may contribute to systemic autoimmunity in genetically susceptible individuals. The links between the gut microbiome and various autoimmune diseases, such as rheumatoid arthritis, type 1 diabetes and multiple sclerosis, as well as the gut-liver axis, involving intestinal microbiome and autoimmune liver diseases, are discussed in more detail.
Abstract
Microbial cells significantly outnumber human cells in the body, and the microbial flora at mucosal sites are shaped by environmental factors and, less intuitively, act on host immune responses, as demonstrated by experimental data in germ-free and gnotobiotic studies. Our understanding of this link stems from the established connection between infectious bacteria and immune tolerance breakdown, as observed in rheumatic fever triggered by Streptococci via molecular mimicry, epitope spread and bystander effects. The availability of high-throughput techniques has significantly advanced our capacity to sequence the microbiome and demonstrated variable degrees of dysbiosis in numerous autoimmune diseases, including rheumatoid arthritis, type 1 diabetes, multiple sclerosis and autoimmune liver disease. It remains unknown whether the observed differences are related to the disease pathogenesis or follow the therapeutic and inflammatory changes and are thus mere epiphenomena. In fact, there are only limited data on the molecular mechanisms linking the microbiota to autoimmunity, and microbial therapeutics is being investigated to prevent or halt autoimmune diseases. As a putative mechanism, it is of particular interest that the apoptosis of intestinal epithelial cells in response to microbial stimuli enables the presentation of self-antigens, giving rise to the differentiation of autoreactive Th17 cells and other T helper cells. This comprehensive review will illustrate the data demonstrating the crosstalk between intestinal microbiome and host innate and adaptive immunity, with an emphasis on how dysbiosis may influence systemic autoimmunity. In particular, a gut-liver axis involving the intestinal microbiome and hepatic autoimmunity is elucidated as a paradigm, considering its anatomic and physiological connections.
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Reversing the immune ageing clock: lifestyle modifications and pharmacological interventions.
Duggal, NA
Biogerontology. 2018;19(6):481-496
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Advancing age is accompanied by a compromised ability of older adults to combat bacterial and viral infections, increased risk of autoimmunity, poor vaccination responses and the re-emergence of latent infections. This review discusses current understanding of immunesenescence [the gradual deterioration of our immune system as we get older] and also focuses on lifestyle interventions and therapeutic strategies that have been shown to restore immune functioning in aged individuals. Findings show that: - changes in nutrition and lifestyle can be an effective approach towards improving immune outcome in older adults but may be hard to achieve at a population level. - improving immune responses, such as the developments of vaccines, may be used as an early biomarker for anti-ageing effects. Authors conclude that immunomodulation represents a promising therapeutic approach to improve the health of older adults.
Abstract
It is widely accepted that ageing is accompanied by remodelling of the immune system, including reduced numbers of naïve T cells, increased senescent or exhausted T cells, compromise to monocyte, neutrophil and natural killer cell function and an increase in systemic inflammation. In combination these changes result in increased risk of infection, reduced immune memory, reduced immune tolerance and immune surveillance, with significant impacts upon health in old age. More recently it has become clear that the rate of decline in the immune system is malleable and can be influenced by environmental factors such as physical activity as well as pharmacological interventions. This review discusses briefly our current understanding of immunesenescence and then focuses on lifestyle interventions and therapeutic strategies that have been shown to restore immune functioning in aged individuals.
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SunGold Kiwifruit Supplementation of Individuals with Prediabetes Alters Gut Microbiota and Improves Vitamin C Status, Anthropometric and Clinical Markers.
Wilson, R, Willis, J, Gearry, RB, Hughes, A, Lawley, B, Skidmore, P, Frampton, C, Fleming, E, Anderson, A, Jones, L, et al
Nutrients. 2018;10(7)
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Increased plasma glucose levels are linked with increased oxidative stress. An increase in the uptake of antioxidants such as vitamin C through diet has been demonstrated by several studies as contributing to the maintenance of normal glucose levels and reducing the risk factors for Type 2 diabetes. The aim of this study was to investigate the vitamin C status, anthropometric measurements and faecal microbiota of an individual on consumption of high vitamin C kiwi fruit for a period of 12 weeks. Baseline measures were compared at the end of 12 weeks resulting in significant increase in plasma vitamin C status (14 µmol/L, p < 0.001). Significant reduction in blood pressure measurement (4 mmHg, p = 0.029), reduction in waist- to- hip ratio and waist- circumference, decrease in blood glucose marker HbA1c (1 mmol/mol, p = 0.005) and increase in fasting glucose (0.1 mmol/L, p = 0.046) were also observed at the end of twelve weeks. Faecal microbiota composition showed an increase in the abundance of uncharacterised bacterial family. The authors concluded that these result were not sufficiently significant to draw conclusions and further studies with larger sample sizes are required to confirm the outcomes of this study.
Abstract
Kiwifruit are a nutrient dense food and an excellent source of vitamin C. Supplementation of the diet with kiwifruit enhances plasma vitamin C status and epidemiological studies have shown an association between vitamin C status and reduced insulin resistance and improved blood glucose control. In vitro experiments suggest that eating kiwifruit might induce changes to microbiota composition and function; however, human studies to confirm these findings are lacking. The aim of this study was to investigate the effect of consuming two SunGold kiwifruit per day over 12 weeks on vitamin C status, clinical and anthropometric measures and faecal microbiota composition in people with prediabetes. This pilot intervention trial compared baseline measurements with those following the intervention. Participants completed a physical activity questionnaire and a three-day estimated food diary at baseline and on completion of the trial. Venous blood samples were collected at each study visit (baseline, 6, 12 weeks) for determination of glycaemic indices, plasma vitamin C concentrations, hormones, lipid profiles and high-sensitivity C-reactive protein. Participants provided a faecal sample at each study visit. DNA was extracted from the faecal samples and a region of the 16S ribosomal RNA gene was amplified and sequenced to determine faecal microbiota composition. When week 12 measures were compared to baseline, results showed a significant increase in plasma vitamin C (14 µmol/L, p < 0.001). There was a significant reduction in both diastolic (4 mmHg, p = 0.029) and systolic (6 mmHg, p = 0.003) blood pressure and a significant reduction in waist circumference (3.1 cm, p = 0.001) and waist-to-hip ratio (0.01, p = 0.032). Results also showed a decrease in HbA1c (1 mmol/mol, p = 0.005) and an increase in fasting glucose (0.1 mmol/L, p = 0.046), however, these changes were small and were not clinically significant. Analysis of faecal microbiota composition showed an increase in the relative abundance of as yet uncultivated and therefore uncharacterised members of the bacterial family Coriobacteriaceae. Novel bacteriological investigations of Coriobacteriaceae are required to explain their functional relationship to kiwifruit polysaccharides and polyphenols.
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Navy Beans Impact the Stool Metabolome and Metabolic Pathways for Colon Health in Cancer Survivors.
Baxter, BA, Oppel, RC, Ryan, EP
Nutrients. 2018;11(1)
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Colorectal cancer (CRC) is one of the leading cause of cancer-related death around the world. Emerging evidence supports that increased consumption of pulses / legumes, such as navy beans, can reduce risk. Consuming navy beans as part of one's diet has been previously shown to positively affect the relationship between a person's gut bacteria and their health status. This study looked at stool samples to assess the impact of navy bean consumption on health based on the by-products of metabolism generated by gut bacteria (metabolites). The study was a 4-week, randomised-controlled trial with overweight and obese CRC survivors and involved consumption of 1 meal and 1 snack daily. People in the intervention group ate 35g of cooked navy bean daily whereas those in the control group had 0g of navy beans. From amongst the hundreds of metabolites identified in both groups, there was a 5-fold increase in ophthalmate for navy bean consumers, which can indicate an increase in glutathione. Glutathione is an antioxidant and detoxifying substance produced in the human liver. It is involved in cancer control mechanisms such as detoxification of xenobiotics (toxins), antioxidant defense, proliferation, and apoptosis. Other interesting results include the metabolism of the amino acid lysine, which supports health immune function, and an increase in plant-based nutrients or phytochemicals in those who consumed navy bean vs the control group. These results are indicative of an acute response to increased navy bean intake, which merit further investigation for improving colonic health after long-term consumption.
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer-related death in the United States and emerging evidence supports that increased consumption of legumes, such as navy beans, can reduce risk. Navy bean consumption was previously shown to modulate host and microbiome metabolism, and this investigation was performed to assess the impact on the human stool metabolome, which includes the presence of navy bean metabolites. This 4-week, randomized-controlled trial with overweight and obese CRC survivors involved consumption of 1 meal and 1 snack daily. The intervention contained 35 g of cooked navy bean or macronutrient matched meals and snacks with 0 g of navy beans for the control group (n = 18). There were 30 statistically significant metabolite differences in the stool of participants that consumed navy bean at day 28 compared to the participants' baseline (p ≤ 0.05) and 26 significantly different metabolites when compared to the control group. Of the 560 total metabolites identified from the cooked navy beans, there were 237 possible navy bean-derived metabolites that were identified in the stool of participants consuming navy beans, such as N-methylpipecolate, 2-aminoadipate, piperidine, and vanillate. The microbial metabolism of amino acids and fatty acids were also identified in stool after 4 weeks of navy bean intake including cadaverine, hydantoin-5 propionic acid, 4-hydroxyphenylacetate, and caprylate. The stool relative abundance of ophthalmate increased 5.25-fold for navy bean consumers that can indicate glutathione regulation, and involving cancer control mechanisms such as detoxification of xenobiotics, antioxidant defense, proliferation, and apoptosis. Metabolic pathways involving lysine, and phytochemicals were also modulated by navy bean intake in CRC survivors. These metabolites and metabolic pathways represent an acute response to increased navy bean intake, which merit further investigation for improving colonic health after long-term consumption.
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From good health to illness with post-infectious fatigue syndrome: a qualitative study of adults' experiences of the illness trajectory.
Stormorken, E, Jason, LA, Kirkevold, M
BMC family practice. 2017;18(1):49
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In 2004, the parasite Giardia lamblia [parasitic microorganism] contaminated the municipal drinking water reservoir in Bergen, Norway, which caused an outbreak of gastrointestinal infection. The aim of this study was to explore the evolvement of illness trajectory from the onset of the Giardia l. enteritis [inflammation of the small intestine] and identify any concomitant disabilities over the subsequent four years. This study had a retrospective explorative qualitative design. In-depth qualitative interviews were done in order to gain access to the participants’ experiences and conducted an inductive qualitative content analysis. Findings show five distinct progressive phases of the illness and disability trajectory. The time to develop post-infectious fatigue syndrome varied from one participant to the other. None of the participants experienced full remission, pre-illness functional level, or experienced a good outcome. Authors conclude that comparison of the functional trajectory in post-infectious fatigue syndrome cases and cases with an unknown trigger mechanism would be helpful to identify any differences in trajectories.
Abstract
BACKGROUND Municipal drinking water contaminated with the parasite Giardia lamblia in Bergen, Norway, in 2004 caused an outbreak of gastrointestinal infection in 2500 people, according to the Norwegian Prescription Database. In the aftermath a minor group subsequently developed post-infectious fatigue syndrome (PIFS). Persons in this minor group had laboratory-confirmed parasites in their stool samples, and their enteritis had been cured by one or more courses of antibiotic treatment. The study's purpose was to explore how the affected persons experienced the illness trajectory and various PIFS disabilities. METHODS A qualitative design with in-depth interviews was used to obtain first-hand experiences of PIFS. To get an overall understanding of their perceived illness trajectory, the participants were asked to retrospectively rate their functional level at different points in time. A maximum variation sample of adults diagnosed with PIFS according to the international 1994 criteria was recruited from a cohort of persons diagnosed with PIFS at a tertiary Neurology Outpatient Clinic in Western Norway. The sample comprised 19 women and seven men (mean age 41 years, range 26-59). The interviews were fully transcribed and subjected to a qualitative content analysis. RESULTS All participants had been living healthy lives pre-illness. The time to develop PIFS varied. Multiple disabilities in the physical, cognitive, emotional, neurological, sleep and intolerance domains were described. Everyone more or less dropped out from studies or work, and few needed to be taken care of during the worst period. The severity of these disabilities varied among the participants and during the illness phases. Despite individual variations, an overall pattern of illness trajectory emerged. Five phases were identified: prodromal, downward, turning, upward and chronic phase. All reached a nadir followed by varying degrees of improvement in their functional ability. None regained pre-illness health or personal and professional abilities. CONCLUSIONS The needs of persons with this condition are not met. Early diagnosis and interdisciplinary rehabilitation could be beneficial in altering the downward trajectory at an earlier stage, avoiding the most severe disability and optimising improvement. Enhanced knowledge among health professionals, tailored treatment, rest as needed, financial support and practical help would likely improve prognosis.
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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.