Potential role of microbiome in Chronic Fatigue Syndrome/Myalgic Encephalomyelits

Abstract:

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is a severe multisystemic disease characterized by immunological abnormalities and dysfunction of energy metabolism. Recent evidences suggest strong correlations between dysbiosis and pathological condition. The present research explored the composition of the intestinal and oral microbiota in CFS/ME patients as compared to healthy controls. The fecal metabolomic profile of a subgroup of CFS/ME patients was also compared with the one of healthy controls. The fecal and salivary bacterial composition in CFS/ME patients was investigated by Illumina sequencing of 16S rRNA gene amplicons. The metabolomic analysis was performed by an UHPLC-MS.

The fecal microbiota of CFS/ME patients showed a reduction of Lachnospiraceae, particularly Anaerostipes, and an increased abundance of genera Bacteroides and Phascolarctobacterium compared to the non-CFS/ME groups. The oral microbiota of CFS/ME patients showed an increase of Rothia dentocariosa. The fecal metabolomic profile of CFS/ME patients revealed high levels of glutamic acid and argininosuccinic acid, together with a decrease of alpha-tocopherol. Our results reveal microbial signatures of dysbiosis in the intestinal microbiota of CFS/ME patients. Further studies are needed to better understand if the microbial composition changes are cause or consequence of the onset of CFS/ME and if they are related to any of the several secondary symptoms.

Source: Lupo, G.F.D., Rocchetti, G., Lucini, L. et al. Potential role of microbiome in Chronic Fatigue Syndrome/Myalgic Encephalomyelits (CFS/ME). Sci Rep 11, 7043 (2021). https://doi.org/10.1038/s41598-021-86425-6 https://www.nature.com/articles/s41598-021-86425-6 (Full text)

Multi-omics examination of Q fever fatigue syndrome identifies similarities with chronic fatigue syndrome

Abstract:

Background: Q fever fatigue syndrome (QFS) is characterised by a state of prolonged fatigue that is seen in 20% of acute Q fever infections and has major health-related consequences. The molecular mechanisms underlying QFS are largely unclear. In order to better understand its pathogenesis, we applied a multi-omics approach to study the patterns of the gut microbiome, blood metabolome, and inflammatory proteome of QFS patients, and compared these with those of chronic fatigue syndrome (CFS) patients and healthy controls (HC).

Methods: The study population consisted of 31 QFS patients, 50 CFS patients, and 72 HC. All subjects were matched for age, gender, and general geographical region (South-East part of the Netherlands). The gut microbiome composition was assessed by Metagenomic sequencing using the Illumina HiSeq platform. A total of 92 circulating inflammatory markers were measured using Proximity Extension Essay and 1607 metabolic features were assessed with a high-throughput non-targeted metabolomics approach.

Results: Inflammatory markers, including 4E-BP1 (P = 9.60-16 and 1.41-7) and MMP-1 (P = 7.09-9 and 3.51-9), are significantly more expressed in both QFS and CFS patients compared to HC. Blood metabolite profiles show significant differences when comparing QFS (319 metabolites) and CFS (441 metabolites) patients to HC, and are significantly enriched in pathways like sphingolipid (P = 0.0256 and 0.0033) metabolism. When comparing QFS to CFS patients, almost no significant differences in metabolome were found. Comparison of microbiome taxonomy of QFS and CFS patients with that of HC, shows both in- and decreases in abundancies in Bacteroidetes (with emphasis on Bacteroides and Alistiples spp.), and Firmicutes and Actinobacteria (with emphasis on Ruminococcus and Bifidobacterium spp.). When we compare QFS patients to CFS patients, there is a striking resemblance and hardly any significant differences in microbiome taxonomy are found.

Conclusions: We show that QFS and CFS patients are similar across three different omics layers and 4E-BP1 and MMP-1 have the potential to distinguish QFS and CFS patients from HC.

Source: Raijmakers RPH, Roerink ME, Jansen AFM, Keijmel SP, Gacesa R, Li Y, Joosten LAB, van der Meer JWM, Netea MG, Bleeker-Rovers CP, Xu CJ. Multi-omics examination of Q fever fatigue syndrome identifies similarities with chronic fatigue syndrome. J Transl Med. 2020 Nov 26;18(1):448. doi: 10.1186/s12967-020-02585-5. PMID: 33243243. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-020-02585-5  (Full text)

Deep phenotyping of myalgic encephalomyelitis/chronic fatigue syndrome in Japanese population

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and debilitating disease with no molecular diagnostics and no treatment options. To identify potential markers of this illness, we profiled 48 patients and 52 controls for standard laboratory tests, plasma metabolomics, blood immuno-phenotyping and transcriptomics, and fecal microbiome analysis. Here, we identified a set of 26 potential molecular markers that distinguished ME/CFS patients from healthy controls. Monocyte number, microbiome abundance, and lipoprotein profiles appeared to be the most informative markers.

When we correlated these molecular changes to sleep and cognitive measurements of fatigue, we found that lipoprotein and microbiome profiles most closely correlated with sleep disruption while a different set of markers correlated with a cognitive parameter. Sleep, lipoprotein, and microbiome changes occur early during the course of illness suggesting that these markers can be examined in a larger cohort for potential biomarker application. Our study points to a cluster of sleep-related molecular changes as a prominent feature of ME/CFS in our Japanese cohort.

Source: Kitami T, Fukuda S, Kato T, Yamaguti K, Nakatomi Y, Yamano E, Kataoka Y, Mizuno K, Tsuboi Y, Kogo Y, Suzuki H, Itoh M, Morioka MS, Kawaji H, Koseki H, Kikuchi J, Hayashizaki Y, Ohno H, Kuratsune H, Watanabe Y. Deep phenotyping of myalgic encephalomyelitis/chronic fatigue syndrome in Japanese population. Sci Rep. 2020 Nov 16;10(1):19933. doi: 10.1038/s41598-020-77105-y. PMID: 33199820; PMCID: PMC7669873.  https://www.nature.com/articles/s41598-020-77105-y (Full text)

Modification of Immunological Parameters, Oxidative Stress Markers, Mood Symptoms, and Well-Being Status in CFS Patients after Probiotic Intake: Observations from a Pilot Study

Abstract:

The present study discusses about the effects of a combination of probiotics able to stimulate the immune system of patients affected by Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). To this purpose, patients diagnosed according to Fukuda’s criteria and treated with probiotics were analyzed by means of clinical and laboratory evaluations, before and after probiotic administrations.

Probiotics were selected considering the possible pathogenic mechanisms of ME/CFS syndrome, which has been associated with an impaired immune response, dysregulation of Th1/Th2 ratio, and high oxidative stress with exhaustion of antioxidant reserve due to severe mitochondrial dysfunction. Immune and oxidative dysfunction could be related with the gastrointestinal (GI) chronic low-grade inflammation in the lamina propria and intestinal mucosal surface associated with dysbiosis, leaky gut, bacterial translocation, and immune and oxidative dysfunction.

Literature data demonstrate that bacterial species are able to modulate the functions of the immune and oxidative systems and that the administration of some probiotics can improve mucosal barrier function, modulating the release of proinflammatory cytokines, in CFS/ME patients. This study represents a preliminary investigation to verifying the safety and efficacy of a certain combination of probiotics in CFS/ME patients. The results suggest that probiotics can modify the well-being status as well as inflammatory and oxidative indexes in CFS/ME patients.

No adverse effects were observed except for one patient, which displayed a flare-up of symptoms, although all inflammatory parameters (i.e., cytokines, fecal calprotectin, ESR, and immunoglobulins) were reduced after probiotic intake. The reactivation of fatigue symptoms in this patient, whose clinical history reported the onset of CFS/ME following mononucleosis, could be related to an abnormal stimulation of the immune system as suggested by a recent study describing an exaggerated immune activation associated with chronic fatigue.

Copyright © 2019 Letizia Venturini et al.

Source: Venturini L, Bacchi S, Capelli E, Lorusso L, Ricevuti G, Cusa C. Modification of Immunological Parameters, Oxidative Stress Markers, Mood Symptoms, and Well-Being Status in CFS Patients after Probiotic Intake: Observations from a Pilot Study. Oxid Med Cell Longev. 2019 Nov 23;2019:1684198. doi: 10.1155/2019/1684198. eCollection 2019. https://www.hindawi.com/journals/omcl/2019/1684198/ (Full study)

Phylogenetic Tree-based Microbiome Association Test

Abstract:

MOTIVATION: Ecological patterns of the human microbiota exhibit high inter-subject variation, with few operational taxonomic units (OTUs) shared across individuals. To overcome these issues, non-parametric approaches, such as the Mann-Whitney U-test and Wilcoxon rank-sum test, have often been used to identify OTUs associated with host diseases. However, these approaches only use the ranks of observed relative abundances, leading to information loss, and are associated with high false-negative rates. In this study, we propose a phylogenetic tree-based microbiome association test (TMAT) to analyze the associations between microbiome OTU abundances and disease phenotypes. Phylogenetic trees illustrate patterns of similarity among different OTUs, and TMAT provides an efficient method for utilizing such information for association analyses. The proposed TMAT provides test statistics for each node, which are combined to identify mutations associated with host diseases.

RESULTS: Power estimates of TMAT were compared with existing methods using extensive simulations based on real absolute abundances. Simulation studies showed that TMAT preserves the nominal type-1 error rate, and estimates of its statistical power generally outperformed existing methods in the considered scenarios. Furthermore, TMAT can be used to detect phylogenetic mutations associated with host diseases, providing more in-depth insight into bacterial pathology.

AVAILABILITY: The 16S rRNA amplicon sequencing metagenomics datasets for colorectal carcinoma and myalgic encephalomyelitis/chronic fatigue syndrome are available from the European Nucleotide Archive (ENA) database under project accession number PRJEB6070 and PRJEB13092, respectively. TMAT was implemented in the R package. Detailed information is available at http://healthstat.snu.ac.kr/software/tmat.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

© The Author(s) (2019). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Source: Kim KJ, Park J, Park SC, Won S. Phylogenetic Tree-based Microbiome Association Test. Bioinformatics. 2019 Sep 3. pii: btz686. doi: 10.1093/bioinformatics/btz686. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31504188

Gut bacteria associated with chronic pain for first time

Press Release:

Scientists have found a correlation between a disease involving chronic pain and alterations in the gut microbiome.

Fibromyalgia affects 2-4 percent of the population and has no known cure. Symptoms include fatigue, impaired sleep and cognitive difficulties, but the disease is most clearly characterized by widespread chronic pain. In a paper published today in the journal Pain, a Montreal-based research team has shown, for the first time, that there are alterations in the bacteria in the gastrointestinal tracts of people with fibromyalgia. Approximately 20 different species of bacteria were found in either greater or are lesser quantities in the microbiomes of participants suffering from the disease than in the healthy control group.

Greater presence or absence of certain species of bacteria

“We used a range of techniques, including Artificial Intelligence, to confirm that the changes we saw in the microbiomes of fibromyalgia patients were not caused by factors such as diet, medication, physical activity, age, and so on, which are known to affect the microbiome,” says Dr. Amir Minerbi, from the Alan Edwards Pain Management Unit at the McGill University Health Centre (MUHC), and first author on the paper. The team also included researchers from McGill University and Université de Montréal as well as others from the Research Institute of the MUHC.

Dr. Minerbi adds, “We found that fibromyalgia and the symptoms of fibromyalgia – pain, fatigue and cognitive difficulties – contribute more than any of the other factors to the variations we see in the microbiomes of those with the disease. We also saw that the severity of a patient’s symptoms was directly correlated with an increased presence or a more pronounced absence of certain bacteria – something which has never been reported before.”

Are bacteria simply the markers of the disease?

At this point, it’s not clear whether the changes in gut bacteria seen in patients with fibromyalgia are simply markers of the disease or whether they play a role in causing it. Because the disease involves a cluster of symptoms, and not simply pain, the next step in the research will be to investigate whether there are similar changes in the gut microbiome in other conditions involving chronic pain, such as lower back pain, headaches and neuropathic pain.

The researchers are also interested in exploring whether bacteria play a causal role in the development of pain and fibromyalgia. And whether their presence could, eventually, help in finding a cure, as well as speed up the process of diagnosis.

Confirming a diagnosis and next steps towards finding a cure

Fibromyalgia is a disease that has proved difficult to diagnose. Patients can wait as long as 4 to 5 years to get a final diagnosis. But this may be about to change.

“We sorted through large amounts of data, identifying 19 species that were either increased or decreased in individuals with fibromyalgia,” says Emmanuel Gonzalez, from the Canadian Center for Computational Genomics and the Department of Human Genetics at McGill University. “By using machine learning, our computer was able to make a diagnosis of fibromyalgia, based only on the composition of the microbiome, with an accuracy of 87 per cent. As we build on this first discovery with more research, we hope to improve upon this accuracy, potentially creating a step-change in diagnosis.”

“People with fibromyalgia suffer not only from the symptoms of their disease but also from the difficulty of family, friends and medical teams to comprehend their symptoms,” says Yoram Shir, the senior author on the paper who is the Director of the Alan Edwards Pain Management Unit at the MUHC and an Associate Investigator from the BRaiN Program of the RI-MUHC. “As pain physicians, we are frustrated by our inability to help, and this frustration is a good fuel for research. This is the first evidence, at least in humans, that the microbiome could have an effect on diffuse pain, and we really need new ways to look at chronic pain.”

How the research was done

The research was based on a cohort of 156 individuals in the Montreal area, 77 of whom suffer from fibromyalgia. Participants in the study were interviewed and gave stool, blood, saliva and urine samples, which were then compared with those of healthy control subjects, some of whom lived in the same house as the fibromyalgia patients or were their parents, offspring or siblings.

The researchers’ next steps will be to see whether they get similar results in another cohort, perhaps in a different part of the world, and to do studies in animals to discover whether changes in bacteria play a role in the development of the disease.

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To read the article, “Altered microbiome composition in individuals with fibromyalgia” by Amir Minerbi et al in Pain: https://journals.lww.com/pain/Abstract/publishahead/Altered_microbiome_composition_in_individuals_with.98647.aspx

The research was funded by the Louise and Alan Edwards Foundation and the Israeli Society for Musculoskeletal Medicine.

Contact:

Julie Robert
Communications (Research)
McGill University Health Centre
T : 514 934-1934 ext. 71381
C : 514 971-4747
julie.robert@muhc.mcgill.ca
muhc.ca I rimuhc.ca

Altered microbiome composition in individuals with fibromyalgia

Abstract:

Fibromyalgia (FM) is a prevalent syndrome, characterised by chronic widespread pain, fatigue and impaired sleep, that is challenging to diagnose and difficult to treat. The microbiomes of 77 women with FM and that of 79 control participants were compared using 16S rRNA gene amplification and whole genome sequencing.

When comparing FM patients to unrelated controls using differential abundance analysis, significant differences were revealed in several bacterial taxa. Variance in the composition of the microbiomes was explained by FM-related variables more than by any other innate or environmental variable and correlated with clinical indices of FM. In line with observed alteration in butyrate metabolising species, targeted serum metabolite analysis verified differences in the serum levels of butyrate and propionate in FM patients.

Using machine learning algorithms, the microbiome composition alone allowed for the classification of patients and controls (ROC AUC 87.8%). To the best of our knowledge, this is the first demonstration of gut microbiome alteration in non-visceral pain. This observation paves the way for further studies, elucidating the pathophysiology of FM, developing diagnostic aids and possibly allowing for new treatment modalities to be explored.

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Source: Minerbi, Amir; Gonzalez, Emmanuel; Brereton, Nicholas J.B.; Anjarkouchian, Abraham; Dewar, Ken; Fitzcharles, Mary-Ann; Chevalier, Stéphanie; Shir, Yoram. Altered microbiome composition in individuals with fibromyalgia. PAIN: June 18, 2019 – Volume Articles in Press doi: 10.1097/j.pain.0000000000001640 https://journals.lww.com/pain/Abstract/publishahead/Altered_microbiome_composition_in_individuals_with.98647.aspx

A systematic review of enteric dysbiosis in chronic fatigue syndrome/myalgic encephalomyelitis

Abstract:

BACKGROUND: Chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is an illness characterised by profound and pervasive fatigue in addition to a heterogeneous constellation of symptoms. The aetiology of this condition remains unknown; however, it has been previously suggested that enteric dysbiosis is implicated in the pathogenesis of CFS/ME. This review examines the evidence currently available for the presence of abnormal microbial ecology in CFS/ME in comparison to healthy controls, with one exception being probiotic-supplemented CFS/ME patients, and whether the composition of the microbiome plays a role in symptom causation.

METHODS: EMBASE, Medline (via EBSCOhost), Pubmed and Scopus were systematically searched from 1994 to March 2018. All studies that investigated the gut microbiome composition of CFS/ME patients were initially included prior to the application of specific exclusion criteria. The association between these findings and patient-centred outcomes (fatigue, quality of life, gastrointestinal symptoms, psychological wellbeing) are also reported.

RESULTS: Seven studies that met the inclusion criteria were included in the review. The microbiome composition of CFS/ME patients was compared with healthy controls, with the exception of one study that compared to probiotic-supplemented CFS/ME patients. Differences were reported in each study; however, only three were considered statistically significant, and the findings across all studies were inconsistent. The quality of the studies included in this review scored between poor (< 54%), fair (54-72%) and good (94-100%) using the Downs and Black checklist.

CONCLUSIONS: There is currently insufficient evidence for enteric dysbiosis playing a significant role in the pathomechanism of CFS/ME. Recommendations for future research in this field include the use of consistent criteria for the diagnosis of CFS/ME, reduction of confounding variables by controlling factors that influence microbiome composition prior to sample collection and including more severe cases of CFS/ME.

Source: Du Preez S, Corbitt M, Cabanas H, Eaton N, Staines D, Marshall-Gradisnik S. A systematic review of enteric dysbiosis in chronic fatigue syndrome/myalgic encephalomyelitis. Syst Rev. 2018 Dec 20;7(1):241. doi: 10.1186/s13643-018-0909-0. https://systematicreviewsjournal.biomedcentral.com/articles/10.1186/s13643-018-0909-0 (Full article)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in the Era of the Human Microbiome: Persistent Pathogens Drive Chronic Symptoms by Interfering With Host Metabolism, Gene Expression, and Immunity

Abstract:

The illness ME/CFS has been repeatedly tied to infectious agents such as Epstein Barr Virus. Expanding research on the human microbiome now allows ME/CFS-associated pathogens to be studied as interacting members of human microbiome communities. Humans harbor these vast ecosystems of bacteria, viruses and fungi in nearly all tissue and blood. Most well-studied inflammatory conditions are tied to dysbiosis or imbalance of the human microbiome. While gut microbiome dysbiosis has been identified in ME/CFS, microbes and viruses outside the gut can also contribute to the illness.

Pathobionts, and their associated proteins/metabolites, often control human metabolism and gene expression in a manner that pushes the body toward a state of illness. Intracellular pathogens, including many associated with ME/CFS, drive microbiome dysbiosis by directly interfering with human transcription, translation, and DNA repair processes. Molecular mimicry between host and pathogen proteins/metabolites further complicates this interference. Other human pathogens disable mitochondria or dysregulate host nervous system signaling. Antibodies and/or clonal T cells identified in patients with ME/CFS are likely activated in response to these persistent microbiome pathogens.

Different human pathogens have evolved similar survival mechanisms to disable the host immune response and host metabolic pathways. The metabolic dysfunction driven by these organisms can result in similar clusters of inflammatory symptoms. ME/CFS may be driven by this pathogen-induced dysfunction, with the nature of dysbiosis and symptom presentation varying based on a patient’s unique infectious and environmental history. Under such conditions, patients would benefit from treatments that support the human immune system in an effort to reverse the infectious disease process.

Source: Proal A, Marshall T. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in the Era of the Human Microbiome: Persistent Pathogens Drive Chronic Symptoms by Interfering With Host Metabolism, Gene Expression, and Immunity. Front Pediatr. 2018 Dec 4;6:373. doi: 10.3389/fped.2018.00373. eCollection 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288442/ (Full article)

Chronic fatigue syndrome patients have alterations in their oral microbiome composition and function

Abstract:

Host-microbe interactions have been implicated in the pathogenesis of chronic fatigue syndrome (CFS), but whether the oral microbiome is altered in CFS patients is unknown. We explored alterations of the oral microbiome in Chinese Han CFS patients using 16S rRNA gene sequencing and alterations in the functional potential of the oral microbiome using PICRUSt.

We found that Shannon and Simpson diversity indices were not different in CFS patients compared to healthy controls, but the overall oral microbiome composition was different (MANOVA, p < 0.01). CFS patients had a higher relative abundance of Fusobacteria compared with healthy controls. Further, the genera Leptotrichia, Prevotella, and Fusobacterium were enriched and Haemophilus, Veillonella, and Porphyromonas were depleted in CFS patients compared to healthy controls. Functional analysis from inferred metagenomes showed that bacterial genera altered in CFS patients were primarily associated with amino acid and energy metabolism.

Our findings demonstrate that the oral microbiome in CFS patients is different from healthy controls, and these differences lead to shifts in functional pathways with implications for CFS pathogenesis. These findings increase our understanding of the relationship between the oral microbiota and CFS, which will advance our understanding of CFS pathogenesis and may contribute to future improvements in treatment and diagnosis.

Source: Wang T, Yu L, Xu C, Pan K, Mo M, Duan M, Zhang Y, Xiong H. Chronic fatigue syndrome patients have alterations in their oral microbiome composition and function. PLoS One. 2018 Sep 11;13(9):e0203503. doi:
10.1371/journal.pone.0203503. eCollection 2018. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203503 (Full article)