TGI Friday! Our weekly round-up of recently published research abstracts | 18 November 2016

November 18, 2016

From Gut Microbes, 3 November 2016.

Support for the Microgenderome Invites Enquiry into Sex Differences

Amy Wallis(1), Henry Butt(2), Michelle Ball(1), Donald P. Lewis(3) & Dorothy Bruck (1)
(1) Psychology Department, Victoria University, Victoria, Australia
(2) Bioscreen (Aust) Pty Ltd, Victoria, Australia
(3) CFS Discovery Clinic, Donvale, Victoria, Australia


The microgenderome defines the interaction between microbiota, sex hormones and the immune system. Our recent research inferred support for the microgenderome by showing sex differences in microbiota-symptom associations in a clinical sample of patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS).

This addendum expands upon the sex-specific pattern of associations that were observed. Interpretations are hypothesised in relation to genera versus species-level analyses and D-lactate theory.

Evidence of sex-differences invites future research to consider sex comparisons in microbial function even when microbial abundance is statistically similar. Pairing assessment of clinical symptoms with microbial culture, DNA sequencing and metabolomics methods will help advance our current understandings of the role of the microbiome in health and disease.

From Fatigue: Biomedicine, Health & Behavior (journal of the International Association for CFS/ME), 12 October 2016.

Mortality in patients with myalgic encephalomyelitis and chronic fatigue syndrome

Stephanie L. McManimen, Andrew R. Devendorf, Abigail A. Brown, Billie C. Moore, James H. Moore & Leonard A. Jason
Center for Community Research, De Paul University, Chicago, Illinois, USA



There is a dearth of research examining mortality in individuals with myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). Some studies suggest there is an elevated risk of suicide and earlier mortality compared to national norms. However, findings are inconsistent.


This study sought to determine if patients are reportedly dying earlier than the overall population from the same cause.


Family, friends, and caregivers of deceased patients were recruited. This study analyzed data including cause and age of death for 56 individuals.


The findings suggest patients in this sample are at a significantly increased risk of earlier all-cause (M = 55.9 years) and cardiovascular-related (M = 58.8 years) mortality, and they had a directionally lower age of death for suicide (M = 41.3 years) and cancer (M = 66.3 years) compared to the overall U.S. population [M = 73.5 (all-cause), 77.7 (cardiovascular), 47.4 (suicide), and 71.1 (cancer) years of age].


Results suggest there is an increase in risk for earlier mortality in patients. Due to sample size and over-representation of severely ill patients, the findings should be replicated to determine if the directional differences for suicide and cancer mortality are significantly different from the overall population.

From PLoS One, 2 November 2016.

Metagenomic Investigation of Plasma in Individuals with ME/CFS Highlights the Importance of Technical Controls to Elucidate Contamination and Batch Effects

Ruth R. Miller, Miguel Uyaguari-Diaz, Mark N. McCabe, Vincent Montoya, Jennifer L. Gardy, Shoshana Parker, Theodore Steiner, William Hsiao, Matthew J. Nesbitt, Patrick Tang, David M. Patrick , for the CCD Study Group

Ruth R. Miller
chool of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada
Miguel Uyaguari-Diaz
British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada
Mark N. McCabe
British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada
Vincent Montoya
British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada
Jennifer L. Gardy
School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada, British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada
Shoshana Parker
Centre for Health Evaluation and Outcome Sciences, Vancouver, British Columbia, Canada
Theodore Steiner
Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
William Hsiao
British Columbia Public Health Microbiology and Reference Laboratory, Vancouver, British Columbia, Canada, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
Matthew J. Nesbitt
Coastal Genomics Inc., Burnaby, British Columbia, Canada
Patrick Tang
Department of Pathology, Sidra Medical and Research Center, Doha, Qatar
David M. Patrick
* E-mail:
School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada, British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada
for the CCD Study Group


Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease causing indefinite fatigue. ME/CFS has long been hypothesised to have an infectious cause; however, no specific infectious agent has been identified.

We used metagenomics to analyse the RNA from plasma samples from 25 individuals with ME/CFS and compare their microbial content to technical controls as well as three control groups: individuals with alternatively diagnosed chronic Lyme syndrome (N = 13), systemic lupus erythematosus (N = 11), and healthy controls (N = 25).

We found that the majority of sequencing reads were removed during host subtraction, thus there was very low microbial RNA content in the plasma. The effects of sample batching and contamination during sample processing proved to outweigh the effects of study group on microbial RNA content, as the few differences in bacterial or viral RNA abundance we did observe between study groups were most likely caused by contamination and batch effects.

Our results highlight the importance of including negative controls in all metagenomic analyses, since there was considerable overlap between bacterial content identified in study samples and control samples. For example, Proteobacteria, Firmicutes, Actinobacteria, and Bacteriodes were found in both study samples and plasma-free negative controls.

Many of the taxonomic groups we saw in our plasma-free negative control samples have previously been associated with diseases, including ME/CFS, demonstrating how incorrect conclusions may arise if controls are not used and batch effects not accounted for.

From the Journal of international Medical Research, 10 November 2016.

Single nucleotide polymorphisms and genotypes of transient receptor potential ion channel and acetylcholine receptor genes from isolated B lymphocytes in myalgic encephalomyelitis/chronic fatigue syndrome patients

Sonya Marshall-Gradisnik(1,2⇑). Samantha Johnston(1,2), Anu Chacko(1,2), Thao Nguyen(1,2), Peter Smith(2), Donald Staines(1,2).
1) School of Medical Science, Griffith University, Gold Coast, QLD, Australia
2) The National Centre for Neuroimmunology and Emerging Diseases, Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD Australia
Corrspondence: Sonya Marshall-Gradisnik, Griffith University, Menzies Health Institute Queensland, National Centre for Neuroimmunology and Emerging Diseases, Southport, QLD 4222, Australia. Email:



The pathomechanism of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is unknown; however, a small subgroup of patients has shown muscarinic antibody positivity and reduced symptom presentation following anti-CD20 intervention. Given the important roles of calcium (Ca2+) and acetylcholine (ACh) signalling in B cell activation and potential antibody development, we aimed to identify relevant single nucleotide polymorphisms (SNPs) and genotypes in isolated B cells from CFS/ME patients.


A total of 11 CFS/ME patients (aged 31.82 ± 5.50 years) and 11 non-fatigued controls (aged 33.91 ± 5.06 years) were included. Flow cytometric protocols were used to determine B cell purity, followed by SNP and genotype analysis for 21 mammalian TRP ion channel genes and nine mammalian ACh receptor genes. SNP association and genotyping analysis were performed using ANOVA and PLINK analysis software.


Seventy-eight SNPs were identified in nicotinic and muscarinic acetylcholine receptor genes in the CFS/ME group, of which 35 were in mAChM3. The remaining SNPs were identified in nAChR delta (n = 12), nAChR alpha 9 (n = 5), TRPV2 (n = 7), TRPM3 (n = 4), TRPM4 (n = 1) mAChRM3 2 (n = 2), and mAChRM5 (n = 3) genes. Nine genotypes were identified from SNPs in TRPM3 (n = 1), TRPC6 (n = 1), mAChRM3 (n = 2), nAChR alpha 4 (n = 1), and nAChR beta 1 (n = 4) genes, and were located in introns and 3′ untranslated regions. Odds ratios for these specific genotypes ranged between 7.11 and 26.67 for CFS/ME compared with the non-fatigued control group.


This preliminary investigation identified a number of SNPs and genotypes in genes encoding TRP ion channels and AChRs from B cells in patients with CFS/ME. These may be involved in B cell functional changes, and suggest a role for Ca2+ dysregulation in AChR and TRP ion channel signalling in the pathomechanism of CFS/ME.

From The Journal of Pain, 12 November 2016.

Chronic Fatigue Syndrome and chronic widespread pain in adolescence: Population birth cohort study

Tom Norris(a,*), Kevin Deere(b), Jon H. Tobias(b), Esther Crawley(a)
a) Centre for Child and Adolescent Health, School of Social and Community Medicine, Oakfield House, Oakfield Grove, Bristol, BS8 2BN
b) Musculoskeletal Research Unit, School of Clinical Sciences, Learning and Research Building, Bristol, BS10 5NB
* Corresponding author. Tom Norris, Oakfield House, Oakfield Grove, Bristol, UK BS8 2BN. Phone: 44-117 331 4099.
Email: tom.norris@…


Whilst many studies have investigated the overlap between pain phenotypes and chronic fatigue syndrome (CFS) in adults, little is known about the relationship between these conditions in adolescents. The study's aim was therefore to identify whether a relationship exists between chronic widespread pain (CWP) and CFS in adolescents and investigate whether the two share common associations with a set of covariates.

A questionnaire was administered to offspring of the Avon Longitudinal Study of Parents and Children at age 17, asking about site, duration, and pain intensity, from which participants with CWP were identified. At the same research clinic, a computer-based Revised Clinical Interview Schedule (CIS-R) was filled out, from which a classification of CFS was obtained.

The relationship between selected covariates and CFS and CWP was investigated using a variety of logistic, ordinal logistic and multinomial regressions.

We identified 3214 adolescents with complete data for all outcomes and covariates. There were 82 (2.6%) individuals classified as CFS and 145 (4.5%) as CWP. A classification of CFS resulted in an increased likelihood of having CWP (OR: 3.87; 95% CI: 2.05-7.31).

Females were approximately twice as likely to have CFS or CWP, with multinomial regression revealing a greater sex-effect for CWP compared to CFS. Those with exclusive CFS were more likely to report higher levels of pain and greater effect of pain compared to those without CFS, though associations attenuated to the null after adjustment for covariates, which did not occur in those with exclusive CWP.

Multinomial regression revealed that relative to having neither CFS nor CWP, a one-unit increase in the depression and anxiety scales increased the risk of having exclusive CFS and, to a greater extent, the risk of having co-morbid CFS and CWP, but not exclusive CWP, which was only related to anxiety.

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