Butt – American ME and CFS Society

Open-label pilot for treatment targeting gut dysbiosis in myalgic encephalomyelitis/chronic fatigue syndrome: neuropsychological symptoms and sex comparisons

Abstract:

BACKGROUND: Preliminary evidence suggests that the enteric microbiota may play a role in the expression of neurological symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Overlapping symptoms with the acute presentation of D-lactic acidosis has prompted the use of antibiotic treatment to target the overgrowth of species within the Streptococcus genus found in commensal enteric microbiota as a possible treatment for neurological symptoms in ME/CFS.

METHODS: An open-label, repeated measures design was used to examine treatment efficacy and enable sex comparisons. Participants included 44 adult ME/CFS patients (27 females) from one specialist medical clinic with Streptococcus viable counts above 3.00 × 105 cfu/g (wet weight of faeces) and with a count greater than 5% of the total count of aerobic microorganisms. The 4-week treatment protocol included alternate weeks of Erythromycin (400 mg of erythromycin as ethyl succinate salt) twice daily and probiotic (D-lactate free multistrain probiotic, 5 × 1010 cfu twice daily). 2 × 2 repeated measures ANOVAs were used to assess sex-time interactions and effects across pre- and post-intervention for microbial, lactate and clinical outcomes. Ancillary non-parametric correlations were conducted to examine interactions between change in microbiota and clinical outcomes.

RESULTS: Large treatment effects were observed for the intention-to-treat sample with a reduction in Streptococcus viable count and improvement on several clinical outcomes including total symptoms, some sleep (less awakenings, greater efficiency and quality) and cognitive symptoms (attention, processing speed, cognitive flexibility, story memory and verbal fluency). Mood, fatigue and urine D:L lactate ratio remained similar across time. Ancillary results infer that shifts in microbiota were associated with more of the variance in clinical changes for males compared with females.

CONCLUSIONS: Results support the notion that specific microorganisms interact with some ME/CFS symptoms and offer promise for the therapeutic potential of targeting gut dysbiosis in this population. Streptococcus spp. are not the primary or sole producers of D-lactate. Further investigation of lactate concentrations are needed to elucidate any role of D-lactate in this population. Concurrent microbial shifts that may be associated with clinical improvement (i.e., increased Bacteroides and Bifidobacterium or decreased Clostridium in males) invite enquiry into alternative strategies for individualised treatment.

Trial Registration Australian and New Zealand Clinical Trial Registry (ACTRN12614001077651) 9th October 2014. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=366933&isReview=true.

Source: Wallis A, Ball M, Butt H, Lewis DP, McKechnie S, Paull P, Jaa-Kwee A, Bruck D. Open-label pilot for treatment targeting gut dysbiosis in myalgic encephalomyelitis/chronic fatigue syndrome: neuropsychological symptoms and sex comparisons. J Transl Med. 2018 Feb 6;16(1):24. doi: 10.1186/s12967-018-1392-z. https://www.ncbi.nlm.nih.gov/pubmed/29409505

Examining clinical similarities between myalgic encephalomyelitis/chronic fatigue syndrome and D-lactic acidosis: a systematic review

Abstract:

BACKGROUND: The pursuit for clarity in diagnostic and treatment pathways for the complex, chronic condition of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) continues. This systematic review raises a novel question to explore possible overlapping aetiology in two distinct conditions. Similar neurocognitive symptoms and evidence of D-lactate producing bacteria in ME/CFS raise questions about shared mechanisms with the acute condition of D-lactic acidosis (D-la).

METHODS: D-la case reports published between 1965 and March 2016 were reviewed for episodes describing both neurological symptoms and high D-lactate levels. Fifty-nine D-la episodes were included in the qualitative synthesis comparing D-la symptoms with ME/CFS diagnostic criteria. A narrative review of D-la mechanisms and relevance for ME/CFS was provided.

RESULTS: The majority of neurological disturbances reported in D-la episodes overlapped with ME/CFS symptoms. Of these, the most frequently reported D-la symptoms were motor disturbances that appear more prominent during severe presentations of ME/CFS. Both patient groups shared a history of gastrointestinal abnormalities and evidence of bacterial dysbiosis, although only preliminary evidence supported the role of lactate-producing bacteria in ME/CFS.

LIMITATIONS: Interpretation of results are constrained by both the breadth of symptoms included in ME/CFS diagnostic criteria and the conservative methodology used for D-la symptom classification. Several pathophysiological mechanisms in ME/CFS were not examined.

CONCLUSIONS: Shared symptomatology and underlying microbiota-gut-brain interactions raise the possibility of a continuum of acute (D-la) versus chronic (ME/CFS) presentations related to D-lactate absorption. Measurement of D-lactate in ME/CFS is needed to effectively evaluate whether subclinical D-lactate levels affect neurological symptoms in this clinical population.

Source: Wallis A, Ball M, McKechnie S, Butt H, Lewis DP, Bruck D. Examining clinical similarities between myalgic encephalomyelitis/chronic fatigue syndrome and D-lactic acidosis: a systematic review. J Transl Med. 2017 Jun 7;15(1):129. doi: 10.1186/s12967-017-1229-1. https://www.ncbi.nlm.nih.gov/pubmed/28592308

Support for the microgenderome invites enquiry into sex differences

Abstract:

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 hypothesized 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.

Source: Wallis A, Butt H, Ball M, Lewis DP, Bruck D. Support for the microgenderome invites enquiry into sex differences. Gut Microbes. 2017 Jan 2;8(1):46-52. doi: 10.1080/19490976.2016.1256524. Epub 2016 Nov 3. https://www.ncbi.nlm.nih.gov/pubmed/27808584

Sleep quality and the treatment of intestinal microbiota imbalance in Chronic Fatigue Syndrome: A pilot study

Abstract:

Chronic Fatigue Syndrome (CFS) is a multisystem illness, which may be associated with imbalances in gut microbiota. This study builds on recent evidence that sleep may be influenced by gut microbiota, by assessing whether changes to microbiota in a clinical population known to have both poor sleep and high rates of colonization with gram-positive faecal Streptococcus, can improve sleep.

Twenty-one CFS participants completed a 22- day open label trial. Faecal microbiota analysis was performed at baseline and at the end of the trial. Participants were administered erythromycin 400 mg b.d. for 6 days. Actigraphy and questionnaires were used to monitor sleep, symptoms and mood. Changes in patients who showed a clinically significant change in faecal Streptococcus after treatment (responders; defined as post-therapy distribution<6%) were compared to participants who did not respond to treatment.

In the seven responders, there was a significant increase in actigraphic total sleep time (p=0.028) from baseline to follow up, compared with non-responders. Improved vigour scores were associated with a lower Streptococcus count (ρ=-0.90, p=0.037). For both the responders and the whole group, poorer mood was associated with higher Lactobacillus.

Short term antibiotic treatment appears to be insufficient to effect sustainable changes in the gut ecosystem in most CFS participants. Some improvement in objective sleep parameters and mood were found in participants with reduced levels of gram-positive gut microbiota after antibiotic treatment, which is encouraging. Further study of possible links between gut microorganisms and sleep and mood disturbances is warranted.

Source: Jackson ML, Butt H, Ball M, Lewis DP, Bruck D. Sleep quality and the treatment of intestinal microbiota imbalance in Chronic Fatigue Syndrome: A pilot study. Sleep Sci. 2015 Nov;8(3):124-33. doi: 10.1016/j.slsci.2015.10.001. Epub 2015 Oct 23. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688574/ (Full article)

Support for the Microgenderome: Associations in a Human Clinical Population

Abstract:

The ‘microgenderome’ provides a paradigm shift that highlights the role of sex differences in the host-microbiota interaction relevant for autoimmune and neuro-immune conditions. Analysis of cross-sectional self-report and faecal microbial data from 274 patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) suggests that commensal gut microorganisms may play both protective and deleterious roles in symptom expression.

Results revealed significant sex-specific interactions between Firmicutes (Clostridium, Streptococcus, Lactobacillus and Enterococcus) and ME/CFS symptoms (including neurological, immune and mood symptoms), regardless of compositional similarity in microbial levels across the sexes. Extending animal studies, we provide support for the microgenderome in a human clinical population. Applied and mechanistic research needs to consider sex-interactions when examining the composition and function of human microbiota.

Source: Wallis A, Butt H, Ball M, Lewis DP, Bruck D. Support for the Microgenderome: Associations in a Human Clinical Population. Sci Rep. 2016 Jan 13;6:19171. doi: 10.1038/srep19171. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4725945/ (Full article)

Metabolism in chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a poorly understood condition that presents as long-term physical and mental fatigue with associated symptoms of pain and sensitivity across a broad range of systems in the body. The poor understanding of the disorder comes from the varying clinical diagnostic definitions as well as the broad array of body systems from which its symptoms present.

Studies on metabolism and CFS suggest irregularities in energy metabolism, amino acid metabolism, nucleotide metabolism, nitrogen metabolism, hormone metabolism, and oxidative stress metabolism. The overwhelming body of evidence suggests an oxidative environment with the minimal utilization of mitochondria for efficient energy production. This is coupled with a reduced excretion of amino acids and nitrogen in general.

Metabolomics is a developing field that studies metabolism within a living system under varying conditions of stimuli. Through its development, there has been the optimisation of techniques to do large-scale hypothesis-generating untargeted studies as well as hypothesis-testing targeted studies. These techniques are introduced and show an important future direction for research into complex illnesses such as CFS.

Source: Armstrong CW, McGregor NR, Butt HL, Gooley PR. Metabolism in chronic fatigue syndrome. Adv Clin Chem. 2014;66:121-72. https://www.ncbi.nlm.nih.gov/pubmed/25344988

NMR metabolic profiling of serum identifies amino acid disturbances in chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a debilitating multisystem disorder characterised by long-term fatigue with a variety of other symptoms including cognitive dysfunction, unrefreshing sleep, muscle pain, and post-exertional malaise. It is a poorly understood condition that occurs in ~5 in every 1000 individuals. We present here a preliminary study on the analysis of blood samples from 11 CFS and 10 control subjects through NMR metabolic profiling.

Identified metabolites that were found to be significantly altered between the groups were subjected to correlation analysis to potentially elucidate disturbed metabolic pathways. Our results showed a significant reduction of glutamine (P=0.002) and ornithine (P<0.05) in the blood of the CFS samples. Correlation analysis of glutamine and ornithine with other metabolites in the CFS sera showed relationships with glucogenic amino acids and metabolites that participate in the urea cycle. This indicates a possible disturbance to amino acid and nitrogen metabolism. It would be beneficial to identify any potential biomarkers of CFS for accurate diagnosis of the disorder.

Source: Armstrong CW, McGregor NR, Sheedy JR, Buttfield I, Butt HL, Gooley PR. NMR metabolic profiling of serum identifies amino acid disturbances in chronic fatigue syndrome. Clin Chim Acta. 2012 Oct 9;413(19-20):1525-31. doi: 10.1016/j.cca.2012.06.022. Epub 2012 Jun 21. https://www.ncbi.nlm.nih.gov/pubmed/22728138

Increased d-lactic Acid intestinal bacteria in patients with chronic fatigue syndrome

Abstract:

Patients with chronic fatigue syndrome (CFS) are affected by symptoms of cognitive dysfunction and neurological impairment, the cause of which has yet to be elucidated. However, these symptoms are strikingly similar to those of patients presented with D-lactic acidosis.

A significant increase of Gram positive facultative anaerobic faecal microorganisms in 108 CFS patients as compared to 177 control subjects (p<0.01) is presented in this report. The viable count of D-lactic acid producing Enterococcus and Streptococcus spp. in the faecal samples from the CFS group (3.5 x 10(7) cfu/L and 9.8 x 10(7) cfu/L respectively) were significantly higher than those for the control group (5.0 x 10(6) cfu/L and 8.9 x 10(4) cfu/L respectively). Analysis of exometabolic profiles of Enterococcus faecalis and Streptococcus sanguinis, representatives of Enterococcus and Streptococcus spp. respectively, by NMR and HPLC showed that these organisms produced significantly more lactic acid (p<0.01) from (13)C-labeled glucose, than the Gram negative Escherichia coli. Further, both E. faecalis and S. sanguinis secrete more D-lactic acid than E. coli.

This study suggests a probable link between intestinal colonization of Gram positive facultative anaerobic D-lactic acid bacteria and symptom expressions in a subgroup of patients with CFS. Given the fact that this might explain not only neurocognitive dysfunction in CFS patients but also mitochondrial dysfunction, these findings may have important clinical implications.

Source: Sheedy JR, Wettenhall RE, Scanlon D, Gooley PR, Lewis DP, McGregor N, Stapleton DI, Butt HL, DE Meirleir KL. Increased d-lactic Acid intestinal bacteria in patients with chronic fatigue syndrome. In Vivo. 2009 Jul-Aug;23(4):621-8. http://iv.iiarjournals.org/content/23/4/621.long (Full article)

Hematologic and urinary excretion anomalies in patients with chronic fatigue syndrome

Abstract:

Patients with chronic fatigue syndrome (CFS) have a broad and variable spectrum of signs and symptoms with variable onsets. This report outlines the results of a single-blind, cross-sectional research project that extensively investigated a large cohort of 100 CFS patients and 82 non fatigued control subjects with the aim of performing a case-control evaluation of alterations in standard blood parameters and urinary amino and organic acid excretion profiles.

Blood biochemistry and full blood counts were unremarkable and fell within normal laboratory ranges. However, the case-control comparison of the blood cell data revealed that CFS patients had a significant decrease in red cell distribution width and increases in mean platelet volume, neutrophil counts, and the neutrophil-lymphocyte ratio.

Evaluation of the urine excretion parameters also revealed a number of anomalies. The overnight urine output and rate of amino acid excretion were both reduced in the CFS group (P < 0.01). Significant decreases in the urinary excretion of asparagine (P < 0.0001), phenylalanine (P < 0.003), the branch chain amino acids (P < 0.005), and succinic acid (P < 0.0001), as well as increases in 3-methylhistidine (P < 0.05) and tyrosine (P < 0.05) were observed.

It was concluded that the urinary excretion and blood parameters data supported the hypothesis that alterations in physiologic homeostasis exist in CFS patients.

Source: Niblett SH, King KE, Dunstan RH, Clifton-Bligh P, Hoskin LA, Roberts TK, Fulcher GR, McGregor NR, Dunsmore JC, Butt HL, Klineberg I, Rothkirch TB. Hematologic and urinary excretion anomalies in patients with chronic fatigue syndrome. Exp Biol Med (Maywood). 2007 Sep;232(8):1041-9. https://www.ncbi.nlm.nih.gov/pubmed/17720950

A biochemical analysis of people with chronic fatigue who have Irlen Syndrome: speculation concerning immune system dysfunction

Abstract:

This study investigated the biological basis of visual processing disabilities in adults with Chronic Fatigue Syndrome. The study involved 61 adults with symptoms of Chronic Fatigue Syndrome who were screened for visual processing problems (Irlen Syndrome) and divided into two groups according to the severity of symptoms of Irlen Syndrome.

Significant variations were identified in blood lipids and urine amino and organic acids of the two groups, which may be indicative of activation of the immune system due to some infective agent. It was suggested that metabolic profiling may help the development of more valid diagnostic categories and allow more investigation of immune system dysfunction as a possible causal factor in a range of learning and behaviour disorders.

Source: Robinson GL, McGregor NR, Roberts TK, Dunstan RH, Butt H. A biochemical analysis of people with chronic fatigue who have Irlen Syndrome: speculation concerning immune system dysfunction. Percept Mot Skills. 2001 Oct;93(2):486-504. http://www.ncbi.nlm.nih.gov/pubmed/11769907